Miracle-dz/UniFAR-FTUs huggingface dataset:
Prediction of radiation doses from therapy using tracer studies with iodine-131-labeled antibodies.

UNLABELLED Tracer pharmacokinetic studies are often used in treatment planning for radionuclide therapy including radioimmunotherapy. This study evaluates the validity of using tracer studies to predict radiation doses from therapy with the same radiolabeled antibody. METHODS Quantitative imaging and blood radioactivity were used to obtain the pharmacokinetics and radiation doses that were delivered to the total body, blood, marrow, lungs, liver, kidneys, thyroid, spleen and tumors. Tracer and therapy data for eight patients with lymphoma and one patient with breast cancer were compared using linear regression statistics. Doses of 131I-labeled antibody for the tracer studies ranged from 0.1 to 0.4 GBq (2 to 10 mCi), and therapy doses ranged from 0.7 to 5.6 GBq (20 to 150 mCi). RESULTS Radiation doses to tissues and, in particular, the bone marrow and tumors were reliably predicted from tracer studies. In this group of patients, median dose to marrow from marrow targeting, total body and blood was 9.2 cGy/GBq for tracer studies and 7.6 cGy/GBq for therapy studies with a median difference of 0.5 cGy/GBq. Median dose to tumors was 81.1 cGy/GBq for tracer studies and 70.3 cGy/GBq for therapy studies with a median difference of 5.9 cGy/GBq. CONCLUSION In these patients, tracer studies were predictive of the radiation doses from therapy for total body, major organs and tumors. The radiation doses to marrow and tumors, which are the usual determinants of the therapeutic index, correlated well between tracer and therapy studies (r > or = 0.95).
Early Whole Blood Transcriptional Signatures Are Associated with Severity of Lung Inflammation in Cynomolgus Macaques with Mycobacterium tuberculosis Infection

Whole blood transcriptional profiling offers great diagnostic and prognostic potential. Although studies identified signatures for pulmonary tuberculosis (TB) and transcripts that predict the risk for developing active TB in humans, the early transcriptional changes immediately following Mycobacterium tuberculosis infection have not been evaluated. We evaluated the gene expression changes in the cynomolgus macaque model of TB, which recapitulates all clinical aspects of human M. tuberculosis infection, using a human microarray and analytics platform. We performed genome-wide blood transcriptional analysis on 38 macaques at 11 postinfection time points during the first 6 mo of M. tuberculosis infection. Of 6371 differentially expressed transcripts between preinfection and postinfection, the greatest change in transcriptional activity occurred 20–56 d postinfection, during which fluctuation of innate and adaptive immune response–related transcripts was observed. Modest transcriptional differences between active TB and latent infection were observed over the time course with substantial overlap. The pattern of module activity previously published for human active TB was similar in macaques with active disease. Blood transcript activity was highly correlated with lung inflammation (lung [18F]fluorodeoxyglucose [FDG] avidity) measured by positron emission tomography and computed tomography at early time points postinfection. The differential signatures between animals with high and low lung FDG were stronger than between clinical outcomes. Analysis of preinfection signatures of macaques revealed that IFN signatures could influence eventual clinical outcomes and lung FDG avidity, even before infection. Our data support that transcriptional changes in the macaque model are translatable to human M. tuberculosis infection and offer important insights into early events of M. tuberculosis infection.
Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record.

AIM Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European-Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose. PATIENTS & METHODS We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European-Americans (n = 1022) and African-Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose. RESULTS Associations between variants in VKORC1, CYP2C9 and CYP4F2 with weekly dose were observed in European-Americans as well as additional variants in CYP2C9 and CALU in African-Americans. Compared with traditional 5 mg/day dosing, implementing the US FDA recommendations or the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm reduced error in weekly dose in European-Americans (13.5-12.4 and 9.5 mg/week, respectively) but less so in African-Americans (15.2-15.0 and 13.8 mg/week, respectively). By further incorporating associated variants specific for European-Americans and African-Americans in an expanded algorithm, dose-prediction error reduced to 9.1 mg/week (95% CI: 8.4-9.6) in European-Americans and 12.4 mg/week (95% CI: 10.0-13.2) in African-Americans. The expanded algorithm explained 41 and 53% of dose variation in African-Americans and European-Americans, respectively, compared with 29 and 50%, respectively, for the IWPC algorithm. Implementing these predictions via dispensable pill regimens similarly reduced dosing error. CONCLUSION These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery.
Optimization of Hybrid Silicon Lasers for High-Speed Direct Modulation

