Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma

Sorafenib is an orally active multikinase inhibitor that targets serine and threonine, and tyrosine kinases that are involved in tumor‐cell signal transduction and tumor angiogenesis. This phase I trial was conducted to evaluate the pharmacokinetics (PK), safety, and preliminary efficacy of sorafenib in Japanese patients with hepatocellular carcinoma (HCC) with underlying liver dysfunction. Patients with unresectable HCC, Child–Pugh status A or B, and adequate organ functions were treated. A single dose of sorafenib was administered, followed by a 7‐day wash‐out period, after which patients received either sorafenib 200 mg (cohort 1) or 400 mg (cohort 2) twice daily. The PK were investigated after a single dose and during steady state. The efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors. A total of 27 patients were evaluated for PK, safety, and efficacy. Although both area under the concentration–time curve for 0–12 h and maximal concentration at steady state were slightly lower in Child–Pugh B patients than in Child–Pugh A patients, the difference was not considered to be clinically relevant. Common adverse drug events included elevated lipase, amylase, rash or desquamation, diarrhea, and hand–foot skin reaction. A dose‐limiting toxicity of hand–foot skin reaction was observed in one patient (cohort 2). Among the 24 patients evaluable for tumor response, one patient (4%) achieved a partial response, 20 (83%) had stable disease, and three (13%) had progressive disease. Sorafenib demonstrated a favorable tolerability and safety profile in Japanese HCC patients. Moreover, promising preliminary antitumor activity has been observed. Finally, there were no clinically relevant differences in PK between Child–Pugh A and B patients. (Cancer Sci 2008; 99: 159–165)
Surgical treatment of intrahepatic cholangiocarcinoma: outcomes and predictive factors.

BACKGROUND Intrahepatic cholangiocarcinoma (ICC) remains a rare tumour, although its incidence is increasing. Surgical resection is the mainstay of treatment. Published data regarding prognostic factors and optimal patient selection for resection are scant. We sought to determine the clinicopathologic characteristics of resectable ICC and outcomes following surgical treatment. METHODS We reviewed prospectively collected clinical data including patient, pathologic and operative details. Survival and recurrence outcomes were analysed using Cox hazard models and the Kaplan-Meier method. RESULTS We identified 31 surgically treated patients. Their 3-year overall survival rate (OS) was 40.1%; median follow-up was 16.2 months (range: 0.2-86.9 months). R0 resection was associated with significantly improved OS compared with R1/R2 resection (3-year OS was 68.6% in R0 vs. 24.0% in R1/R2; P= 0.042). The postoperative complication rate was 58.1%. Two patients died of postoperative liver failure within 30 days. Preoperative hypoalbuminaemia was significantly associated with worse survival. CONCLUSIONS Surgical therapy for ICC is associated with longterm survival in the subset of nutritionally replete patients in whom an R0 resection can be achieved. Surgical mortality is significant in patients undergoing extended resection. The margin involvement rate is high and surgeons should consider the infiltrative nature of the disease in operative planning.
The human cytomegalovirus immediate early 2 protein dissociates cellular DNA synthesis from cyclin‐dependent kinase activation

Passage through the restriction point late in G1 normally commits cells to replicate their DNA. Here we show that the previously reported cell cycle block mediated by the human cytomegalovirus (HCMV) immediate early 2 (IE2) protein uncouples this association. First, IE2 expression leads to elevated levels of cyclin E‐associated kinase activity via transcriptional activation of the cyclin E gene. This contributes to post‐restriction point characteristics of IE2‐expressing cells. Then these cells fail to undergo substantial DNA replication although they have entered S phase, and the induction of DNA replication observed after overexpression of cyclin E or D can be antagonized by IE2 without impinging on cyclin‐associated kinase activities. These data suggest that IE2 secures restriction‐point transition of cells before it stops them from replicating their genome. Our results fit well with HCMV physiology and support the view that IE2 is part of a viral activity which, on the one hand, promotes cell cycle‐dependent expression of cellular replication factors but, on the other hand, disallows competitive cellular DNA synthesis.
Generating stable chinese hamster ovary cell clones to produce a truncated SARS‐CoV spike protein for vaccine development

