Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeted therapy for haematological malignancies: clinical update from the American Society of Hematology, 2004

Recent advances in the treatment and management of haematological malignancies are due in large part to an improved understanding of the basic biology that drives tumour cell growth and survival. This improved understanding has led to the clinical study and approval of a number of different targeted agents across a number of different haematological tumours. This review of clinical data covers some of the exciting clinical advances that were reported at the recent American Society of Hematology meeting in San Diego, USA. This paper focuses on three important areas of biological research that has yielded clinical trials that have affected clinical outcomes. The areas covered include proteasome inhibition and myeloma, tyrosine kinase inhibitors that are directed at the BCR-ABL fusion protein and chronic myeloid leukaemia/acute lymphoblastic leukaemia, and FLT3 inhibitors and acute myeloid leukaemia acute lymphoblastic leukaemia therapy.
MICROCIRCULATORY FAILURE AFTER RAT LIVER TRANSPLANTATION IS RELATED TO KUPFFER CELL-DERIVED OXIDANT STRESS BUT NOT INVOLVED IN EARLY GRAFT DYSFUNCTION1

Background. Microcirculatory failure, activation of Kupffer cells (KC), and the formation of reactive oxygen species (ROS) are considered pivotal mechanisms of reperfusion injury after orthotopic liver transplantation. However, the sequence of these events and their impact on early graft function remain controversial. We therefore investigated whether KC induce microcirculatory disturbances through ROS release and whether microcirculatory failure contributes to early graft function after liver transplantation. Methods. Donor livers of Lewis rats were pretreated either with saline or with gadolinium chloride (GdCl3), an inhibitor of KC function (n=8 each). Syngeneic OLT was performed after 24 hr of hypothermic preservation in University of Wisconsin solution. Results. Intravital microscopy revealed significantly higher sinusoidal perfusion rates in GdCl3-treated allografts (92±1.1% vs. 75.7±0.8%;P <0.001) compared with untreated controls; permanent leukocyte sticking in sinusoids (23.5±2.1 vs. 62.6±3.3 cells/lobule, P <0.001) and in postsinusoidal venules (153.1±10.4 vs. 446.6±46.4 cells/mm2, P <0.001) were markedly attenuated in GdCl3-treated allografts. Improvement of microcirculatory parameters in GdCl3-treated livers was correlated with a significant reduction of plasma glutathione disulfide formation by KC-derived ROS (0.96±0.1 &mgr;M vs. 1.79±0.5 &mgr;M;P <0.01). Despite these beneficial effects, GdCl3-pretreatment failed to improve postischemic alanine aminotransferase release and bile flow. Conclusions. Microcirculatory failure after liver transplantation is related to KC-derived oxidant stress but not involved in early graft dysfunction.
Magnetohydrodynamic Simulation of a Coaxial High-Density Plasma Opening Switch

The plasma dynamics and the magnetic-field penetration in a coaxial plasma opening switch (POS) are studied self-consistently based on the two-dimensional magnetohydrodynamic (MHD) equation conjunction with the generalized Ohm's law. The energy transfers between the plasma and the magnetic field are considered during the penetration of the magnetic field, in which both the Ohmic heating and the heat transfer are included in the energy-balance equation. The profiles of magnetic field, plasma density, and plasma temperature are simulated with the initial plasma density n0=1016 cm-3. For the high-density plasma, it is shown that the convection effect dominates the magnetic-field penetration; the plasma near the cathode is rapidly compressed by the magnetic pressure, and the temperature of the plasma in the shock region increases noticeably because of the compression effect. Furthermore, the increase of temperature in the shock region enhances the magnetic-field penetration near the cathode. The energy analysis shows that more than half of the input energy is stored as magnetic-field energy, and a significant amount of the input energy goes into the plasma thermal energy. The scaling relation between the maximal conduction current and the initial plasma density is also studied, and the simulation results agree with the theoretical law and experimental data well
Preventing discrimination against volunteers in prophylactic HIV vaccine trials: lessons from a phase II trial.

