nils-herrmann/clean_scirepeval huggingface dataset:
First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors.

AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population.



Standard 3+3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies.



Sixty-two patients were treated with doses ranging from 10 to 120 mg/m(2) twice weekly and 150 to 310 mg/m(2) once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m(2), which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m(2) as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients.



AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.
Creatine Fails to Augment the Benefits from Resistance Training in Patients with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Study

Progressive resistance exercise training (PRT) improves physical functioning in patients with HIV infection. Creatine supplementation can augment the benefits derived from training in athletes and improve muscle function in patients with muscle wasting. The objective of this study was to determine whether creatine supplementation augments the effects of PRT on muscle strength, energetics, and body composition in HIV-infected patients.



This is a randomized, double blind, placebo-controlled, clinical research center-based, outpatient study in San Francisco. 40 HIV-positive men (20 creatine, 20 placebo) enrolled in a 14-week study. Subjects were randomly assigned to receive creatine monohydrate or placebo for 14 weeks. Treatment began with a loading dose of 20 g/day or an equivalent number of placebo capsules for 5 days, followed by maintenance dosing of 4.8 g/day or placebo. Beginning at week 2 and continuing to week 14, all subjects underwent thrice-weekly supervised resistance exercise while continuing on the assigned study medication (with repeated 6-week cycles of loading and maintenance). The main outcome measurements included muscle strength (one repetition maximum), energetics ((31)P magnetic resonance spectroscopy), composition and size (magnetic resonance imaging), as well as total body composition (dual-energy X-ray absorptiometry). Thirty-three subjects completed the study (17 creatine, 16 placebo). Strength increased in all 8 muscle groups studied following PRT, but this increase was not augmented by creatine supplementation (average increase 44 vs. 42%, difference 2%, 95% CI -9.5% to 13.9%) in creatine and placebo, respectively). There were no differences between groups in changes in muscle energetics. Thigh muscle cross-sectional area increased following resistance exercise, with no additive effect of creatine. Lean body mass (LBM) increased to a significantly greater extent with creatine.  Resistance exercise improved muscle size, strength and function in HIV-infected men. While creatine supplementation produced a greater increase in LBM, it did not augment the robust increase in strength derived from PRT.
DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC study.

Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).



We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.



The mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m(2) in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD.



Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.
Comparison of the pharmacokinetic and pharmacodynamic profiles of insulin degludec and insulin glargine.

A medical need remains for a once-daily insulin with 24-h basal coverage in all patients. We characterize the steady-state (SS) pharmacokinetic/pharmacodynamic properties of insulin degludec (IDeg) versus insulin glargine (IGlar).



In this controlled, single-center study, 66 type 1 diabetes patients were randomized to two 8-day periods of once-daily IDeg or IGlar at 0.4, 0.6 or 0.8 U/kg. At SS, subjects underwent a 42-h euglycemic glucose clamp (5.5 mmol/l; 100 mg/dl). Glucose infusion rate (GIR), distribution of GIR and half-life were assessed.



Mean 24-h GIR profiles were flatter and more stable for all doses of IDeg versus IGlar. The evenly distributed glucose-lowering effect of IDeg was confirmed by the AUCGIR across one dosing interval, as each of the four 6-h intervals across one dosing interval contributed ∼ 25% of the AUCGIR,τ,SS. IGlar was most effective during the first 12 - 18 h after dosing. At SS, the half-life was 25.4 (IDeg) versus 12.1 h (IGlar). No safety concerns were identified for IDeg or IGlar.



IDeg has a longer half-life (> 25 h) than IGlar. Exposure and glucose-lowering effects are more stable and evenly distributed across one dosing interval for IDeg versus IGlar (Clinical trials.gov identifier: NCT01114542).
Optimal treatment for Spinal Cord Injury associated with cervical canal Stenosis (OSCIS): a study protocol for a randomized controlled trial comparing early versus delayed surgery

The optimal management of acute cervical spinal cord injury (SCI) associated with preexisting canal stenosis remains to be established. The objective of this study is to examine whether early surgical decompression (within 24 hours after admission) would result in greater improvement in motor function compared with delayed surgery (later than two weeks) in cervical SCI patients presenting with canal stenosis, but without bony injury.



