RNA splicing, the spliceosome-catalyzed process by which pre-messenger RNA (pre-mRNA) is processed to mature mRNA, is altered in a number of ways in cancer. Tumor-specific splicing alterations are created by mutations that disrupt splicing-regulatory elements within genes and impair splicing recognition or by altering the RNA-binding preferences of individual splicing factors. This SnapShot summarizes our current understanding of splicing-factor alterations in cancers. To view this SnapShot, open or download the PDF.

We present two novel methods to predict native protein-ligand binding positions. Both methods identify the native binding position as the most probable position corresponding to a maximum of a probability distribution function (PDF) of possible binding positions in a protein active site. Possible binding positions are the origins of clusters composed, on the basis of root-mean square deviations (RMSD), from the multiple ligand positions determined by a docking algorithm. The difference between the methods lies in the ways the PDF is derived. To validate the suggested methods, we compare the averaged RMSD of the predicted ligand docked positions relative to the experimentally determined positions for a set of 135 PDB protein-ligand complexes. We demonstrate that the suggested methods improve docking accuracy by as much as 21-24% in comparison with a method that simply identifies the binding position as the energy top-scored ligand position.

BACKGROUND

Various information technologies currently are used to improve the efficiency of clinical trials. However, electronic medical records (EMRs) are not yet linked to the electronic data capture (EDC) system. Therefore, the data must be extracted from medical records and transcribed to the EDC system. Clinical pathways are planned process patterns that are used in routine clinical practice and are easily applicable to the medical care and evaluation defined in a trial protocol. However, few clinical pathways are intended to increase the efficiency of clinical trials.

OBJECTIVE

Our purpose is to describe the design and development of a new clinical trial process model that enables the primary use of EMRs in clinical trials by integrating clinical pathways and EMRs.

METHODS

We designed a new clinical trial model that uses EMR data directly in clinical trials and developed a system to follow this model. We applied the system to an investigator-initiated clinical trial and examined whether all data were extracted correctly. At the protocol development stage, our model measures endpoints based on clinical pathways with the same diagnosis. Next, medical record descriptions and the format of the statistical data are defined. According to these observations, screens for entry of data, which are used both in clinical practice and for study, are prepared into EMRs with an EMR template, and screens are prepared for data checks on our EMR retrieval system (ERS). In an actual trial, patients are registered and randomly assigned to a protocol treatment. The protocol treatment is executed according to clinical pathways, and the data are recorded to EMRs using EMR templates. The data are checked by a local data manager using reports created by the ERS. After edit checks and corrections, the data are extracted by the ERS, archived in portable document format (PDF) with an electronic signature, and transferred in comma-separated values (CSV) format to a coordinating centre. At the coordinating centre, the data are checked, integrated, and made available for a statistical analysis.

RESULTS

We verified that the data could be extracted correctly and found no unexpected problems.

CONCLUSIONS

To execute clinical trials in our system, the EMR template and efficient ERSs are required. Additionally, to execute multi-institutional clinical trials, it is necessary to create templates appropriate for EMRs at all participating sites and for the coordinating centre to validate local templates and procedures.

CONCLUSIONS

We proposed and pilot tested a new eClinical trial model. Because our model is integrated with routine documentation of clinical practice and clinical trials, redundant data entries were avoided and the burden on the investigator was minimised. The reengineering of the clinical trial process would facilitate the establishment of evidence in the future.

Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster CLOCK (CLK) and CYCLE (CYC) initiates the circadian system by promoting rhythmic transcription of hundreds of genes. However, it is still not clear whether high amplitude transcriptional oscillations are essential for circadian timekeeping. In order to address this issue, we generated flies in which the amplitude of CLK-driven transcription can be reduced partially (approx. 60%) or strongly (90%) without affecting the average levels of CLK-target genes. The impaired transcriptional oscillations lead to low amplitude protein oscillations that were not sufficient to drive outputs of peripheral oscillators. However, circadian rhythms in locomotor activity were resistant to partial reduction in transcriptional and protein oscillations. We found that the resilience of the brain oscillator is depending on the neuronal communication among circadian neurons in the brain. Indeed, the capacity of the brain oscillator to overcome low amplitude transcriptional oscillations depends on the action of the neuropeptide PDF and on the pdf-expressing cells having equal or higher amplitude of molecular rhythms than the rest of the circadian neuronal groups in the fly brain. Therefore, our work reveals the importance of high amplitude transcriptional oscillations for cell-autonomous circadian timekeeping. Moreover, we demonstrate that the circadian neuronal network is an essential buffering system that protects against changes in circadian transcription in the brain.