CONTEXT Preventive HIV vaccines can temporarily cause uninfected individuals to have positive results on HIV testing. As preparations are underway to mount larger efficacy trials, the social risks of trial participation should be studied. OBJECTIVE To describe frequency of HIV testing and discrimination among participants in a preventive phase II HIV vaccine trial. PARTICIPANTS 266 vaccine trial volunteers were eligible; 247 participated in a confidential survey. RESULTS 63 volunteers (26% of respondents) reported 185 HIV tests during the prior 12 to 24 months; most tests were for other research studies, health care, insurance, incarceration, or employment. Only 5 volunteers reported having positive HIV test results. Volunteers reported 99 adverse social incidents or problems, 53 of which were related to the trial. The most common type of event occurred when volunteers disclosed their trial participation and were mistakenly presumed to be infected with HIV. Few reported difficulty obtaining insurance, job loss, and inadvertent disclosure of their participation in the trial. CONCLUSION In this vaccine trial, few serious social harms were reported. Those who conduct HIV tests for insurance, employment, health care, or other reasons should be made aware that HIV vaccines can cause false-positive HIV test results. Those planning future trials must continue to provide needed support to volunteers. Social harms should be monitored with the same vigilance accorded to physical harms.
Impact of Guglielmi detachable coils on outcomes of patients with intracranial aneurysms treated by a multidisciplinary team at a single institution.

OBJECT The goal of this study was to investigate the impact of the introduction of the Guglielmi detachable coil (GDC) therapeutic option on the overall management outcome of intracranial aneurysms. The authors accomplished this by assessing patient morbidity and mortality, inflation-adjusted hospital charges, lengths of stay in the hospital and the intensive care unit (ICU), and treatment efficacy. METHODS The authors conducted a retrospective analysis of consecutive cases of intracranial intradural aneurysms managed by a single multidisciplinary neurovascular team at a tertiary care, academic referral center during the 24 months preceding the introduction of the GDC procedure (Group I or pre-GDC era, 77 patients) and during the first 24 months after its introduction (Group II or GDC era, 99 patients). Treatment with GDCs was considered for cases of higher clinical grade or poor surgical risk, or in response to patient preference (27 [27%] of 99 patients in Group II). Host and lesion parameters in our cohort were validated against outcome parameters by using univariate and multivariate analyses. The pre-GDC and GDC subgroups of patients were comparable for major disease severity parameters (patient age, lesion location, clinical grade, and hemorrhage severity). There was no significant difference in clinical outcome at 6 months, infarcts on computerized tomography scanning, or aneurysm obliteration rates before and after introduction of GDC treatment. Decreasing trends in duration of hospital and ICU stay and in inflation-adjusted hospital charges occurred well before and thus were unrelated to the introduction of the GDC therapeutic option. CONCLUSIONS The results of this study do not demonstrate any significant impact of integration of the GDC modality on clinical outcome, mortality, morbidity, or effectiveness of treatment. Ongoing improvements in hospital charges and length of hospital stay appeared unrelated to the introduction of the GDC option.
An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children

Objective:The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein (P-gp) and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of antiretroviral agents. This research examined the impact of single nucleotide polymorphisms (SNP) of MDR1 and CYP genes on nelfinavir and efavirenz pharmacokinetics and the response to highly active antiretroviral therapy (HAART) in HIV-1 infected children. Methods:Seventy-one HIV-1-infected children from PACTG 382 receiving nelfinavir, efavirenz and one or two nucleoside reverse transcriptase inhibitors had genomic DNA from PBMC evaluated for MDR1 and CYP SNP by real-time PCR. Plasma drug concentrations, CD4 lymphocyte counts and HIV-1 RNA were measured during HAART. Results:The frequencies of C/C, C/T and T/T genotypes in the MDR1-3435-C→T polymorphisms were 44% (n = 31), 46% (n = 33) and 10% (n = 7), respectively. Ninety-one percent of children with the C/T genotype reached plasma HIV-1 RNA < 400 copies/ml by week 8 compared to 59% of children with the C/C genotype (P = 0.01). Children with the C/T genotypes had higher 8 h postdose concentration (P = 0.02) and lower clearance rate (P = 0.04) for nelfinavir compared to those with the C/C genotype. The seven children with the T/T genotype had nelfinavir pharmacokinetics and virologic response similar to those with the C/C genotype. No compensatory polymorphisms were observed between MDR1 and CYP genotypes. Conclusions:HIV-1 infected children with the MDR1-3435-C/T genotype had more rapid virologic responses to HAART at week 8 with higher plasma nelfinavir concentrations compared to those with the C/C genotype. These findings suggest that P-gp may play an important role in the pharmacokinetics and virologic response to HAART containing nelfinavir.
Human toxoplasmosis and cat contact in Costa Rica.

