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A Ca 2+ dependent conformational change in dimeric S100B(ββ) is required for it to bind p53 and inhibit phosphorylation of this tumor suppressor in its C-terminal negative regulatory domain. A peptide derived from this region of p53 (residues 367–388) was found to have no regular structure in its native form by NMR spectroscopy, but becomes helical when bound to Ca 2+ loaded S100B(ββ). The three-dimensional structure of this complex reveals several favorable hydrophobic and electrostatic interactions between S100B(ββ) and the p53 peptide in the binding pocket, where S100B(ββ) sterically blocks sites of phosphorylation and acetylation on p53 that are important for transcription activation.

Renal-carcinoma-inducing oncogene Using large-scale exome sequencing, Andrew Futreal and colleagues have identified a second frequently mutated gene (after VHL ) in clear cell renal cell carcinomas, the most frequent type of kidney cancer. PBRM1 , a member of the SWI/SNF complex involved in transcriptional regulation, is mutated in about 40% of cases and is shown to function as a tumour suppressor gene. PBRM1 was independently found as a putative cancer gene involved in pancreatic cancer in a mouse transposon screen. These results — together with the fact that other components of the same complex are known cancer genes — unambiguously identify PBRM1 as a major cancer gene. Using large-scale exome sequencing, this study identifies a second (after VHL ) frequently mutated gene in clear cell renal cell carcinomas, the most frequent type of kidney cancer. PBRM1 , a member of the SWI/SNF complex involved in transcriptional regulation, is mutated in about 40% of cases and shown to function as tumour suppressor gene. PBRM1 was independently found as a putative cancer gene involved in pancreatic cancer in a mouse transposon screen. The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A ) 1 , JARID1C (also known as KDM5C ) and SETD2 (ref. 2 ). These genes encode enzymes that demethylate ( UTX , JARID1C ) or methylate ( SETD2 ) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control 3 . However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4 ) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection. This was a multinational, randomised, controlled, phase 2 trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m2, a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo. Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This study is registered with ClinicalTrials.gov (NCT05182840) and is completed. Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m2 (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was –3% (95% CI –19 to 17) with placebo, –22% (–36 to –7) with BI 690517 3 mg, –39% (–50 to –26) with BI 690517 10 mg, and –37% (–49 to –22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study. BI 690517 dose-dependently reduced albuminuria with concurrent renin–angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals. Boehringer Ingelheim.

Critics have suggested that delighting the customer \"raises the bar\" of customer expectations, making it more difficult to satisfy the customer in the next purchase cycle and hurting the firm in the long run. A study explores this issue by using a mathematical model of delight, based on assumptions gathered from the customer satisfaction literature. Although delighting the customer heightens repurchase expectations and makes satisfying the customer more difficult in the future, and the delighting firm is injured by raised customer expectations, the (nondelighting) competition is hurt worse through customer attrition to the delighting firm. If customers forget delighting incidents to some degree from occasion to occasion, the delighting firm suffers if it is in a position to take customers from the competition. If taking customers from the competition is difficult, the delighting firm actually benefits from customer forgetting, because the same delighting experience can be repeated again, with the same effect.

The behavioral basis for customer delight is examined, based on empirical tests of its hypothesized antecedents and consequences. Structural equation results support the proposition that unexpected high levels of satisfaction or performance initiate an arousal which leads to pleasure which, in turn, leads to delight sequence. Mixed support is found for the hypothesis that delight is a combined result of pleasure and arousal. Satisfaction, acting in parallel with delight, was strongly related to pleasure and disconfirmation and had a clear effect on behavioral intention; the effect of delight on intention, however, appears to be moderate by the service context. Managerial implications include the consideration of whether delight is a reasonable and meaningful consumer expression in particular service contexts, the necessity of focusing on surprising levels of satisfaction or performance when attempting to produce delighting consumption experiences and potentially separate strategies for inducing satisfaction and delight.

Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with intermittent dosing. To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis. We conducted a randomized controlled trial in 25 intensive care units (ICUs). Participants commenced on piperacillin-tazobactam, ticarcillin-clavulanate, or meropenem were randomized to receive the prescribed antibiotic via continuous or 30-minute intermittent infusion for the remainder of the treatment course or until ICU discharge. The primary outcome was the number of alive ICU-free days at Day 28. Secondary outcomes were 90-day survival, clinical cure 14 days post antibiotic cessation, alive organ failure-free days at Day 14, and duration of bacteremia. We enrolled 432 eligible participants with a median age of 64 years and an Acute Physiology and Chronic Health Evaluation II score of 20. There was no difference in ICU-free days: 18 days (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24). In critically ill patients with severe sepsis, there was no difference in outcomes between β-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).

Opioid abuse and addiction have increased in frequency in the United States over the past 20 years. In 2009, an estimated 5.3 million persons used opioid medications nonmedically within the past month, 200 000 used heroin, and approximately 9.6% of African Americans used an illicit drug. Racial and ethnic minorities experience disparities in availability and access to mental health care, including substance use disorders. Primary care practitioners are often called upon to differentiate between appropriate, medically indicated opioid use in pain management vs inappropriate abuse or addiction. Racial and ethnic minority populations tend to favor primary care treatment settings over specialty mental health settings. Recent therapeutic advances allow patients requiring specialized treatment for opioid abuse and addiction to be managed in primary care settings. The Drug Addiction Treatment Act of 2000 enables qualified physicians with readily available short-term training to treat opioid-dependent patients with buprenorphine in an office-based setting, potentially making primary care physicians active partners in the diagnosis and treatment of opioid use disorders. Methadone and buprenorphine are effective opioid replacement agents for maintenance and/or detoxification of opioid-addicted individuals. However, restrictive federal regulations and stigmatization of opioid addiction and treatment have limited the availability of methadone. The opioid partial agonist-antagonist buprenorphine/naloxone combination has proven an effective alternative. This article reviews the literature on differences between buprenorphine and methadone regarding availability, efficacy, safety, sideeffects, and dosing, identifying resources for enhancing the effectiveness of medication-assisted recovery through coordination with behavioral/psychological counseling, embedded in the context of recovery-oriented systems of care.