OSCIS is a randomized, controlled, parallel-group, assessor-blinded, multicenter trial. We will recruit 100 cervical SCI patients who are admitted within 48 hours of injury (aged 20 to 79 years; without fractures or dislocations; American Spinal Injury Association (ASIA) grade C; preexisting spinal canal stenosis). Patients will be enrolled from 36 participating hospitals across Japan and randomly allocated in a 1:1 ratio to either early surgical decompression (within 24 hours after admission) or delayed surgery following at least two weeks of conservative treatment. The primary outcomes include: 1) the change from baseline to one year in the ASIA motor score; 2) the total score of the Spinal Cord Independence Measure and 3) the proportion of patients who are able to walk without human assistance. The secondary outcomes are: 1) the health-related quality of life as measured by the Medical Outcomes Study Short Form 36 and the EuroQol 5 Dimension; 2) the Neuropathic Pain Symptom Inventory and 3) the walking status as evaluated with the Walking Index for Spinal Cord Injury II. The analysis will be on an intention-to-treat basis. The primary analysis will be a comparison of the primary and secondary outcomes one year after the injury.



The results of this study will provide evidence of the potential benefit of early surgical decompression compared to the current 'watch and wait' strategy.
Acute effects of remote ischemic preconditioning on cutaneous microcirculation - a controlled prospective cohort study

Therapeutic strategies aiming to reduce ischemia/reperfusion injury by conditioning tissue tolerance against ischemia appear attractive not only from a scientific perspective, but also in clinics. Although previous studies indicate that remote ischemic intermittent preconditioning (RIPC) is a systemic phenomenon, only a few studies have focused on the elucidation of its mechanisms of action especially in the clinical setting. Therefore, the aim of this study is to evaluate the acute microcirculatory effects of remote ischemic preconditioning on a distinct cutaneous location at the lower extremity which is typically used as a harvesting site for free flap reconstructive surgery in a human in-vivo setting.



Microcirculatory data of 27 healthy subjects (25 males, age 24 ± 4 years, BMI 23.3) were evaluated continuously at the anterolateral aspect of the left thigh during RIPC using combined Laser-Doppler and photospectrometry (Oxygen-to-see, Lea Medizintechnik, Germany). After baseline microcirculatory measurement, remote ischemia was induced using a tourniquet on the contralateral upper arm for three cycles of 5 min.



After RIPC, tissue oxygen saturation and capillary blood flow increased up to 29% and 35% during the third reperfusion phase versus baseline measurement, respectively (both p = 0.001). Postcapillary venous filling pressure decreased statistically significant by 16% during second reperfusion phase (p = 0.028).



Remote intermittent ischemic preconditioning affects cutaneous tissue oxygen saturation, arterial capillary blood flow and postcapillary venous filling pressure at a remote cutaneous location of the lower extremity. To what extent remote preconditioning might ameliorate reperfusion injury in soft tissue trauma or free flap transplantation further clinical trials have to evaluate.
Poor nutrition is a relative contraindication to negative pressure wound therapy for pressure ulcers: preliminary observations in patients with spinal cord injury.

To assess the efficacy of negative-pressure wound therapy (NPWT) for healing of pressure ulcers (PrUs) in individuals with spinal-cord injury (SCI).



Multicenter, 28-day observational study.



Ten Veterans Affairs Medical Center SCI centers.



Eighty-six SCI inpatients with Stage III/IV pelvic PrUs.



Standard wound care with NPWT versus standard wound care alone (NoNPWT).



Change in wound surface area (WSA) using the Verg Videometer Measurement Documentation software.



The proportion of patients demonstrating a decrease in WSA (healing subgroup) was not significantly different between the NPWT (n = 33) and NoNPWT (n = 53) groups (67% vs 70%, respectively). In the healing subgroup, there was no significant difference between the NPWT versus NoNPWT groups in WSA decrease (-43 ± 22% vs -50% ± 26%, not statistically significant). Similarly, in the nonhealing subgroup, there was no significant difference between NPWT and NoNPWT groups (31% ± 26% vs 32% ± 34%). In the NPWT group, the nonhealing subgroup (11/33) had significantly lower serum albumin levels than the healing subgroup (22/33) (2.9 ± 0.4 vs 3.3 ± 0.5 mg/dL, P < .05). In the NoNPWT group, there was no significant difference in serum albumin levels between the healing versus nonhealing subgroups (3.2 ± 0.3 vs 3.2 ± 0.3 mg/dL).



