nils-herrmann/clean_scirepeval huggingface dataset:
For fission yeast nuclei, it takes two to tango

Tsaalbi-Shtylik et al. reveal that DNA mismatch repair (MMR) proteins suppress UV-induced mutagenesis by removing nucleotides introduced by error-prone DNA polymerases. The MMR pathway is best known for its role in correcting the rare mistakes of replicative DNA polymerases. However, the MMR proteins Msh2 and Msh6 have also been implicated in preventing the introduction of DNA mutations following exposure to low, physiological doses of UV light. UV-damaged nucleotides can't undergo base pairing and are therefore not replicated by normal DNA polymerases. This results in patches of single-stranded DNA that can be fi lled in by specialized DNA polymerases in a process called translesion synthesis (TLS). These polymerases are error prone, however, so they frequently incorporate incorrect nucleotides opposite the photo-damaged nucleotide. Tsaalbi-Shtylik et al. found that Msh2 and Msh6 recognize the incorrect nucleotides introduced by TLS opposite photolesions and trigger their removal, regenerating patches of single-stranded DNA around photo-damaged nucleotides. These patches induced the Chk1 DNA damage signaling pathway that arrests cells in S phase. If the single-stranded patches weren't fi lled in before the subsequent S phase, they were converted to double-strand breaks that initiated apoptosis. In the absence of Msh2/Msh6, nucleotides incorrectly incorporated by TLS remained in place, reducing checkpoint activation and cell death but introducing an increased number of DNA mutations. Patients with Lynch syndrome, who inherit mutations in MMR genes, may therefore suffer a high incidence of colorectal cancers because their intestinal cells are susceptible to genotoxic insults that cause similar damage to UV light. Senior author Niels de Wind now wants to investigate whether other MMR proteins are also involved in this " post-TLS " repair pathway. Two minus end–directed microtubule motors work in parallel to bring hap-loid nuclei together during fission yeast mating, Scheffl er et al. reveal. Mating yeast cells must move their nuclei toward each other so that they can fuse and undergo meiosis. In budding yeast, nuclear congression is driven by Kar3, a member of the kine-sin-14 family of minus end–directed motor proteins. To investigate whether the kinesin-14 Klp2 performs a similar function in fi ssion yeast, Scheffl er et al. trapped cells in microfluidic chambers so they could follow the mating process by live imaging. Nuclear congression was delayed in the absence of Klp2 but, unlike in budding yeast lacking Kar3, haploid nuclei eventually converged and fused together. The process was also delayed in fi ssion yeast lacking the minus …
Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial.

Use of nonpharmacological behavioral therapy has been suggested for treatment of chronic primary insomnia, but well-blinded, placebo-controlled trials demonstrating effective behavioral therapy for sleep-maintenance insomnia are lacking.



To test the efficacy of a hybrid cognitive behavioral therapy (CBT) compared with both a first-generation behavioral treatment and a placebo therapy for treating primary sleep-maintenance insomnia.



Randomized, double-blind, placebo-controlled clinical trial conducted at a single academic medical center, with recruitment from January 1995 to July 1997.



Seventy-five adults (n = 35 women; mean age, 55.3 years) with chronic primary sleep-maintenance insomnia (mean duration of symptoms, 13.6 years).



Patients were randomly assigned to receive CBT (sleep education, stimulus control, and time-in-bed restrictions; n = 25), progressive muscle relaxation training (RT; n = 25), or a quasi-desensitization (placebo) treatment (n = 25). Outpatient treatment lasted 6 weeks, with follow-up conducted at 6 months.



Objective (polysomnography) and subjective (sleep log) measures of total sleep time, middle and terminal wake time after sleep onset (WASO), and sleep efficiency; questionnaire measures of global insomnia symptoms, sleep-related self-efficacy, and mood.



Cognitive behavioral therapy produced larger improvements across the majority of outcome measures than did RT or placebo treatment. For example, sleep logs showed that CBT-treated patients achieved an average 54% reduction in their WASO whereas RT-treated and placebo-treated patients, respectively, achieved only 16% and 12% reductions in this measure. Recipients of CBT also showed a greater normalization of sleep and subjective symptoms than did the other groups with an average sleep time of more than 6 hours, middle WASO of 26.6 minutes, and sleep efficiency of 85.1%. In contrast, RT-treated patients continued to report a middle WASO of 43.3 minutes and sleep efficiency of 78.8%.