The aim of the study was to determine whether the treatment outcome differs for males and females in the mixed-gender methadone maintenance program. A prospective non-randomized study was performed to evaluate the efficiency of the treatment over a period of 6 months. In this study, 91 patients (60 male and 31 female) were included and the groups were compared by the variables such as relapses, frequency of relapses, type of substance used and the manner of drug use. The results showed that 16 (51.6%) female addicts had 147 relapses and 23 (38.3%) male addicts had 118 relapses, but these differences were statistically not significant. Women made a significant relapse 43.7% more than men 21.7%, with heroine alone. The injectable drug abuse dominates in both genders, i.e. 56.2% of female examinees and 69.6% of male examinees injected the drugs, but this difference was not statistically proven.

CONCLUSIONS

Gender has an influence on the response to the treatment. The outcome of the treatment measured through the drug use differs in the substance used. Women use more heroine than men, who in turn use more combinations of different drugs and legal psychoactive substances during the treatment (Tab. 7, Ref. 31). Full Text (Free, PDF) www.bmj.sk.

We describe a novel neuroinformatic platform, the BAMS2 Workspace (http://brancusi1.usc.edu), designed for storing and processing information on gray matter region axonal connections. This de novo constructed module allows registered users to collate their data directly by using a simple and versatile visual interface. It also allows construction and analysis of sets of connections associated with gray matter region nomenclatures from any designated species. The Workspace includes a set of tools allowing the display of data in matrix and networks formats and the uploading of processed information in visual, PDF, CSV, and Excel formats. Finally, the Workspace can be accessed anonymously by third-party systems to create individualized connectivity networks. All features of the BAMS2 Workspace are described in detail and are demonstrated with connectivity reports collated in BAMS and associated with the rat sensory-motor cortex, medial frontal cortex, and amygdalar regions.

In the Visible Korean project, 642 three-dimensional (3D) surface models have been built from the sectioned images of a male cadaver. It was recently discovered that popular PDF file enables users to approach the numerous surface models conveniently on Adobe Reader. Purpose of this study was to present a PDF file including systematized surface models of human body as the beneficial contents. To achieve the purpose, fitting software packages were employed in accordance with the procedures. Two-dimensional (2D) surface models including the original sectioned images were embedded into the 3D surface models. The surface models were categorized into systems and then groups. The adjusted surface models were inserted to a PDF file, where relevant multimedia data were added. The finalized PDF file containing comprehensive data of a whole body could be explored in varying manners. The PDF file, downloadable freely from the homepage (http://anatomy.co.kr), is expected to be used as a satisfactory self-learning tool of anatomy. Raw data of the surface models can be extracted from the PDF file and employed for various simulations for clinical practice. The technique to organize the surface models will be applied to manufacture of other PDF files containing various multimedia contents.

OBJECTIVE

The Portable Document Format (PDF) is the de-facto standard for the exchange of electronic documents. It is platform-independent, suitable for the exchange of medical data, and allows for the embedding of three-dimensional (3D) surface mesh models. In this article, we present the first clinical routine application of interactive 3D surface mesh models which have been integrated into PDF files for the presentation and the exchange of Computer Assisted Surgery Planning (CASP) results in liver surgery. We aimed to prove the feasibility of applying 3D PDF in medical reporting and investigated the user experience with this new technology.

METHODS

We developed an interactive 3D PDF report document format and implemented a software tool to create these reports automatically. After more than 1000 liver CASP cases that have been reported in clinical routine using our 3D PDF report, an international user survey was carried out online to evaluate the user experience.