We report the optimization of hybrid silicon lasers for high-speed direct modulations by studying the small- and large-signal modulation responses based on the simple carrier transport model in this paper. The theoretical model matches well with published experimental data as the same structure parameters are used. To investigate the strong heating effect in hybrid lasers, we apply all of the carrier diffusion/capture and thermionic escape lifetimes to be temperature dependent in simulations. The frequency response of the small-signal analysis shows that the modulation bandwidth is much more sensitive to the temperature and the separate confinement heterostructure (SCH) thickness compared with the other limiting factors, such as the confinement factor, the interlayer thickness, etc. The largest modulation bandwidth decreases from 6.2 to 2.2 GHz under an injection current of 100 mA and an SCH thickness of 80 nm when the temperature rises from 300 to 350 K. The modulation speed will be greatly improved with a thinner SCH layer, particularly the p-type SCH layer, which helps shorten the diffusion lifetime. Furthermore, eye diagrams are also calculated under different bit rates, SCH thicknesses, and temperatures, respectively. With the increase of the temperature or SCH thickness, the quality of eye diagrams becomes worse. It shows that the modulation frequency can reach 10 Gb/s. We believe that this paper can serve as a guideline for the optimization of next-generation high-speed modulated hybrid silicon lasers.
A three‐dimensional model of aromatase cytochrome P450

P450 hemeproteins comprise a large gene superfamily that catalyzes monooxygenase reactions in the presence of a redox partner. Because the mammalian members are, without exception, membrane‐bound proteins, they have resisted structure‐function analysis by means of X‐ray crystallographic methods. Among P450‐catalyzed reactions, the aromatase reaction that catalyzes the conversion of C19 steroids to estrogens is one of the most complex and least understood. Thus, to better understand the reaction mechanism, we have constructed a three‐dimensional model of P450arom not only to examine the active site and those residues potentially involved in catalysis, but to study other important structural features such as substrate recognition and redox‐partner binding, which require examination of the entire molecule (excepting the putative membrane‐spanning region). This model of P450arom was built based on a “core structure” identified from the structures of the soluble, bacterial P450s (P450cam, P450terp, and P450BM‐P) rather than by molecular replacement, after which the less conserved elements and loops were added in a rational fashion. Minimization and dynamic simulations were used to optimize the model and the reasonableness of the structure was evaluated. From this model we have postulated a membrane‐associated hydrophobic region of aliphatic and aromatic residues involved in substrate recognition, a redoxpartner binding region that may be unique compared to other P450s, as well as residues involved in active site orientation of substrates and an inhibitor of P450arom, namely vorozole. We also have proposed a scheme for the reaction mechanism in which a “threonine switch” determines whether oxygen insertion into the substrate molecule involves an oxygen radical or a peroxide intermediate.
Chronic Ureteral Obstruction in the Rat Suppresses Renal Tubular Bcl-2 and Stimulates Apoptosis

Unilateral ureteral obstruction (UUO) results in widespread tubular apoptosis in obstructed kidneys of both adults and neonates. The oncoprotein bcl-2 inhibits many forms of apoptosis, whereas the related protein bax promotes apoptosis. To evaluate the interaction of bcl-2, bax, and apoptosis in the renal response to UUO, adult and neonatal rats were subjected to UUO or sham operation, and kidneys were harvested 14 days later. Apoptotic cells were identified by the Tunel technique, and the distribution of bcl-2 and bax was determined by immunochemistry. In both adults and neonates, tubular and interstitial apoptosis was present in the obstructed kidney, but not in intact kidneys. In both adults and neonates, there was diffuse tubular bcl-2 and bax staining of sham-operated and intact kidneys. While bcl-2 was increased in scattered nonapoptotic tubules of the obstructed kidney, there was minimal staining of dilated apoptotic tubules. These results are consistent with the premise that bcl-2 normally suppresses renal tubular apoptosis. The distribution of bax staining in tubules of the obstructed kidney overlapped that of bcl-2. We conclude that chronic UUO inhibits bcl-2 expression in selected tubules of the obstructed kidney which contributes to activation of apoptosis and progressive renal damage in either neonatal or adult kidneys. Dysregulation of apoptosis may be a response to renal injury similar to that underlying the development of cystic kidney disease or renal dysplasia.
Possible role of liver cytosolic and mitochondrial aldehyde dehydrogenases in acetaldehyde metabolism.