Our results suggest that CBT represents a viable intervention for primary sleep-maintenance insomnia. This treatment leads to clinically significant sleep improvements within 6 weeks and these improvements appear to endure through 6 months of follow-up.
Femoral and Vertebral Strength Improvements in Postmenopausal Women With Osteoporosis Treated With Denosumab

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by -4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis.
Long-term follow-up of vertebral osteoporotic fractures treated by percutaneous vertebroplasty

The aim of this study was:to assess the long-term efficacy and safety of percutaneous vertebroplasty (PVP) for treating painful vertebral osteoporotic fractures, and to estimate the risk of vertebral fracture in the vicinity of a cemented vertebra. A prospective open study was conducted. PVP were carried out between July 1995 and September 2000 for 16 patients with symptomatic osteoporotic vertebral fracture that had not responded to extensive conservative medical therapy. All the patients were followed-up for more than 1 year. The efficacy of the PVP was assessed by the changes over time in pain on Huskisson’s visual analog scale (VAS) and on the McGill-Melzack scoring system (MGM). The efficacy of the procedure was also assessed by measuring the changes over time in quality of life assessed by the Nottingham Health Profile (NHP instrument): twenty-one vertebrae treated by PVP in 16 patients were evaluated. The mean duration of follow-up was 35 months. Pain assessed by the VAS significantly decreased from a mean of 71.4 mm±13 before PVP to 36 mm±30 after 6 months, and to 39 mm±33 at the time of maximal follow-up (p<0.05 for both comparisons). The results were also significant for the MGM: 3.00±0.57 before PVP to 1.6±1.4 at the long-term follow-up (p<0.05). The solely statistically significant decrease for quality of life was noted for pain. A slight but not significant improvement was noted for 3/6 dimensions of the NHP scores. A slight but significant increase in social isolation was also found. No severe complication occurred immediately after PVP. At the long term follow-up (35 months) there was a slight but not significantly increased risk of vertebral fracture in the vicinity of a cemented vertebra: odds ratio 3.18 (95% confidence interval (CI) 0.51–19.64). The odds ratio of a vertebral fracture in the vicinity of an uncemented fractured vertebra was 2.14 (95% CI: 0.17–26.31). In conclusion, PVP appears to be safe and effective for treating persistent painful osteoporotic fractures. Controlled studies with long-term follow-up are needed to evaluate the risk of vertebral fractures in the vicinity of a cemented vertebra.
Sputum cytology: a limited role.

To determine the cost and sensitivity of sputum cytology in routine use and to determine when sputum cytology is most appropriate.



A retrospective study, based on all sputum cytology requests received in five histopathology/cytopathology laboratories in Yorkshire from 1 January to 31 December 1993. Cytology findings were correlated with histological diagnosis or clinical outcome, and related to the speciality of the referring clinician.



Laboratory practice and performance was similar in all five centres. The average laboratory cost of sputum cytology was 26.93. The mean absolute sensitivity was 36% and the specificity was 99.6%. The majority of specimens was submitted by general physicians or geriatricians. The largest proportion of positive specimens were submitted by chest physicians.



Often sputum cytology is used inappropriately as a screening investigation on, or soon after, admission. In addition, it is used inappropriately before bronchoscopy. Sputum cytology should be limited to individuals in whom a histological diagnosis is desired, but in whom bronchoscopy is inappropriate or unsuccessful.
A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer.

This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed.



Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression.



Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (>150μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated.



Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.
Effects of dehydroepiandrosterone therapy on pubic hair growth and psychological well-being in adolescent girls and young women with central adrenal insufficiency: a double-blind, randomized, placebo-controlled phase III trial.

The efficacy of oral dehydroepiandrosterone (DHEA) in the treatment of atrichia pubis and psychological distress in young females with central adrenal insufficiency is unknown. Our study aimed to evaluate this therapy.



A total of 23 young females (mean age 18 yr, range 13-25) was enrolled in a double-blind randomized placebo-controlled trial. Inclusion criteria were ACTH deficiency plus two or more additional pituitary deficiencies, serum DHEA less than 400 ng/ml, and pubertal stage more than B2. Exclusion criteria were cerebral radiation with more than 30 Gy, tumor remission less than 1 yr, amaurosis, hypothalamic obesity, psychiatric disorders, and unstable hormone medication.



Patients were randomized to placebo (n = 12) or 25 mg HPLC-purified DHEA/d (n = 11) orally for 12 months after stratification into a nontumor (n = 7) and a tumor group (n = 16).



