Identification of genes differentially expressed in cultured human osteoblasts versus human fibroblasts by DNA microarray analysis

Little is known about patterns of gene expression from cells populating the connective tissues. This study investigated the possible variance of gene expression profile between human osteoblasts (HO) and human fibroblasts (HF) in vitro, using DNA microarray technology. Clustering identification was used to compare expression patterns between HO and HF for biological significance. Our results showed that genes encoding the extracellular matrix or apoptosis-related proteins tended to be expressed in greater abundance in HO, while more proteolysis-related proteins were expressed in higher level in HF. Significant differences in expression were also noted with genes related to signaling pathways. To confirm the array results, three genes (periostin, MFG-E8, MMP-10) were selected and analyzed independently by RT-PCR and northern blot. The results were found consistent with the array data in HO and HF. The present findings suggest that HO and HF differ not only phenotypically but in the expression level of tissue specific genes to assure the turnover and homeostasis of their respective tissues.     

A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer

ContextMolecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use.ObjectiveTo perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC).Evidence acquisitionThe review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446–52) and American Urology Association (AUA) criteria.Evidence synthesisIn total, 42 studies and 30 407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n = 12 141), prospective registries (n = 17 053), and prospective and post hoc randomized trial analyses (n = 1213). In 32 studies (n = 12 600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n = 8543). GC use changed the management in active surveillance (number needed to test [NNT] = 9) and postprostatectomy (NNT = 1.5–4) settings in five studies (n = 4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state.ConclusionsConsistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making.Patient summaryIn this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making.     

The burden of cutaneous disease in solid organ transplant recipients of color

Organ transplant recipients (OTRs) are at increased risk of cutaneous malignancy. Skin disorders in OTRs of color (OTRoC) have rarely been systematically assessed. We aimed to ascertain the burden of skin disease encountered in OTRoC by prospectively collecting data from OTRs attending 2 posttransplant skin surveillance clinics: 1 in London, UK and 1 in Philadelphia, USA. Retrospective review of all dermatological diagnoses was performed. Data from 1766 OTRs were analyzed: 1024 (58%) white, 376 (21%) black, 261 (15%) Asian, 57 (3%) Middle Eastern/Mediterranean (ME/M), and 48 (2.7%) Hispanic; and 1128 (64%) male. Viral infections affected 45.1% of OTRs, and were more common in white and ME/M patients (P < .001). Fungal infections affected 28.1% and were more common in ME/M patients (P < .001). Inflammatory skin disease affected 24.5%, and was most common in black patients (P < .001). In addition, 26.4% of patients developed skin cancer. There was an increased risk of skin cancer in white vs nonwhite OTRs (HR 4.4, 95% CI 3.5-5.7, P < .001): keratinocyte cancers were more common in white OTRs (P < .001) and Kaposi sarcoma was more common in black OTRs (P < .001). These data support the need for programs that promote targeted dermatology surveillance for all OTRs, regardless of race/ethnicity or country of origin.     

Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor.

PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.     

Nocturnal blood pressure and 24-hour pulse pressure are potent indicators of mortality in hemodialysis patients

BACKGROUND: Cardiovascular (CV) complications are the leading cause of mortality in hemodialysis patients. The role of arterial hypertension on the prognosis of CV in hemodialysis patients is not as clear as in the general population. The purpose of this study was to investigate the prognostic role of ambulatory blood pressure (BP) on CV mortality in treated hypertensive hemodialysis patients. METHODS: Fifty-seven treated hypertensive hemodialysis patients (56.87 +/- 16.22 years, 30 men) were prospectively studied. All patients initially underwent an ambulatory BP monitoring between two dialysis sessions. The outcome event studied was CV death; kidney transplantation and deaths not related to CV disease were censored. RESULTS: The duration of follow-up was 34.4 +/- 20.39 months, during which 10 CV and 8 non-CV fatal events occurred. In the 10 patients who died from CV complications, age, previous CV events, ambulatory systolic BP, ambulatory pulse pressure (PP), and life-long smoking level were significantly higher, and the office diastolic BP was lower at the time of inclusion than in those who did not die from CV complications (N = 47). Based on Cox analysis and after adjustment for age, sex, and previous CV events, a low office diastolic BP [relative risk (RR) 0.49, 95% CI, 0.25 to 0.93, P = 0.03], an elevated 24-hour PP (RR 1.85, 95% CI, 1.28 to 2.65, P = 0.009), and an elevated nocturnal systolic BP (RR 1.41, 95% CI, 1.08 to 1.84, P = 0.01) were predictors of CV mortality (RR associated with a 10 mm Hg increase in BP and in PP). CONCLUSION: This study demonstrates that nocturnal BP and 24-hour PP are independent predictors of CV mortality in treated hypertensive hemodialysis patients. Randomized trials are needed to investigate whether nocturnal BP and 24-hour PP are superior to office BP as targets for antihypertensive therapy in this high-risk group.     

Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy.

PURPOSE: To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH). PATIENTS AND METHODS: Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed. RESULTS: Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy. CONCLUSION: Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.     

Bioequivalence evaluation of two marketed brands of stavudine 40 mg capsules in healthy human South African volunteers.

Stavudine (d4T), a thymidine nucleoside analogue has been effectively used for treatment of patients infected with HIV. A randomized, two-way, crossover study was conducted in 24 fasting, healthy, Caucasian male volunteers to compare plasma pharmacokinetic (PK) profile and single-dose tolerability of a new d4T formulation (Stavir, Cipla Ltd, India; 40 mg capsule, test, T) with that of reference (R) formulation (Zerit), Bristol-Myers Squib, NJ, USA; capsule, 40 mg). Each volunteer received T and R formulation separated by at least 10 days of drug free wash-out period. Plasma concentrations of d4T, determined upto 24h post-dose by a validated LC-MS/MS assay were utilized to assess PK parameters such as maximum observed plasma concentration (Cmax), time to Cmax (tmax), and area under plasma concentration curve (AUC(infinity)). The primary plasma PK parameters, Cmax, and AUC(infinity), of anti-retroviral were comparable for either of the formulations. tmax was achieved within an hour suggesting rapid absorption of d4T from both formulations. Geometric mean ratios (GMR) (percentage reference) of AUC(infinity) and Cmax, and their 90% confidence intervals (CI) were 106.32 [102.52-110.26] and 102.32 [90.25-116.00], respectively. As the 90% CI of GMR were entirely within 80-125% for log-transformed parameters, two formulations were considered bioequivalent, in the extent and rate of absorption. Both formulations exhibited similar tolerability under fasting conditions.     

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

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