To provide a molecular basis for understanding the possible mechanism of action of antidipsotropic agents in laboratory animals, aldehyde dehydrogenase (ALDH) isozymes were purified and characterized from the livers of hamsters and rats and compared with those from humans. The mitochondrial ALDHs from these species exhibit virtually identical kinetic properties in the oxidation and hydrolysis reactions. However, the cytosolic ALDH of human origin differs significantly from those of the rodents. Thus, for human ALDH-1, the Km value for acetaldehyde is 180 +/- 10 micromolar, whereas those for hamster ALDH-1 and rat ALDH-1 are 12 +/- 3 and 15 +/- 3 micromolar, respectively. Km values determined at pH 9.5 are virtually identical to those measured at pH 7.5. In vitro human ALDH-1 is 10 times less sensitive to disulfiram inhibition than are the hamster and rat cytosolic ALDHs. Competition between acetaldehyde and aromatic aldehydes or naphthaldehydes for the binding and catalytic sites of ALDHs shows their topography to be complex with more than one binding site. This also follows from data on substrate inhibition and activation, effects of NAD+ on ALDH-catalyzed hydrolysis of p-nitrophenyl esters, substrate specificity toward aldehydes and p-nitrophenyl esters, and inhibition by disulfiram in relation to oxidation and hydrolysis catalyzed by the ALDHs. The data further suggest that acetaldehyde cannot be considered as a "standard" ALDH substrate for studies aimed at aromatic ALDH substrates, e.g. biogenic aldehydes. Apparently, in human liver, only mitochondrial ALDH oxidizes acetaldehyde at physiological concentrations, whereas in hamster or rat liver, both the mitochondrial and cytosolic isozymes will do so.
Bundling actin filaments from membranes: some novel players

Progress in live-cell imaging of the cytoskeleton has significantly extended our knowledge about the organization and dynamics of actin filaments near the plasma membrane of plant cells. Noticeably, two populations of filamentous structures can be distinguished. On the one hand, fine actin filaments which exhibit an extremely dynamic behavior basically characterized by fast polymerization and prolific severing events, a process referred to as actin stochastic dynamics. On the other hand, thick actin bundles which are composed of several filaments and which are comparatively more stable although they constantly remodel as well. There is evidence that the actin cytoskeleton plays critical roles in trafficking and signaling at both the cell cortex and organelle periphery but the exact contribution of actin bundles remains unclear. A common view is that actin bundles provide the long-distance tracks used by myosin motors to deliver their cargo to growing regions and accordingly play a particularly important role in cell polarization. However, several studies support that actin bundles are more than simple passive highways and display multiple and dynamic roles in the regulation of many processes, such as cell elongation, polar auxin transport, stomatal and chloroplast movement, and defense against pathogens. The list of identified plant actin-bundling proteins is ever expanding, supporting that plant cells shape structurally and functionally different actin bundles. Here I review the most recently characterized actin-bundling proteins, with a particular focus on those potentially relevant to membrane trafficking and/or signaling.
Histopathologic Basis for the Favorable Survival after Resection of Intraductal Papillary Mucinous Neoplasm-Associated Invasive Adenocarcinoma of the Pancreas