Clinical scoring of pubic hair stage was performed at 0, 6, and 12 months (primary endpoint), and psychometrical evaluation (Symptom Check-List-90-R and the Centre for Epidemiological Studies-Depression Scale) at 0 and 12 months (secondary endpoint). Androgen levels and safety parameters were measured at 0, 6, and 12 months; 24-h androgen urinary excretion rates were calculated at 0 and 12 months.



In the placebo group, four patients dropped out because of recurrence of craniopharyngioma, manifestation of type 1 diabetes, and change of residence (n = 2); in the DHEA group, one patient dropped out because of recurrent anxiety attacks. DHEA substitution resulted in normalization of DHEA sulfate and androstanediol glucuronide morning serum levels 2 h after drug intake (P < 0.006), and of its 24 h urinary metabolite levels (P < 0.0001), placebo had no effect. Morning serum levels of androstenedione increased in the DHEA group (P < 0.02) but did not normalize. The DHEA group exhibited significant progress in pubic hair growth from Tanner stage I-III to II-V (mean: +1.5 stages), whereas the placebo group did not (relative risk 0.138; 95% confidence interval 0.021-0.914; P = 0.0046). Importantly, eight of the 10 Symptom Check-List-90-R scores, including those for depression, anxiety, and interpersonal sensitivity, and the global severity index improved in the DHEA group in comparison to the placebo group (P < 0.048). DHEA was well tolerated.



In adolescent girls with central adrenal insufficiency, daily replacement with 25 mg DHEA orally is beneficial: atrichia pubis vanishes, and psychological well-being improves significantly.
Diagnosis of Bleeding Meckel's Diverticulum in Adults

Various modalities have been used to diagnose Meckel's diverticulum (MD) in practice, but with their diagnostic accuracy deemed to be unsatisfactory for clinical practice. Moreover, the usefulness of these modalities has not been evaluated for the diagnosis of bleeding MD in adults, due to the relative rarity of this condition. Therefore, the aim of our multicenter study was to determine the most accurate modality for the preoperative diagnosis of bleeding MD in adults.



We conducted a retrospective analysis of the diagnostic accuracy for small bowel bleeding associated with MD of different modalities in patients ≥18 years old who underwent assessment for MD, with confirmation at the time of explorative surgery. Diagnostic accuracy of the different modalities was evaluated against the diagnosis obtained using technetium-99m pertechnetate scintigraphy (also known as Meckel's scan), considered to be the gold standard for the diagnosis of bleeding MD in pediatrics.



Thirty-five adults were identified with bleeding in MD over the study period, between 2005 and 2012. Among these patients, only 24 (68.6%) were diagnosed with MD preoperatively. The mean (95% confidence interval) diagnostic accuracy of selected modalities was as follows: Meckel's scan, 21.4% (5.7%-51.2%); capsule endoscopy, 35.7% (14.0%-64.4%); balloon-assisted enteroscopy (BAE), 85.0% (61.1%-96.0%); angiography, 0.0% (0.0%-80.2%); computed tomography, 31.8% (14.7%-54.9%); and small-bowel follow-through, 62.5% (25.9%-90.0%). The diagnostic accuracy was significantly higher for BAE than for Meckel's scan (P = 0.001).



Among available diagnostic modalities, BAE provides the highest accuracy for the diagnosis of bleeding MD in adults and, therefore, should be considered as the preferred modality for preoperative diagnosis.
Pregabalin in generalized anxiety disorder: a placebo-controlled trial.

Current drug therapies for generalized anxiety disorder have limitations. In a controlled trial, the novel agent pregabalin was studied for the treatment of patients with generalized anxiety disorder.



In this double-blind study, patients with DSM-IV generalized anxiety disorder were randomly assigned to receive pregabalin (150 mg/day or 600 mg/day), lorazepam (6 mg/day), or placebo. A 1-week placebo lead-in was followed by 4 weeks of treatment and then a 1-week dose taper. The primary efficacy measure was the Hamilton Anxiety Rating Scale score at endpoint.



A total of 276 patients were randomly assigned to a treatment group and received at least one dose of their assigned medication. Fewer patients given lorazepam (59%, N=40 of 68) completed the trial than did those given placebo (73%, N=50 of 69), 600 mg/day of pregabalin (71%, N=50 of 70), or 150 mg/day or pregabalin (90%, N=62 of 69). The mean baseline-to-endpoint decreases in total Hamilton anxiety scale score in the patients given 150 mg/day of pregabalin (-9.2), 600 mg/day of pregabalin (-10.3), and lorazepam (-12.0) were significantly greater than the decrease in those given placebo (-6.8). As early as the week 1 observation, pregabalin significantly reduced the total Hamilton anxiety scale score compared with placebo. The most frequent adverse events reported for pregabalin and lorazepam were somnolence and dizziness. There were no serious adverse events reported by patients given pregabalin, and no withdrawal syndrome was associated with pregabalin treatment.