We studied the prevalence of antibody to Toxoplasma gondii in 883 Costa Ricans between the ages of 15 and 26 years (mean 20.3). There were seven populations, two rural and five urban. The overall antibody prevalence was 61.4%. Because antibody prevalence was 57.1% in the 14 people who ate raw meat, and 61.6% in the 294 people who consumed raw eggs, meat and eggs could be excluded as important modes of transmission. We ascertained the presence of cats, type of soil contact, and flooring in the kitchen for every residence in which each individual lived from birth until interviewed. The 66% of people who indicated contact with cats had an antibody prevalence of 64%, and those without contact 56% (P = 0.02). In six of the seven populations, we found a positive correlation between cat contact and antibody prevalence; hence these six were studied together, and San Ramon, with a negative correlation, was examined separately. In the San Jose metropolitan population and in the total urban sample, cat contact was associated with a significantly higher antibody prevalence (P < 0.01). It was found that humans, even without acknowledged soil contact, acquire infection inside houses, especially with cement floors, when cats defecate in the house. Humans also acquire infection in or around houses with wooden floors, where the crawl space is an often unrecognized refuge of cats and a source of persistent soil contamination. San Ramon was the urban area with the highest human-cat contact (77%) and with the highest antibody prevalence in cats (75%). Although suggesting equal opportunities for infection, irrespective of cat contact, we cannot be certain in a retrospective study in which most of the infections took place an average of 15 years earlier. The most frequent antibody titer in our Costa Rican population was 1:1,024 (21%), much higher than the most frequent titers in a Colombian (1:64 to 1:128) and a U.S. population (1:16) of comparable age.
Functional Characterization of the 11 Non-ATPase Subunit Proteins in the Trypanosome 19 S Proteasomal Regulatory Complex* 210

The ubiquitin-proteasome pathway is responsible for selective degradation of short-lived and dysfunctional proteins in eukaryotes. The recently demonstrated presence of a functional 26 S proteasome in Trypanosoma brucei led to the identification and isolation of genes encoding all 11 non-ATPase (Rpn) subunit proteins in the trypanosome 19 S regulatory complex. Using the technique of RNA interference, expression of individual RPNgenes was disrupted in the procyclic form of T. brucei, resulting, in each case, in intracellular accumulation of polyubiquitinated protein, cell arrest at the G2/M phase, and eventual cell death. With the exception of Rpn10, depletion of individual Rpn proteins disrupted also trypanosome 19 S complex formation, with the complex virtually depleted in the cell lysate. This functional and structural essentiality of 10 of the 11 Rpn proteins in T. brucei differs significantly from that observed in other organisms. When Rpn10 was deficient in trypanosomes, a 19 S complex without Rpn10 was still formed, whereas cell growth was arrested. This structural dispensability but functional indispensability of Rpn10 may constitute another unique aspect of the proteasomes in T. brucei.
Gene Expression Patterns in the Human Breast after Pregnancy