The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS‐CoV) is important for vaccine development. STR2 (an 88 kDa truncated SARS‐CoV TW1 S protein carrying the S fragments S‐74‐253, S‐294‐739, and S‐1129‐1255) is capable of expressing a major form of glycoprotein as endo H‐sensitive (∼115 kDa) in CHO cells. To establish stable expressing cell clones, we transfected CHO/dhFr‐cells with the amplifiable vectors ISID (IRES‐driven dhfr) and ISIZ (SV40‐driven dhfr) to select stepwise MTX, and observed enhanced ∼115 kDa glycoform generation through gene amplification. Following stepwise MTX selection, we compared gene amplification levels between two vectors in engineered CHO cell chromosomes. These results confirm that the IRES‐driven dhfr promoter generates greater gene amplification, which in turn enhances STR2 expression. Our results indicate that the ∼115 kDa glycoform of STR2 protein was capable of increasing after gene amplification. The STR2 glycoform did not change between suspension and serum‐free cultures, suggesting that the stable and amplified cell clones analyzed in this study have potential for producing homologous STR2 on a large scale. © 2010 American Institute of Chemical Engineers Biotechnol. Prog. , 2010
May–Thurner syndrome (iliac vein compression) and thrombosis in adolescents

May–Thurner syndrome refers to anatomic compression of the left iliofemoral vein by the overriding right iliac artery. We report three adolescents who presented to our pediatric hospital with iliac vein thrombosis and were diagnosed with May–Thurner syndrome. Each received catheter‐directed thrombolysis followed by balloon angioplasty to restore flow. Two patients had endovascular stents placed. The procedures were well tolerated, without major complications. Additional thrombophilic risk factors were identified in each patient. Though uncommon, pediatric hematologists should consider May–Thurner syndrome in adolescents who present with a left lower extremity thrombosis. Aggressive therapy may be warranted due to the risk of post‐thrombotic syndrome. Pediatric Blood Cancer 2006;47:834–838. © 2005 Wiley‐Liss, Inc.
Alpha-[11C] methyl-L-tryptophan and glucose metabolism in patients with temporal lobe epilepsy.

OBJECTIVE To determine whether metabolism in the brain serotonergic system, including the kynurenine pathway, is involved in temporal lobe epilepsy (TLE). METHODS The authors studied 14 patients with intractable TLE by PET using alpha-[11C] methyl-L-tryptophan (alpha-MTrp) and 2-[18F]-fluoro-deoxy-glucose (FDG) and compared results with 21 healthy control subjects who had alpha-MTrp PET studies. Seven patients had unilateral hippocampal atrophy (HA), and seven had normal hippocampal volumes (NV). The regional uptake constant (K*) for alpha-MTrp and regional FDG uptake were calculated in regions with high serotonergic innervation, including the hippocampus, amygdala, lateral temporal lobe, frontal lobe, thalamus, lenticular nucleus, and cingulate cortex. RESULTS A significant increase of alpha-MTrp uptake was observed in the hippocampus ipsilateral to the seizure focus in seven TLE patients with NV compared to seven patients with HA as well as to healthy controls. In patients with TLE, glucose utilization in the lateral temporal lobe ipsilateral to the seizure focus was correlated negatively with K* for alpha-MTrp in the ipsilateral hippocampus and positively with K* in the ipsilateral lenticular nucleus and cingulate cortex. Glucose utilization in the frontal lobe ipsilateral to the seizure shows a reduction in the glucose utilization which relates to the increase in the alpha-MTrp uptake in the ipsilateral lateral temporal lobe. CONCLUSION This study demonstrates dysfunction of the serotonergic system, which could include metabolism through the kynurenine pathway in TLE patients with normal hippocampal volumes. alpha-MTrp PET studies might be useful for lateralizing the epileptic focus in TLE patients with normal hippocampal volumes.
Down-Regulation of Circadian Clock Gene Period 2 in Uterine Endometrial Stromal Cells of Pregnant Rats During Decidualization

