Lethal predators: psychopathic, sadistic, and sane

The violent criminals defined in this article are a small, exceptionally dangerous group of offenders designated by the authors as "lethal predators." They have a history of sexual predation, have killed at least once, and are mentally abnormal but legally sane. They are highly likely to keep killing as long as they are free. Laws permitting civil commitment of dangerous and mentally abnormal sexual predators after they have completed criminal prison sentences have been upheld by the U.S. Supreme Court. Such laws can provide a legal means of keeping these highly dangerous killers confined so they cannot kill again.     

Effect of antithymocyte globulin on quantitative immune recovery and graft-versus-host disease after partially T-cell-depleted bone marrow transplantation: a comparison between recipients of matched related and matched unrelated donor grafts

The effect of antithymocyte globulin (ATG) on quantitative immune recovery and graft-versus-host disease (GVHD) after partially T-cell-depleted bone marrow transplantation was analyzed in 59 and 32 recipients of grafts from matched related donors and matched unrelated donors (MUDs), respectively. The conditioning regimen was similar in all patients, except for ATG which was given only to MUD recipients. Thirteen MUD patients were treated with high-dose (20 mg/kg) ATG and 19 with low-dose (8 mg/kg) ATG. During the posttransplant period, CD3+, CD4+, and CD8+ T-cell numbers and the incidence of acute and chronic GVHD were significantly lower in MUD recipients compared with matched related donor recipients. MUD recipients treated with high-dose ATG showed the worst T-cell and subsets recovery. These data indicate that ATG, often used as part of conditioning regimens in recipients of T-cell-depleted grafts from MUDs, contributes to the severe and prolonged T-cell deficiency that is typical of these patients. On the other hand, it effectively reduces the incidence and severity of GVHD.     

Differential immunogenicity of HLA mismatches: HLA-A2 versus HLA-A28

The immunogenicity of human leukocyte antigen (HLA)-A2 versus HLA-A28 was analyzed by antibody production, cytotoxic T-lymphocyte (CTL) induction, and graft survival. We observed that an HLA-A2 mismatched child in HLA-A28 women leads to HLA-A2 specific antibodies in 32% of the women (n=31), whereas in the case of an HLA-A28 child and HLA-A2 women (n=30), no HLA-A28 specific antibodies were found ( P<0.002). Also, the CTL precursor frequencies were significantly lower against HLA-A28 compared with CTLp frequencies against HLA-A2 ( P=0.012). Finally, the kidney graft survival was slightly better in HLA-A2 positive recipients transplanted with HLA-A28 mismatches. We can conclude that single HLA-A28 mismatches are less immunogenic in HLA-A2 individuals compared with single HLA-A2 mismatches in HLA-A28 individuals, which is probably because the mismatched epitopes on the HLA-A2 molecule are unique epitopes, whereas the mismatched epitopes on HLA-A28 are shared by other HLA-A and HLA-B molecules.     

Respiratory gating for liver tumors: use in dose escalation

PURPOSE: To determine the clinical impact of the Varian Real-Time Position Monitor (RPM) respiratory gating system for treatment of liver tumors. METHODS AND MATERIALS: Ten patients with liver tumors were selected for evaluation of this passive system, which tracks motion of reflective markers mounted on the abdomen with an infrared-sensitive camera. At simulation, a fluoroscopic movie, breathing trace, and CT scans synchronized at end-expiration (E-E) and end-inspiration were acquired in treatment position using the RPM system. Organs and gross tumor volume were contoured on each CT. Each organ's positional change between two scan sets was quantified by calculation of the center of volume shift and an "index coefficient," defined as the volume common to the two versions of the organ to the volume included in at least one (intersection/union). Treatment dose was determined by use of normal tissue complication probability calculations and dose-volume histograms. Gated portal images were obtained to monitor gating reproducibility with treatment. RESULTS: Eight patients received 177 treatments with RPM gating. Average superior-to-inferior (SI) diaphragm motion on initial fluoroscopy was reduced from 22.7 mm without gating to 5.1 mm with gating. Comparing end-inspiration to E-E CT scans, average SI movement of the right diaphragm was 11.5 mm vs. 2.2 mm for two E-E CT scans. For all organs, average E-I SI organ motion was 12.8 mm vs. 2.0 mm for E-E studies. Index coefficients were closer to 1.0 for E-E than end-inspiration scans, indicating gating reproducibility. The average SI displacement of diaphragm apex on gated portal images compared with DRR was 2.3 mm. Treatment was prolonged less than 10 minutes with gating. The reproducible decrease in organ motion with gating enabled reduction in gross tumor volume-to-planning target volume margin from 2 to 1 cm. This allowed for calculated dose increases of 7%-27% (median: 21.3%) in 6 patients and enabled treatment in 2. CONCLUSION: Gating of radiotherapy for liver tumors enables safe margin reduction on tumor volume, which, in turn, may allow for dose escalation.     