RESULTS

Our solution enables the user to interactively explore the anatomical configuration and to have different analyses and various resection proposals displayed within a 3D PDF document covering only a single page that acts more like a software application than like a typical PDF file ("PDF App"). The new 3D PDF report offers many advantages over the previous solutions. According to the results of the online survey, the users have assessed the pragmatic quality (functionality, usability, perspicuity, efficiency) as well as the hedonic quality (attractiveness, novelty) very positively.

CONCLUSIONS

The usage of 3D PDF for reporting and sharing CASP results is feasible and well accepted by the target audience. Using interactive PDF with embedded 3D models is an enabler for presenting and exchanging complex medical information in an easy and platform-independent way. Medical staff as well as patients can benefit from the possibilities provided by 3D PDF. Our results open the door for a wider use of this new technology, since the basic idea can and should be applied for many medical disciplines and use cases.

BACKGROUND

Information systems are a key success factor for medical research and healthcare. Currently, most of these systems apply heterogeneous and proprietary data models, which impede data exchange and integrated data analysis for scientific purposes. Due to the complexity of medical terminology, the overall number of medical data models is very high. At present, the vast majority of these models are not available to the scientific community. The objective of the Portal of Medical Data Models (MDM, https://medical-data-models.org) is to foster sharing of medical data models.

METHODS

MDM is a registered European information infrastructure. It provides a multilingual platform for exchange and discussion of data models in medicine, both for medical research and healthcare. The system is developed in collaboration with the University Library of Münster to ensure sustainability. A web front-end enables users to search, view, download and discuss data models. Eleven different export formats are available (ODM, PDF, CDA, CSV, MACRO-XML, REDCap, SQL, SPSS, ADL, R, XLSX). MDM contents were analysed with descriptive statistics.

RESULTS

MDM contains 4387 current versions of data models (in total 10,963 versions). 2475 of these models belong to oncology trials. The most common keyword (n = 3826) is 'Clinical Trial'; most frequent diseases are breast cancer, leukemia, lung and colorectal neoplasms. Most common languages of data elements are English (n = 328,557) and German (n = 68,738). Semantic annotations (UMLS codes) are available for 108,412 data items, 2453 item groups and 35,361 code list items. Overall 335,087 UMLS codes are assigned with 21,847 unique codes. Few UMLS codes are used several thousand times, but there is a long tail of rarely used codes in the frequency distribution.

CONCLUSIONS

Expected benefits of the MDM portal are improved and accelerated design of medical data models by sharing best practice, more standardised data models with semantic annotation and better information exchange between information systems, in particular Electronic Data Capture (EDC) and Electronic Health Records (EHR) systems. Contents of the MDM portal need to be further expanded to reach broad coverage of all relevant medical domains. Database URL: https://medical-data-models.org.

NVP PDF-713 (LBM 415) is a peptide deformylase inhibitor being progressed into clinical trials. Dry-form broth microdilution panels of NVP PDF-713 were compared to reference MIC panels of 552 recent clinical isolates. Most (99.2%) dry-form MIC results were within +/- 1 log(2) dilution of the reference panel MICs. Of the bacteria tested, Streptococcus pneumoniae and Haemophilus influenzae showed a bias towards higher and lower MICs, respectively. Same-day and between-day reproducibility tests showed that 98.9% and 96.7% of MIC values, respectively, were within +/- 1 log(2) dilution step, thereby demonstrating a high degree of reliability of the dry-form MIC product for clinical studies.