Circadian rhythms are modulated in a variety of peripheral tissues, including in the uterus where endometrial stromal cells (UESCs) undergo proliferation and differentiation (decidualization) during gestation. Here the authors focused on circadian rhythms in UESCs during implantation and decidualization in rodents. As revealed by analyses of cultured UESCs from pregnant Per2 promoter–dLuc transgenic rats, Per2 oscillation of ∼24 h was observed in response to dexamethasone. Per2 oscillation was enhanced in UESCs during implantation, whereas they were attenuated during decidualization. In vivo studies showed that PER2 protein in the uteri displayed a peak at zeitberger time 4 (ZT 4) (day 4.50 of gestation) and a trough at ZT 12 (day 4.83), indicating its circadian rhythmicity. Conversely, no significant circadian rhythm of the PER2 protein was observed during decidualization. Fluorescent immunohistochemical studies also supported circadian rhythmicity of the PER2 protein in its intracellular distribution. In accordance with Per2 mRNA expression, a circadian rhythm of vascular endothelial growth factor (Vegf) gene expression, having several E-box or E-box–like sites at the upstream of the transcription start site, was observed during implantation, showing a peak at ZT 0 and a trough at ZT 12. In contrast, Vegf mRNA expression displayed no circadian rhythm during decidualization. Collectively, the present results prove that Per2 oscillation is down-regulated in UESCs during decidualization. It is strongly suggested that cellular differentiation in UESCs interferes with circadian clockwork. (Author correspondence: mhattori@agr.kyushu-u.ac.jp)
The role of 'paraoxonase-1 activity' as an antioxidant in coronary artery diseases.

BACKGROUND AND OBJECTIVES A majority of the Coronary Artery Diseases (CAD) result from complications of atherosclerosis. There is a growing body of evidence which has revealed that the reduced activity of the HDL-associated enzyme, paraoxonase1 (PON1), is predictive of vascular disease in humans, which include the results from prospective studies. The mechanisms by which PON1 activity influences risk of vascular disease continue to be evaluated. It is generally thought that PON1 contributes to the antioxidant, and thus, to the antiatherogenic properties of High Density Lipoproteins (HDL). Depleted antioxidant levels could be a risk factor for coronary artery disease. Hence, this study was done to evaluate PON1, as antioxidant, in CAD patients. METHODS This study was done to determine serum levels of PON1 activity in 50 controls and in 60 clinically and ECG proven CAD cases and to compare PON1 activity with total cholesterol and triglycerides. RESULTS Serum levels of PON1 activity (p<0.001) were significantly lower in CAD cases than in controls. Serum total cholesterol (p< 0.001) and triglyceride (p< 0.001) levels were significantly higher in CAD cases than in controls. There was a negative correlation between PON 1 activity and total cholesterol and triglycerides. The negative correlation between PON1 activity and total cholesterol was significant (p<0.05). INTERPRETATION AND CONCLUSION From our present study, we can conclude that PON1 can exert a protective effect on HDL by preventing its oxidative damage. Further, a decreased PON 1 activity may be a risk factor for CAD, which is likely to be explained by derangement of PON 1 activity towards lipid peroxidation. This study suggested that serum antioxidant activity of PON1 was an important factor which provided protection from oxidative stress and lipid peroxidation in CAD. Thus, evaluating the effects of PON 1 for CAD patients may be promising in the treatment and prognosis of CAD.
Comparative Effectiveness of Initial Antiretroviral Therapy Regimens: ACTG 5095 and 5142 Clinical Trials Relative to ART-CC Cohort Study

BackgroundThe generalizability of antiretroviral therapy (ART) clinical trial efficacy findings to routine care settings is not well studied. We compared the relative effectiveness of initial ART regimens estimated in AIDS Clinical Trial Group (ACTG) randomized controlled trials with that among patients receiving ART at Antiretroviral Therapy Cohort Collaboration (ART-CC) study sites. MethodsTreatment-naive HIV-infected patients initiating identical ART regimens in ACTG trials (A5095 and A5142) and at 15 ART-CC cohort study sites were included. Virological failure (HIV-1 RNA >200 copies/mL) at 24 and 48 weeks, incident AIDS-defining events and mortality were measured according to study design (ART-CC cohort vs. ACTG trial) and stratified by third drug [abacavir (ABC), efavirenz (EFV), and lopinavir/r (LPV/r)]. We used logistic regression to estimate and compare odds ratios (OR) for virological failure between different regimens and study designs, and used Cox models to estimate and compare hazard ratios for AIDS and death. ResultsCompared with patients receiving ABC, those receiving EFV had roughly half the odds of 24-week virologic failure (>200 copies/mL) in both ACTG 5095 (OR = 0.53, 95% confidence interval: 0.36 to 0.79) and ART-CC (0.46, 0.37 to 0.57). Virologic superiority of EFV (vs. ABC) seemed comparable in ART-CC and ACTG 5095 (ratio of ORs 0.86, 95% confidence interval: 0.54 to 1.35). Odds ratios for 48-week virologic failure, comparing EFV with LPV/r, were also comparable in ACTG 5142 and ART-CC (ratio of ORs: 0.87, 0.45 to 1.69). ConclusionsBetween ART regimen virologic efficacy of third drugs ABC, EFV, and LPV/r observed in the ACTG 5095 and 5142 trials seem generalizable to the routine care setting of ART-CC clinical cohorts.
A Comparison between Unitary and Non-Unitary Precoder Design for MIMO Channels with MMSE Detection and Limited Feedback