In SCI patients with Stage III/IV pelvic PrUs, NPWT did not significantly influence the rate of healing. Additionally, in malnourished individuals (albumin <3.0 mg/dL), NPWT was not efficacious. Healing outcomes in the NPWT group were significantly influenced by albumin levels, whereas no such disparity was noted between the healing and nonhealing PrUs for the NoNPWT group. Nutritional status appears to be important in the effectiveness of NPWT.
The long and the short of it: relational memory impairments in amnesia, even at short lags.

Classic studies of amnesia led to characterizations of hippocampal function emphasizing involvement in long-term memory rather than short-term (or working) memory. In two experiments, we show that when memory for relations among co-occurring items is tested, hippocampal amnesia results in a deficit even at very short lags. Hence, we find evidence for hippocampal involvement in relational memory, even at short lags normally considered the province of working memory.
Dermoscopy of solitary angiokeratomas: a morphological study.

To describe the dermoscopic structures and patterns associated with solitary angiokeratomas and to determine the sensitivity, specificity, positive predictive value, negative predictive value, and reproducibility of these dermoscopic features.



Multicenter retrospective study.



University hospitals in Spain, Italy, Argentina, New York City, and Austria.



There were 256 patients total, and 32 specimens each of solitary angiokeratomas, melanocytic nevi, Spitz-Reed nevi, malignant melanomas, pigmented basal cell carcinomas, dermatofibromas, seborrheic keratoses, and other vascular lesions (19 angiomas, 7 pyogenic granulomas, 3 spider nevi, 2 lymphangiomas, and 1 venous lake) were consecutively collected from the laboratories of 8 hospitals. Diagnoses of all patients' lesions were confirmed histopathologically.



Dermoscopic examination.



The frequency, sensitivity, specificity, positive predictive value, negative predictive value, intraobserver agreement, and interobserver agreement of the different dermoscopic features associated with solitary angiokeratomas were calculated, and the differences were evaluated using the chi(2) or Fisher exact test.



Six dermoscopic structures were evident in at least 50% of the solitary angiokeratomas: dark lacunae (94%), whitish veil (91%), erythema (69%), peripheral erythema (53%), red lacunae (53%), and hemorrhagic crusts (53%). Dark lacunae exhibited a sensitivity of 93.8% and a specificity of 99.1% (P<.001 for both), not being found in malignant melanomas or pigmented basal cell carcinomas. The positive predictive value was 93.8%, and the negative predictive value was 99.1%. The intraobserver agreement was perfect (kappa, 1.00), and the interobserver agreement was excellent (kappa range, 0.83-1.00) (P<.001 for both). Pattern 1, consisting of dark lacunae and whitish veil, exhibited a sensitivity of 84.4% and a specificity of 99.1% and was not found in malignant melanomas or pigmented basal cell carcinomas. The positive predictive value was 93.1%, the negative predictive value was 97.8%, the intraobserver agreement was perfect (kappa, 1.00), and the interobserver agreement was excellent (kappa range, 0.83-1.00) (P<.001 for all).  Dermoscopy is helpful in improving the diagnostic accuracy of solitary angiokeratomas and allows the observer to differentiate them from other cutaneous tumors such as malignant melanomas and pigmented basal cell carcinomas.
Exercise with calorie restriction improves insulin sensitivity and glycogen synthase activity in obese postmenopausal women with impaired glucose tolerance.

Our objective was to compare the effects of in vivo insulin on skeletal muscle glycogen synthase (GS) activity in normal (NGT) vs. impaired glucose-tolerant (IGT) obese postmenopausal women and to determine whether an increase in insulin activation of GS is associated with an improvement in insulin sensitivity (M) following calorie restriction (CR) and/or aerobic exercise plus calorie restriction (AEX + CR) in women with NGT and IGT. We did a longitudinal, clinical intervention study of CR compared with AEX + CR. Overweight and obese women, 49-76 yr old, completed 6 mo of CR (n = 46) or AEX + CR (n = 50) with Vo(2 max), body composition, and glucose tolerance testing. Hyperinsulinemic euglycemic (80 mU·m(-2)·min(-1)) clamps (n = 73) and skeletal muscle biopsies (before and during clamp) (n = 58) were performed before and after the interventions (n = 50). After 120 min of hyperinsulinemia during the clamp, GS fractional activity and insulin's effect to increase GS fractional activity (insulin - basal) were significantly lower in IGT vs. NGT (P < 0.01) at baseline. GS total activity increased during the clamp in NGT (P < 0.05), but not IGT, at baseline. CR and AEX + CR resulted in a significant 8% weight loss with reductions in total fat mass, visceral fat, subcutaneous fat, and intramuscular fat. Overall, M increased (P < 0.01), and the change in M (postintervention - preintervention) was associated with the change in insulin-stimulated GS fractional activity (partial r = 0.44, P < 0.005). In IGT, the change (postintervention - preintervention) in insulin-stimulated GS total activity was greater following AEX + CR than CR alone (P < 0.05). In IGT, insulin-stimulated GS-independent (P < 0.005) and fractional activity (P = 0.06) increased following AEX + CR. We conclude that the greatest benefits at the whole body and cellular level (insulin activation of GS) in older women at highest risk for diabetes are derived from a lifestyle intervention that includes exercise and diet.
Pharmacokinetics and biological activity in subcutaneous long-term administration of recombinant interferon-γ in cancer patients