Role of the RNA-binding protein HuR in colon carcinogenesis

Immunohistochemical analysis of paired tumor and normal tissue specimens revealed that the expression and cytoplasmic abundance of the RNA-binding protein HuR increased with malignancy, particularly in colon carcinomas. Interventions to modulate HuR expression in human RKO colon cancer cells altered gene expression profiles and identified beta-catenin mRNA as a novel HuR target. Subcutaneous injection of HuR-overexpressing RKO cells into nude mice produced significantly larger tumors than those arising from control populations; conversely, RKO cells expressing reduced HuR through small interference RNA- or antisense HuR-based approaches developed significantly more slowly. We propose that HuR-regulated target mRNA expression contributes to colon cancer growth. Our results suggest a pivotal function for HuR in colon carcinogenesis.     

A novel telomerase template antagonist (GRN163) as a potential anticancer agent

Telomerase, the enzyme responsible for proliferative immortality, is expressed in essentially all cancer cells, but not in most normal human cells. Thus, specific telomerase inhibition is potentially a universal anticancer therapy with few side effects. We designed N3'-->P5' thio-phosphoramidate (NPS) oligonucleotides as telomerase template antagonists and found that their ability to form stable duplexes with the telomerase RNA subunit was the key factor for antitelomerase activity. In biochemical assays 11-13-mer NPS oligonucleotides demonstrated sequence- and dose-dependent inhibition of telomerase with IC(50) values <1 nM. Optimization of the sequence, length, and bioavailability resulted in the selection of a 13-mer NPS oligonucleotide, GRN163, as a drug development candidate. GRN163 inhibited telomerase in a cell-free assay at 45 +/- 7 pM, and in various tumor cell lines at approximately 1 nM and approximately 0.3-1.0 micro M in the presence and absence of carriers, respectively. GRN163 was competitive with telomeric primer binding, primarily because of hybridization to human telomerase RNA (hTR) component. Tumor cells treated with GRN163 in culture underwent telomere shortening, followed by cellular senescence or apoptosis after a period of time that generally correlated with initial telomere length. In a flank DU145 (prostate cancer) xenograft model, parenterally administered GRN163 caused suppression of tumor growth in the absence of gross toxicity. These data demonstrate that GRN163 has significant potential for additional development as an anticancer agent.     

The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis

BACKGROUND: Mucositis is a common but poorly studied problem among patients with solid tumors. The authors examined the clinical and economic outcomes of oral and gastrointestinal (GI) mucositis among patients receiving myelosuppressive chemotherapy. METHODS: A retrospective, random sample of 599 patients who developed chemotherapy-induced myelosuppression was followed for development of oral or GI mucositis and for development of subsequent episodes of bleeding or infection. Multilevel regression models of the risk of bleeding and infection were fit with chemotherapy cycles nested within patients. RESULTS: Mucositis developed during 37% of 1236 cycles of chemotherapy. Episodes of bleeding were significantly more common during cycles with GI mucositis than during cycles without GI mucositis (13% vs. 8%; P = 0.04). Episodes of infection were significantly more common during cycles with mucositis (especially GI mucositis) than during cycles without mucositis (73% vs. 36%; P < 0.0001). The mean durations of hospitalization were 4 days, 6 days, and 12 days during cycles with no mucositis, oral mucositis, and GI mucositis, respectively. After accounting for the depth and duration of myelosuppression and for other predictive factors, GI mucositis was associated with both bleeding (odds ratio [OR], 2.0; P = 0.01) and infection (OR, 2.24; P < 0.0001), whereas oral mucositis was associated with infection only (OR, 2.4; P < 0.0001). CONCLUSIONS: Mucositis was clinically and economically significant among patients with solid tumors who were receiving myelosuppressive chemotherapy. New preventive and therapeutic agents are needed.     

Temporal factors and the prevalence of transient exposures at the time of an occupational traumatic hand injury

Temporal factors and the prevalence of exposure to transient risk factors for occupational traumatic hand injury were analyzed among 1166 subjects participating in a case-crossover study. Temporal factors included time of injury and elapsed time to injury since the start of the work shift. Transient exposures included work equipment, work practice, and worker-related factors. The highest frequency of injury was observed from 08:00 am to 12:00 pm (54.6%), with a peak from 10:00 to 11:00 am (14.9%). The median time into the work shift for injury was 3.5 hours. Subjects injured 2 to 3 hours into their work shift most often reported using a machine, tool, or work material that performed differently than usual (23.9%). These results suggest that acute hand injuries occur earlier in the workday and safety programs should place increased vigilance on these times.     

Cholesterol crystallization and macrophage apoptosis: implication for atherosclerotic plaque instability and rupture

The presence of abundant cholesterol crystals symbolizes the disorder of cholesterol metabolism during the development of atherosclerosis. Examination of cultured human THP-1 macrophages treated with the cholesterol oxide, 7-ketocholesterol, revealed a concentration- and time-dependent increase in formation of cholesterol crystals in the cells. Radioisotope labeling and X-ray diffraction confirmed the presence of 7-ketocholesterol crystalline domains (d space 35.8A). Under the normal cell culture condition (5% CO(2), 37 degrees ), incubation with 7-ketocholesterol induced moderate levels of apoptosis. Elevating temperature from 37 to 40 degrees markedly reduces formation of the crystals in the macrophages. Meanwhile, at high temperatures, significantly increased numbers of apoptotic cells were detected in the cells treated with 7-ketocholesterol but not in those with native free cholesterol. These results suggest that hyperthermia inhibits cholesterol crystallization and promotes apoptotic effects of oxysterols on macrophages.