This work studies the design of linear precoder codebooks for NxM MIMO channels with MMSE detection at the receiver. A natural split of precoder-design is unitary precoding and non-unitary precoding. Unitary precoding is only performing rotation of the data in a way beneficial for the channel. Non-unitary precoding additionally also uses power-loading to further improve the performance. Somewhat surprisingly, unitary precoding facilitates a performance boosting by a re-enumeration of the antenna elements at the receiver side that can not be accomodated in the non-unitary precoding setting. This operation leads to substantial performance gains. The question investigated in this paper is whether this re-enumeration can compensate for the lack of power-loading. The outcome is that for small precoder codebooks, unitary precoding performs as good as non-unitary, while for larger codebooks non-unitary precoding outperforms unitary precoding.
Randomized phase II study of pulse erlotinib before or after carboplatin and paclitaxel in current or former smokers with advanced non-small-cell lung cancer.

PURPOSE A prior study demonstrated that addition of continuous daily erlotinib fails to improve response rate or survival in non-small-cell lung cancer (NSCLC) patients treated with carboplatin and paclitaxel. However, preclinical data support the hypothesis that intermittent administration of erlotinib before or after chemotherapy may improve efficacy. We tested this hypothesis in patients with advanced NSCLC. PATIENTS AND METHODS Eligible patients were former or current smokers with chemotherapy-naive stage IIIB or IV NSCLC. All patients received up to six cycles of carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)), with random assignment to one of the following three erlotinib treatments: erlotinib 150 mg on days 1 and 2 with chemotherapy on day 3 (150 PRE); erlotinib 1,500 mg on days 1 and 2 with chemotherapy on day 3 (1,500 PRE); or chemotherapy on day 1 with erlotinib 1,500 mg on days 2 and 3 (1,500 POST). The primary end point was response rate. RESULTS Eighty-six patients received treatment. The response rates for the 150 PRE, 1,500 PRE, and 1,500 POST arms were 18% (five of 28 patients), 34% (10 of 29 patients), and 28% (eight of 29 patients), respectively. The median overall survival times were 10, 15, and 10 months for the 150 PRE, 1,500 PRE, and 1,500 POST arms, respectively. The most common grade 3 and 4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3 and 4 rash and diarrhea were uncommon. CONCLUSION Patients treated on the 1,500 PRE arm had the highest response rate and longest survival, with ranges similar to those reported for carboplatin, paclitaxel, and bevacizumab in a more restricted population. Further evaluation of this strategy in a phase III trial is proposed.
Characterization setup for device level dynamic load modulation measurements

A dynamic load modulation characterization method is presented. The method gives insight into the device operation under dynamic load modulation conditions. The presented method is based on an active injection load-pull system. The load impedance is dynamically controlled to follow an optimum trajectory, resulting in higher efficiency in back-off operation. On-wafer measurements at 2.14 GHz using a LDMOS device are used to demonstrate the method. The measured results show excellent agreement between static characterization and dynamic measurements.
Skin Biopsy for Diagnosis of Ullrich Congenital Muscular Dystrophy: An Observational Study