Although vaccination of guinea pigs with formalin-inactivated Western equine encephalomyelitis virus rendered them specifically immune to an intracerebral challenge dose of 1,000 M.L.D. of Western virus, it failed to protect their central nervous system against the initial effects of the virus: the intracerebral challenge dose was followed by an abortive infection of 20 to 30 hours' duration characterized by fever and histopathological changes which simulated the response at that early stage of non-vaccinated control animals. During the abortive infection of immune animals, virus could occasionally be demonstrated in their brains; indeed, it was detected with about the same frequency it was isolated from brains of similarly inoculated, non-immune guinea pigs during corresponding early phases of the infection. About one week after the abortive infection there was found a marked transitory accumulation of specific neutralizing antibody in the brain tissue. See PDF for Equation equalled at this time 1:1 to 1:10 instead of the value of about 1:300 found under physiological conditions. Guinea pigs which had recovered from an abortive infection with Western virus were resistant for a limited period of time to the effects of intracerebral inoculations of the immunologically distinct viruses of Eastern equine encephalomyelitis or vesicular stomatitis.

1. When solid blocks of isoelectric gelatin are placed in cold distilled water or dilute buffer of pH 4.7, only those of a gelatin content of more than 10 per cent swell, while those of a lower gelatin content not only do not swell but actually lose water. 2. The final quantity of water lost by blocks of dilute gelatin is the same whether the block is immersed in a large volume of water or whether syneresis has been initiated in the gel through mechanical forces such as shaking, pressure, etc., even in the absence of any outside liquid, thus showing that syneresis is identical with the process of negative swelling of dilute gels when placed in cold water, and may be used as a convenient term for it. 3. Acid- or alkali-containing gels give rise to greater syneresis than isoelectric gels, after the acid or alkali has been removed by dialysis. 4. Salt-containing gels show greater syneresis than salt-free gels of the same pH, after the salt has been washed away. 5. The acid and alkali and also the salt effect on syneresis of gels disappears at a gelatin concentration above 8 per cent. 6. The striking similarity in the behavior of gels with respect to syneresis and of gelatin solutions with respect to viscosity suggests the probability that both are due to the same mechanism, namely the mechanism of hydration of the micellae in gelatin by means of osmosis as brought about either by diffusible ions, as in the presence of acid or alkali, or by the soluble gelatin present in the micellae. The greater the pressures that caused swelling of the micellae while the gelatin was in the sol state, the greater is the loss of water from the gels when the pressures are removed. 7. A quantitative study of the loss of water by dilute gels of various gelatin content shows that the same laws which have been found by Northrop to hold for the swelling of gels of high concentrations apply also to the process of losing water by dilute gels, i.e. to the process of syneresis. The general behavior is well represented by the equations: See PDF for Equation and See PDF for Equation where P(1) = osmotic pressure of the soluble gelatin in the gel, P(2) = stress on the micellae in the gelatin solution before setting, K(e) = bulk modulus of elasticity, V(o) = volume of water per gram of dry gelatin at setting and V(e) = volume of water per gram of gelatin at equilibrium.

Medallion-like dermal dendrocyte hamartoma (DH) and superficial (plaque-like) dermatofibrosarcoma protuberans (DFSP) are CD34-positive dermal neoplasms with overlapping clinicopathologic features. We analyzed the clinical, histomorphologic, and molecular criteria of 5 DH and 7 DFSP to delineate diagnostically relevant differences between incipient dermal DFSP and its benign look-alike, DH. We expand the clinical and histologic spectrum of DH. As medallion-like dermal DH is neither of dermal dendrocyte lineage nor a genuine hamartoma, we propose instead the descriptive term of plaque-like CD34-positive dermal fibroma (PDF). Both PDF/DH and DFSP presented as slightly pigmented and indurated plaques on neck, trunk, and extremities. Histologically, DFSP was characterized either by horizontally oriented spindle cell fascicles or by diffusely arranged fibroblasts within a slightly myxoid stroma in the upper two-thirds of the dermis, whereas PDF/DH presented with a cellular band-like fibroblastic proliferation mostly in the papillary and adjacent upper reticular dermis. Only one congenital PDF/DH in a 9-year-old boy extended into the septa of the subcutaneous fat. Formalin-fixed paraffin-embedded archival tissue was used for detection of the COL1A1-PDGFB gene rearrangement by multiplex reverse transcription-polymerase chain reaction (RT-PCR) and by dual color fusion fluorescence in-situ hybridization (FISH). Archival blocs older than 4 years did not yield amplifiable RNA because of RNA degradation, whereas FISH analysis was feasible in all investigated cases. FISH analysis revealed COL1A1-PDGFB gene rearrangement in all DFSP cases (n=7), whereas RT-PCR could detect the COL1A1-PDGFB fusion transcript only in 1 DFSP. Two cases were negative. In 4 archival cases with storage between 4.5 and 12 years, RNA had been degraded making these cases unsuitable for RT-PCR. In PDF/DH, both RT-PCR and FISH analysis did not reveal any evidence of COL1A1-PDGFB gene rearrangement. We show that PDF/DH and superficial (plaque-like) DFSP, subtle clinicopathologic differences notwithstanding, are morphologic look-alikes that can be kept apart by molecular studies of the COL1A1-PDGFB gene fusion. For the detection of the COL1A1-PDGFB gene rearrangement in diagnostically difficult cases, RT-PCR and FISH analysis are reliable and helpful diagnostic tools. In archival formalin-fixed paraffin-embedded tissue, however, FISH analysis is more robust and exhibits a higher clinical sensitivity than RT-PCR.