Objective:To identify pathologic features that may account for the favorable survival after resection of invasive pancreatic adenocarcinoma arising in the setting of intraductal papillary mucinous neoplasm (IPMN) compared with standard pancreatic ductal adenocarcinoma (PDA) in the absence of IPMN. Summary Background Data:The 5-year survival after resection of IPMN-associated invasive adenocarcinoma is reported to be between 40% and 60%, which is superior to the 10–25%, typically cited after resection of standard PDA. It remains unclear whether this represents distinct biology or simply a tendency for earlier presentation of IPMN-associated invasive adenocarcinoma. Methods:A single institution's prospective pancreatic resection database was retrospectively reviewed to identify patients with invasive pancreatic adenocarcinoma who underwent pancreatectomy with curative intent. Log rank and Cox regression analysis were used to identify factors associated with survival. Results:From 1995 to 2006, 1260 consecutive patients were identified, 132 (10%) with IPMN-associated invasive adenocarcinoma and 1128 (90%) with standard PDA. Actuarial 5-year survival was 42% after resection for IPMN-associated versus 19% for standard PDA (P < 0.001). However, compared with standard PDA, invasive adenocarcinoma arising within an IPMN was associated with a lower incidence of (1) advanced T stage (T2–T4, 96% vs. 73%, P < 0.001); (2) regional lymph node metastasis (78% vs. 51%, P < 0.001); (3) poor tumor differentiation (44% vs. 26%, P < 0.001); (4) vascular invasion (54% vs. 33%, P < 0.001); (5) perineural invasion (92% vs. 63%, P < 0.001); and (6) microscopic margin involvement (28% vs. 14%, P < 0.001). Specifically, in the presence of any one of the aforementioned adverse pathologic characteristics, outcomes after resection for IPMN-associated and standard PDA were not significantly different. Conclusion:The favorable biologic behavior of IPMN-associated compared with standard PDA is based on its lower rate of advanced T stage, lymph node metastasis, high tumor grade, positive resection margin, perineural, and vascular invasion. In the presence of any one of the aforementioned adverse pathologic characteristics, however, survival outcomes after resection of IPMN-associated and after resection of standard pancreatic adenocarcinoma are similar.
Repression of Activator Protein-1-mediated Transcriptional Activation by the Notch-1 Intracellular Domain*

Developmental decisions that control cell fate are commonly regulated by the Notch signaling pathway. Activation of transmembrane Notch receptors results in proteolytic liberation of the intracellular domain of Notch, which translocates into the nucleus, binds a repressor (C promoter binding factor 1/RBP-Jκ, Su(H), and Lag-1 (CSL)), and induces target genes. We found that the intracellular domain of human Notch-1 (NIC-1) represses activator protein-1 (AP-1)-mediated transactivation. Because numerous genes that control immune and inflammatory responses are AP-1-dependent and Notch regulates immune cell function, we investigated the underlying molecular mechanisms. Repression of AP-1 by NIC-1 did not represent a general inhibitory effect on transcription because nuclear factor κB-dependent transcription and transcription driven by a constitutive promoter and enhancer were not affected by NIC-1. The physiological relevance of the repression was supported by the facts that repression was apparent in multiple cell lines, endogenous AP-1 target genes were repressed, and similar concentrations of NIC-1 were required for CSL-dependent activation and AP-1 repression. The RBP-Jκ-associated molecule domain of NIC-1 that mediates CSL binding and distinct sequences necessary for transactivation were required for repression. However, there was not a strict correlation between the sequence requirements for CSL-dependent activation and AP-1 repression. Repression correlated with predominant nuclear localization of NIC-1 and was not accompanied by disruption of c-Jun amino-terminal kinase-dependent signaling events required for AP-1 activation or by defective AP-1 DNA binding activity. These results provide evidence for negative cross-talk between Notch and AP-1, which may have important consequences for controlling diverse biological processes.
Caught in the Net

There are many frightening things that cross my computer desktop via the Internet. Most come via e-mail: pernicious viruses with the capacity to cripple my computer, requests for letters of recommendation from students who took a class from me so long ago that I no longer have any clear idea who they are, notes from production editors at American Entomologist wondering when the column that was due two months ago will be arriving, and many more too horrible even to mention. But there is one kind of e-mail message that I often receive that doesn’t frighten me—the kind that starts with the words “This is a true story! ” or words to that effect. Almost invariably, such notes contain what is called an urban legend. According to Jan Brunvand (1981), ac
Promyelocytic Leukemia Protein Modulates Establishment and Maintenance of Latent Gammaherpesvirus Infection in Peritoneal Cells

