Kenneth Lin

Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force.

BACKGROUND Screening can detect prostate cancer at earlier, asymptomatic stages, when treatments might be more effective. PURPOSE To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer. DATA SOURCES MEDLINE (2002 to July 2011) and the Cochrane Library Database (through second quarter of 2011). STUDY SELECTION Randomized trials of prostate-specific antigen-based screening, randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting, and large observational studies of perioperative harms. DATA EXTRACTION Investigators abstracted and checked study details and quality using predefined criteria. DATA SYNTHESIS Of 5 screening trials, the 2 largest and highest-quality studies reported conflicting results. One found that screening was associated with reduced prostate cancer-specific mortality compared with no screening in a subgroup of men aged 55 to 69 years after 9 years (relative risk, 0.80 [95% CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point). The other found no statistically significant effect after 10 years (relative risk, 1.1 [CI, 0.80 to 1.5]). After 3 or 4 screening rounds, 12% to 13% of screened men had false-positive results. Serious infections or urine retention occurred after 0.5% to 1.0% of prostate biopsies. There were 3 randomized trials and 23 cohort studies of treatments. One good-quality trial found that prostatectomy for localized prostate cancer decreased risk for prostate cancer-specific mortality compared with watchful waiting through 13 years of follow-up (relative risk, 0.62 [CI, 0.44 to 0.87]; absolute risk reduction, 6.1%). Benefits seemed to be limited to men younger than 65 years. Treating approximately 3 men with prostatectomy or 7 men with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction. Treating approximately 5 men with prostatectomy would result in 1 additional case of urinary incontinence. Prostatectomy was associated with perioperative death (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction. LIMITATIONS Only English-language articles were included. Few studies evaluated newer therapies. CONCLUSION Prostate-specific antigen-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Structurally distinct and stage-specific adenylyl cyclase genes play different roles in dictyostelium development

We have isolated two adenylyl cyclase genes, designated ACA and ACG, from Dictyostelium. The proposed structure for ACA resembles that proposed for mammalian adenylyl cyclases: two large hydrophilic domains and two sets of six transmembrane spans. ACG has a novel structure, reminiscent of the membrane-bound guanylyl cyclases. An aca- mutant, created by gene disruption, has little detectable adenylyl cyclase activity and fails to aggregate, demonstrating that cAMP is required for cell-cell communication. cAMP is not required for motility, chemotaxis, growth, and cell division, which are unaffected. Constitutive expression in aca- cells of either ACA or ACG, which is normally expressed only during germination, restores aggregation and the ability to complete the developmental program. ACA expression restores receptor and guanine nucleotide-regulated adenylyl cyclase activity, while activity in cells expressing ACG is insensitive to these regulators. Although they lack ACA, which has a transporter-like structure, the cells expressing ACG secrete cAMP constitutively.

Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force.

BACKGROUND Testicular cancer is the most common type of cancer in men aged 15 to 34 years. Because treatment produces favorable outcomes even in advanced stages, the U.S. Preventive Services Task Force (USPSTF) concluded in 2004 that screening asymptomatic men for testicular cancer is unlikely to produce additional benefits over clinical detection. PURPOSE To search for new evidence on the benefits and harms of screening for testicular cancer to assist the USPSTF in updating its 2004 recommendation. DATA SOURCES English-language articles indexed in PubMed and the Cochrane Library and published between 1 January 2001 and 11 November 2009. STUDY SELECTION Randomized, controlled trials; meta-analyses; systematic reviews; cohort studies; and case-control studies were selected to determine the benefits of screening for testicular cancer. Randomized, controlled trials; meta-analyses; systematic reviews; cohort studies; case-control studies; and case series of large, multisite databases were selected to determine the harms of screening. Each author independently reviewed titles, abstracts, and full-text articles for possible inclusion. DATA EXTRACTION One author abstracted information on the benefits and harms of screening for testicular cancer. DATA SYNTHESIS No studies met the inclusion criteria. Three studies were considered for inclusion at the full-text stage of review. These inconclusive studies addressed testicular microlithiasis, XIST gene testing, and testis-sparing surgery. LIMITATION The focused search strategy may have missed some smaller studies or studies published in languages other than English on the benefits or harms of testicular cancer screening. CONCLUSION No new evidence was found on the benefits or harms of screening for testicular cancer that would affect the USPSTFs previous recommendation against screening.

Screening for Hepatitis B Virus Infection in Pregnant Women: Evidence for the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement

BACKGROUND Screening for hepatitis B virus (HBV) infection in pregnant women to identify newborns who will require prophylaxis against perinatal infection is a well-established, evidence-based standard of current medical practice. In 2004, the U.S. Preventive Services Task Force (USPSTF) recommended universal screening of pregnant women for HBV infection at the first prenatal visit. PURPOSE To search for large, high-quality studies related to hepatitis B screening in pregnancy that have been published since the 2004 USPSTF recommendation. DATA SOURCES English-language studies indexed in PubMed and the Cochrane Database of Systematic Reviews and published between 1 January 2001 and 5 March 2008. STUDY SELECTION For benefits of screening and newborn prophylaxis, we included systematic reviews; meta-analyses; and randomized, controlled trials. For harms of screening, we included systematic reviews; meta-analyses; randomized, controlled trials; cohort studies; case-control studies; and case series of large, multisite databases. Abstracts and full articles were independently reviewed for inclusion by both reviewers. DATA EXTRACTION Data on the benefits of screening, including benefits of hepatitis B immune globulin and hepatitis B vaccine prophylaxis of newborns of hepatitis B surface antigen-positive mothers, were extracted by 1 reviewer. DATA SYNTHESIS No new studies met inclusion criteria. A 2006 systematic review of randomized, controlled trials found that newborn prophylaxis reduced perinatal transmission of HBV infection; all relevant trials were published in 1996 or earlier. LIMITATION The focused search strategy, which was restricted to English-language articles, may have missed some smaller studies or new research published in languages other than English. CONCLUSION No new evidence was found on the benefits or harms of screening for HBV infection in pregnant women. Previously published randomized trials support the 2004 USPSTF recommendation for screening.

Random mutagenesis of the cAMP chemoattractant receptor, cAR1, of Dictyostelium. Mutant classes that cause discrete shifts in agonist affinity and lock the receptor in a novel activational intermediate

The cAMP chemoattractant receptor, cAR1, of Dictyostelium transduces extracellular cAMP signals via G protein-dependent and G protein-independent mechanisms. While site-directed mutagenesis studies of G protein-coupled receptors have provided a host of information regarding the domains essential for various functions, many mechanistic and structural questions remain to be resolved. We therefore carried out polymerase chain reaction-mediated random mutagenesis over a large part of the cAR1 sequence (from TMIII through the proximal part of the cytoplasmic tail). We devised a rapid screen for loss-of-function mutations based on the essential role of cAR1 in the developmental program of Dictyostelium. Although there were an average of two amino acid substitutions per receptor, ∼90% of the mutants were able to substitute for wild-type cAR1 when expressed in receptor null cells. About 2% were loss-of-function mutants that expressed wild-type levels of receptor protein. We used biochemical screens to select about 100 of these mutants and chose eight representative mutants for extensive characterization. These fell into distinct classes. One class had a conditional defect in cAMP binding that was reversed by high salt. Another large class had decreased affinity under all conditions. Curiously, the decreases were clustered into three discrete intervals. One of the most interesting class of mutants lost all capacity for signal transduction but was phosphorylated in response to agonist binding. This latter finding suggests that there are at least two activated states of cAR1 that can be recognized by different downstream effectors.