These results indicate that pregabalin is an effective, rapidly acting, and safe treatment for generalized anxiety disorder. In short-term treatment, pregabalin does not appear to have the withdrawal symptoms associated with the benzodiazepines.
Controlled-release carbidopa-levodopa (Sinemet) in combination with standard Sinemet in advanced Parkinson's disease.

Twelve of 23 patients with Parkinson's disease and motor fluctuations who entered a double-blind study comparing controlled-release carbidopa/levodopa (Sinemet CR-4) with standard Sinemet (SS) continued into open label follow-up on a combination of CR-4 and SS (C/S); the rest continued on CR-4 alone. Significant improvement on C/S compared with CR-4 was noted for shorter duration and reduced disability of dyskinesias, and more hours "on" without dyskinesias (all p less than 0.05). Total number of hours "off" was improved on C/S over SS (p less than 0.01). Sinemet CR-4 proved to be better than C/S for sleep disturbance (p less than 0.05). Although the total number of tablets and doses per day of CR-4 was reduced during the C/S period, total levodopa dosage per day was not significantly changed from either of the previous periods. The C/S therapy for advanced parkinsonism can be more efficacious for fluctuators than either CR-4 or SS alone.
A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies.

This Phase I study was performed to assess the feasibility of administering L-778,123, a peptidomimetic farnesyl protein transferase (FPTase) inhibitor, as a continuous i.v. infusion for 7 days every 3 weeks and to determine the recommended dose for subsequent disease-directed trials. This study also sought to characterize the pharmacological behavior of L-778,123 and to determine whether the desired biological effect, inhibition of protein farnesylation, could be detected and assessed during treatment. Patients with advanced solid malignancies were treated with L-778,123 as a continuous i.v. infusion for 7 days every 3 weeks at doses ranging from 35 to 1120 mg/m(2)/day. On the basis of preclinical studies, toxicity assessments included cardiac telemetry, electrocardiograms, and electroretinograms in addition to more routine safety monitoring laboratory tests. Plasma sampling was performed to characterize the pharmacokinetics of L-778,123, and peripheral blood mononuclear cells (PBMCs) were sampled to detect and monitor the inhibitory effects of L-778,123 on the prenylation of HDJ2, a chaperone protein that undergoes farnesylation. Twenty-five patients received 51 complete courses of L-778,123. An unacceptably high incidence of dose-limiting toxicities, consisting of grade 4 thrombocytopenia, significant prolongation of the QT(c) interval, and profound fatigue, was observed at the 1120 mg/m(2)/day dose level. At the next lower L-778,123 dose level, 560 mg/m(2)/day, seven new patients had no unacceptable toxicity. Instead, myelosuppression was mild to moderate and QT(c) prolongation was negligible. Pharmacokinetics were linear, and L-778,123 plasma concentrations at steady-state (mean, 8.09 +/- 3.11 microM at 560 mg/m(2)/day) exceeded IC(50) values (range, 0.07-5.35 microM) required for growth inhibition and cytotoxicity in preclinical studies. The systemic clearance of L-778,123 averaged 106.4 +/- 45.6 ml/min/m(2), and the terminal half-life of elimination was 2.8 +/- 1.0 h. L-778,123 inhibited HDJ2 prenylation for the duration of the drug infusion in a dose-dependent manner, but seemed to plateau above 560 mg/m(2)/day. At the 560 mg/m(2)/day dose level, the mean percentage of HDJ2 protein in its unprenylated form increased from 1.41% +/- 1.71% (pretreatment) to 28.76% +/- 6.10% (day 4) and 30.86 +/- 4.96 (day 8) and declined to 2.28% +/- 2.11% one week after drug discontinuation (day 16). L-778,123 administered as a continuous 7-day i.v. infusion for 7 days every 21 days is well tolerated at doses of 560 mg/m(2)/day and results in biologically relevant concentrations and consistent inhibition of HDJ2 prenylation in PBMCs. Although the relationship between drug-related inhibition of HDJ2 prenylation in PBMCs and both prenylation of relevant proteins and growth inhibition in tumor cells is unknown, serial analyses of HDJ2 prenylation provide a pharmacodynamic marker of protein prenylation that may be useful in optimizing the development of drugs targeting FPTase.