ABSTRACT Promyelocytic leukemia protein (PML) is an essential organizer of PML nuclear bodies (NBs), which carry out a variety of activities, including antiviral functions. Herpesviruses from all subfamilies encode proteins that counteract PML NB-mediated antiviral defenses by multiple mechanisms. However, because of the species specificity of herpesviruses, only a limited number of in vivo studies have been undertaken to investigate the effect of PML or PML NBs on herpesvirus infection. To address this central issue in herpesvirus biology, we studied the course of infection in wild-type and PML −/− mice using murine gammaherpesvirus 68 (MHV68), which encodes a tegument protein that induces PML degradation. While acute infection in PML −/− mice progressed similarly to that in wild-type mice, the lytic reactivation frequency was higher in peritoneal exudate cells, due to both an increase of MHV68 genome-positive cells and greater reactivation efficiency. We also detected a higher frequency of persistent infection in PML −/− peritoneal cells. These findings suggest that the PML protein can repress the establishment or maintenance of gammaherpesvirus latency in vivo. Further use of the PML −/− mouse model should aid in dissecting the molecular mechanisms that underlie the role of PML in gammaherpesvirus latency and may yield clues for how PML modulates herpesvirus latency in general.
Creating Values through Corporate Venture Capital Programs: The Choice between Internal and External Fund Structures

1. Paul Asel 1. is a managing partner at Nokia Growth Partners in Sunnyvale, CA. (paul.asel{at}nokiagrowthpartners.com) 2. Haemin Dennis Park 1. is an assistant professor at the LeBow College of Business at Drexel University in Philadelphia, PA. (parkhd{at}drexel.edu) 3. S.
Doppler Echocardiographic Assessment of Left Ventricular Diastolic Function in Patients with Primary Lung Cancer Treated with Doxorubicin

Eighteen patients were examined by Doppler echocardiography before and after treatment with doxorubicin (DXR). Early left ventricular filling rate decreased from 66±15 to 51±10 cm/sec whereas late filling rate increased from 48±12 to 61±9 cm/sec (p < 0.05) with inversion of the E/A ratio suggesting an impairment of left ventricular diastolic function; conversely no significant changes were found in systolic function indexes. These results suggest that follow-up of patients treated with DXR must include left ventricular diastolic function studies. Doppler echocardiography can be successfully used to detect the presence of diastolic abnormalities.
Differences in cardiovascular risk factors in rural, urban and rural-to-urban migrants in Peru

Objectives To assess differences in cardiovascular risk profiles among rural-to-urban migrants and non-migrant groups. Methods Cross-sectional study in Ayacucho and Lima, Peru. Participants were: rural (n=201); rural-to-urban migrants (n=589); and urban (n=199). Cardiovascular risk factors were assessed according to migrant status (migrants vs non-migrants), age at first migration, length of residency in an urban area and lifetime exposure to an urban area. Results For most risk factors, the migrant group had intermediate levels of risk between those observed for the rural and urban groups. Prevalence for rural, migrant and urban groups was 3%, 20% and 33%, respectively, for obesity, and 0.8%, 3% and 6% for type-2 diabetes. This gradient of risk was not observed uniformly across all risk factors. Blood pressure did not show a clear gradient of difference between groups. The migrant group had similar systolic blood pressure but lower diastolic blood pressure than the rural group. The urban group had higher systolic blood pressure but similar diastolic blood pressure than rural group. Hypertension was more prevalent among the urban (29%) than both the rural and migrant groups (11% and 16%, respectively). For HbA1c, although the urban group had higher levels, the migrant and rural groups were similar to each other. No differences were observed in triglycerides between the three groups. Within migrants, those who migrated when aged older than 12 years had higher odds of diabetes, impaired fasting glucose and metabolic syndrome compared to people who migrated at younger ages. Adjustment for age, sex and socioeconomic indicators had little impact on the patterns observed. Conclusions The impact of rural-to-urban migration on cardiovascular risk profile is not uniform across different risk factors, and is further influenced by the age at which migration occurs. A gradient in levels was observed for some risk factors across study groups. This observation indicates that urbanisation is indeed detrimental to cardiovascular health.