The gold standard diagnostic test for Ullrich congenital muscular dystrophy (UCMD) is molecular testing for COL6 mutation. The facility for genetic testing is sparingly available and it is usually diagnosed by muscle biopsy. The latter is an invasive procedure requiring expertise and sedation. Skin biopsy has shown promise as a simpler diagnostic modality. Eleven and 7 cases, respectively, of phenotypically suspected Ullrich congenital muscular dystrophy and dystrophinopathy underwent simultaneous skin and muscle biopsies, which were subjected to hematoxylin and eosin (H&E) and immunohistochemistry staining for collagen VI and dystrophin 1, 2, and 3. Of the 8 and 5 muscle biopsy–confirmed cases of Ullrich congenital muscular dystrophy and dystrophinopathy, 6 Ullrich congenital muscular dystrophy and 5 dystrophinopathy cases showed absent and preserved COL6 staining, respectively, in the skin biopsy. Skin biopsy as a diagnostic option has shown encouraging results in Ullrich congenital muscular dystrophy. These should be evaluated in larger studies.
The good in evil: a discourse analysis of the galamsey industry in Ghana

Abstract Galamsey, a low-tech, labour-intensive, small-scale mining activity in Ghana, has recently come under intense criticism and state policing despite being an important livelihood source. Based on empirical research, this paper uses discourse analysis to re-examine galamsey politics in Ghana, focusing on why people are engaged in galamsey despite attempts to curtail it. Findings suggest that for most individuals and communities, poverty, displacement from agricultural lands and unemployment explain their initial entry into the industry. However, the legal, regulatory and policing regimes, together with complex, ambivalent relationships between government, large-scale mining companies, traditional authorities and galamsey operators, all help to perpetuate galamsey. These findings provide a counter-narrative to the dominant discourse of opportunism and demonisation which often characterises public discussions on Ghana’s galamsey industry. Rather than the combative approach taken by the state towards the galamsey phenomenon, urgent legislative and policy reforms are needed in order to streamline the licensing regime and address the drivers of galamsey.
Rhabdomyosarcoma of the Urinary Bladder in Adults: Predilection for Alveolar Morphology With Anaplasia and Significant Morphologic Overlap With Small Cell Carcinoma

Rhabdomyosarcoma (RMS) represents the most common malignant soft tissue tumor in children and adolescents with the urinary bladder representing a frequent site. Most of these urinary bladder tumors are embryonal RMS, predominantly the botryoid subtype. RMSs of the urinary bladder in adults are distinctively rare and the subject of only case reports. We report the clinicopathologic features of 5 bladder neoplasms with rhabdomyosarcomatous differentiation in adults and emphasize the differential diagnosis in the adult setting. The patients, 4 men and 1 woman, ranged in age from 23 to 85 years (mean 65.4 y). Gross hematuria was the most common initial symptom, although 2 patients had metastatic disease at presentation. Four cases were pure primary RMSs of the bladder and 1 case was a sarcomatoid urothelial carcinoma with RMS representing the extensive heterologous component. All 5 cases demonstrated a diffuse growth pattern (ie, non-nested), of which 4 cases had nuclear anaplasia (Wilms criteria without the atypical mitotic figure requirement); only 1 case (the sarcomatoid carcinoma) showed obvious rhabdomyoblastic differentiation (ie, strap cells). Three cases were of the alveolar subtype (1 admixed with embryonal histology) and 2 were RMS, not further classified. Microscopically, all tumors had a primitive undifferentiated morphology with cells containing scant cytoplasm, varying round to fusiform nuclei with even chromatin distribution, and frequent mitoses. The degree of morphologic overlap with small cell carcinoma of the bladder, a relatively more common round cell tumor in adults, was striking. The epithelial component of the sarcomatoid carcinoma was high-grade invasive urothelial carcinoma with glandular differentiation. No other case had previous history of bladder cancer or concurrent carcinoma in situ or invasive urothelial carcinoma. All tumors showed immunohistochemical expression for desmin, myogenin, and/or MyoD1. Synaptophysin was performed in 4 cases, and 3 showed weak cytoplasmic immunoreactivity. Two patients received chemotherapy, 2 underwent cystectomy, and 1 had transurethral resection alone. Outcome data were available in 4 cases, and all 4 died of disease (1, 4, 8, and 8 mo). In conclusion, (1) RMS of the urinary bladder in adults more commonly presents as a primitive round blue cell neoplasm that has significant morphologic and immunohistochemical overlap with small cell carcinoma of the bladder. (2) Although RMS in children generally have a botryoid embryonal histology with favorable outcome, bladder RMS in adults frequently demonstrates alveolar or unclassified histology, commonly with anaplasia, and have a uniformly aggressive clinical course.