Epidemiologic studies have established that pregnancy has a bidirectional, time-dependent effect on breast cancer risk; a period of elevated risk is followed by a long-term period of protection. The purpose of the present study was to determine whether pregnancy and involution are associated with gene expression changes in the normal breast, and whether such changes are transient or persistent. We examined the expression of a customized gene set in normal breast tissue from nulliparous, recently pregnant (0-2 years since pregnancy), and distantly pregnant (5-10 years since pregnancy) age-matched premenopausal women. This gene set included breast cancer biomarkers and genes related to immune/inflammation, extracellular matrix remodeling, angiogenesis, and hormone signaling. Laser capture microdissection and RNA extraction were done from formalin-fixed paraffin-embedded reduction mammoplasty and benign biopsy specimens and analyzed using real-time PCR arrays containing 59 pathway-specific and 5 housekeeping genes. We report 14 of 64 (22%) of the selected gene set to be differentially regulated (at P < 0.05 level) in nulliparous versus parous breast tissues. Based on gene set analysis, inflammation-associated genes were significantly upregulated as a group in both parous groups compared with nulliparous women (P = 0.03). Moreover, parous subjects had significantly reduced expression of estrogen receptor α (ERα, ESR1), progesterone receptor (PGR), and ERBB2 (Her2/neu) and 2-fold higher estrogen receptor-β (ESR2) expression compared with nulliparous subjects. These initial data, among the first on gene expression in samples of normal human breast, provide intriguing clues about the mechanisms behind the time-dependent effects of pregnancy on breast cancer risk. Cancer Prev Res; 3(3); 301–11
Effects of JPEG and wavelet compression of spiral low-dose CT images on detection of small lung cancers

Purpose: To compare the effect of compression of spiral low-dose CT images by the Joint Photographic Experts Group (JPEG) and wavelet algorithms on detection of small lung cancers. Material and Methods: Low-dose spiral CT images of 104 individuals (52 with peripheral lung cancers smaller than 20 mm and 52 control subjects) were used. The original images were compressed using JPEG or wavelet algorithms at a ratio of 10:1 or 20:1. Five radiologists interpreted these images and evaluated the image quality on a high-resolution CRT monitor. Observer performance was studied by receiver operating characteristic (ROC) analysis. Results: There was no significant difference in the detection of cancers measuring 6 to 15 mm in uncompressed images and in those compressed by either of the algorithms, although the quality of images compressed at 20:1 with the wavelet algorithm was somewhat inferior. A lower diagnostic accuracy was noted using images compressed by the JPEG or wavelet algorithms at 20:1 in detecting lung cancers measuring 6 to 10 mm and cancers measuring from 6 to 15 mm with ground-glass opacity. Conclusion: Compression of low-dose CT images at a ratio of 10:1 using JPEG and wavelet algorithms does not compromise the detection rate of small lung cancers.
Origin of ascending and spinal pathways from the nucleus tegmenti pedunculopontinus in the rat

The distribution and collaterlization of ascending and descending projections from neurons in the nucleus tegmenti pedunculopontinus (PPN) were studied in the rat by using retrograde transport of HRP, HRP/WGA, and fluorescent dyes. The PPN and its two subdivisions, the subnucleus compactus (PPNc) and subnucleus dissipatus (PPNd), were delineated on sagittal Nisslstained sections by using cytoarchitectural features as guidelines.
Turnover of microbial lipids in the deep biosphere and growth of benthic archaeal populations

Deep subseafloor sediments host a microbial biosphere with unknown impact on global biogeochemical cycles. This study tests previous evidence based on microbial intact polar lipids (IPLs) as proxies of live biomass, suggesting that Archaea dominate the marine sedimentary biosphere. We devised a sensitive radiotracer assay to measure the decay rate of ([14C]glucosyl)-diphytanylglyceroldiether (GlcDGD) as an analog of archaeal IPLs in continental margin sediments. The degradation kinetics were incorporated in model simulations that constrained the fossil fraction of subseafloor IPLs and rates of archaeal turnover. Simulating the top 1 km in a generic continental margin sediment column, we estimated degradation rate constants of GlcDGD being one to two orders of magnitude lower than those of bacterial IPLs, with half-lives of GlcDGD increasing with depth to 310 ky. Given estimated microbial community turnover times of 1.6–73 ky in sediments deeper than 1 m, 50–96% of archaeal IPLs represent fossil signals. Consequently, previous lipid-based estimates of global subseafloor biomass probably are too high, and the widely observed dominance of archaeal IPLs does not rule out a deep biosphere dominated by Bacteria. Reverse modeling of existing concentration profiles suggest that archaeal IPL synthesis rates decline from around 1,000 pg⋅mL−1 sediment⋅y−1 at the surface to 0.2 pg⋅mL−1⋅y−1 at 1 km depth, equivalent to production of 7 × 105 to 140 archaeal cells⋅mL−1 sediment⋅y−1, respectively. These constraints on microbial growth are an important step toward understanding the relationship between the deep biosphere and the carbon cycle.
The Formation Mechanism of Chinese Excessive Capacity under Open Economy:Theoretical Interpretation from Multiple Perspectives