We have investigated the pharmacokinetics, tolerance, and biological activity of recombinant human interferon-γ (rHuIFNγ) administered subcutaneously to cancer patients. Twenty-one patients with lymphoma and metastatic cancer received rHuIFNγ (in doses of 0.1, 0.25, or 0.5 mg/m2) in two or three injections per week for up to 180 days. The most common adverse effects encountered were flu-like symptoms, fever and fatigue. The increase in body temperature after each administration ranged from 0 to 4°C depending on the individual patient, but was unrelated to the rHuIFNγ dose or its plasma concentration. The pharmacokinetic response of the patients after the two treatments showed a low intra-individual variability with respect to the plasma concentration/time profiles. However, as observed for the fever side-effect, the interindividual variation (CV >50%) was high for the parameters area under the data points (AUC0-t ) and maximum plasma concentration (c max). Despite this high interindividual variability, the mean values obtained for AUC0-t andc max after s.c. injection of rHuIFNγ were approximately proportional to the dose administered: the injection of 0.1, 0.25 or 0.5 mg/m2 rHuIFNγ resulted in AUC0-t values of 15.4, 31.5 or 69.6 ng h/ml, respectively andc max was found to be 1.0, 2.4 and 4.9 ng/ml, respectively. With this s.c. administration protocol, objective antitumour responses were observed in two patients, but there was no partial or complete remission.
The role of clusterin in amyloid-β-associated neurodegeneration.

Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.



To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.



This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5).



Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF Aβ1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus.



Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF Aβ1-42-positive individuals but not among CSF Aβ1-42-negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin, as well as CSF Aβ1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts.



In nondemented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
Longitudinal study on the Quality of Life of symptomatic HIV-infected patients in a trial of zidovudine versus zidovudine and interferon-alpha.

To compare the effect of treatment with zidovudine (ZDV) or a combination of ZDV and interferon-alpha (IFN-alpha) on patient Quality-of-Life (QoL); and to document changes over time in QoL.



This study is part of a longitudinal, randomized, controlled clinical trial comparing the efficacy and tolerance of ZDV monotherapy and ZDV plus IFN-alpha. Patients were followed-up for 1 year.



Seven academic or general medical hospitals.



Thirty-six symptomatic HIV-infected patients (Centers for Disease Control and Prevention stage IV) with a CD4+ count > or = 150 x 10(6)/l and Karnofsky Performance Status score > or = 60, who had not received ZDV or IFN-alpha before.



QoL was assessed using two self-report questionnaires (the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire and an AIDS-specific questionnaire), administered before and every 3 months after the start of the treatment.



There were no significant differences in QoL between the two treatment groups over a 1-year period. Emotional, cognitive and social functioning improved in the entire group, and patients reported fewer symptoms (for example, shortness of breath, nausea and vomiting, influenza-like symptoms, diarrhoea, lack of appetite, taste disturbances, dizziness, weight loss, trouble in vision) and a better overall QoL until month 9. Thereafter, emotional, cognitive and social functioning and overall QoL deteriorated and patients reported more symptoms. Major complaints at baseline and follow-up were associated with fatigue and emotional functioning: patients reported a strong need to rest, and felt very tired, worried, tense and irritable.



These results show that both treatments may have a temporary beneficial effect on patient QoL. QoL research may contribute to evaluation of clinical trials and provide patients with information about the effects of treatment on their QoL, thus enabling them to make informed decisions.