In the open economy,the interaction between domestic investment expansion and excessive use of foreign capital as well as inhibition or transformation of the main domestic consumption may lead to excessive capacity.The advancement of industry maturity and standardization of products promoted by international factor mobility and industrial transfer will also lead to the capacity expansion in advance.Technological advances will promote the production efficiency and the acceleration of scale enlargement.Unusual events such as disaster and policies can induce excessive capacity through economic and psychological conduction.The regulation of capacity and prevention of excessive production should be based on multiple perspectives.Both internal and external markets as well as market restoration should go along with policies.
Child Maltreatment and Adult Substance Abuse: The Role of Memory

Child maltreatment is a risk factor for substance abuse in adulthood. This study examines whether memory of maltreatment is a necessary link in the path leading from prospectively measured childhood maltreatment to adult substance use problems. Official Child Protective Services reports and adult retrospective recall of childhood maltreatment were used to predict illegal drug use and alcohol problems in adulthood controlling for covariates. Memory was a necessary link in the path between prospective reports of maltreatment and alcohol problems, and it was an important link in the path between prospective reports and illegal drug use. Implications for prevention and treatment are discussed.
Determination of distal fusion level with segmental pedicle screw fixation in single thoracic idiopathic scoliosis.

STUDY DESIGN A retrospective study was conducted. OBJECTIVE To determine the exact distal fusion level in the treatment of single thoracic idiopathic scoliosis (King Types 3 and 4) with segmental pedicle screw fixation. SUMMARY OF BACKGROUND DATA Pedicle screw fixation effectively shortens the distal fusion extent by improved three-dimensional deformity correction. However, the selection of distal fusion extent remains controversial in single thoracic idiopathic scoliosis. METHODS This study analyzed 42 patients with single thoracic adolescent idiopathic scoliosis (32 King 3 patients and 10 King 4 patients) who underwent segmental pedicle screw fixation and had a minimum follow-up period of 2 years (range, 2-6 years). The patients were grouped according to the distal fusion level with reference to the standing neutral rotated vertebra (NV) for comparison of deformity correction and spinal balance using standing radiographs. Failure to restore an adequate trunk balance and progression or extension of the primary curve (adding on) was considered unsatisfactory. RESULTS Preoperative 50 degrees +/- 11 degrees of thoracic deformity was corrected to 13 degrees +/- 5 degrees, for a curve correction of 74%. Preoperative 23 degrees +/- 7 degrees of lumbar deformity was corrected to 2 degrees +/- 8 degrees, for a curve correction of 93%. Curve correction was not significantly affected by King type or distal fusion level (P > 0.05). Postoperative unsatisfactory results were obtained in 14 patients. When the preoperative NV was the same or one level distal to end vertebra (EV), fusion down to NV was satisfactory (14/14). When the preoperative NV was more than two levels distal to EV, fusion down to one level shorter than NV (NV-1) also was satisfactory (9/9). However, when fusion down to NV-2 or shorter was performed, the chances of adding on were higher (14/19; P < 0.01). Preoperative 17 degrees +/- 8 degrees of thoracic kyphosis was improved to 24 degrees +/- 7 degrees. CONCLUSIONS In single thoracic idiopathic scoliosis, NV is an important factor for the determination of fusion level. When preoperative NV and EV show no more than two-level gap differences, the curve should be fused down to NV. When the gap is more than two levels, fusion down to NV-1 is satisfactory, saving one or two motion segments, as compared with fusion extending to the stable vertebra.