BACKGROUND

Statins have recently been highlighted for their pleiotropic actions distinct from cholesterol-lowering effects. Despite this interest, it is currently unknown whether statin therapy inhibits peritoneal dialysis (PD)-related epithelial-mesenchymal transition (EMT).

METHODS

In vitro, human peritoneal mesothelial cells (HPMCs) were exposed to 5.6 mM glucose (NG) or 100 mM glucose (HG) with or without simvastatin (1 µM). In vivo, PD catheters were inserted into 32 Sprague-Dawley rats, and saline (C, n = 16) or 4.25% peritoneal dialysis fluid (PDF) (PD, n = 16) was infused for 4 weeks. Eight rats from each group were treated with 5 mg/kg/day of simvastatin intraperitoneally. Changes in the protein expression of EMT markers such as E-cadherin, α-SMA, Snail, and fibronectin in HPMCs and the peritoneum were evaluated by Western blot analysis and immunofluorescence or immunohistochemical staining. We also explored whether activation of the mevalonate pathway and its downstream small GTPases were involved in dialysis-related peritoneal EMT and could be inhibited by statin treatment.

RESULTS

Compared to NG cells, E-cadherin expression was significantly decreased, while α-SMA, Snail, and fibronectin expression were significantly increased in HPMCs exposed to HG, and these changes were abrogated by simvastatin (p<0.05). In addition, the cobblestone-like appearance of normal HPMCs was converted into a fibroblast-like morphology after HG treatment, which was reversed by simvastatin. These EMT-like changes were also observed in HPMCs treated with geranyl-geranyl pyrophosphate (5 µM). HG significantly increased the protein expression of RhoA and Rac1 in the membrane fractions, and these increases were ameliorated by simvastatin (p<0.05). In PD rats, E-cadherin in the peritoneum was significantly decreased, whereas α-SMA, Snail, and fibronectin expression were significantly increased (p<0.05) compared to C rats. The thickness of the mesothelial layer in the peritoneum were also significantly greater in PD rats than in C rats (p<0.05). These changes of the peritoneum in PD rats were significantly attenuated by simvastatin.

CONCLUSIONS

This study demonstrated that PD-related EMT was mediated via the mevalonate pathway, and statin treatment inhibited the EMT changes in HG-treated HPMCs and PDF-stimulated PD rats. These findings suggest that statins may be a promising therapeutic strategy for preservation of peritoneal membrane integrity in long-term PD patients.

OBJECTIVE

In the current study we evaluated adverse effects of monosodium glutamate (MSG) on memory formation and its retrieval as well as the role of ascorbic acid (Vitamin-C) in prevention of MSG-induced alteration of neurobehavioral performance in periadolescent rats.

METHODS

Healthy male albino Wistar rats (4-6 weeks old), were randomly allotted in four groups. Group I: normal control, who remained in their homecage throughout the experimental period. Group II: vehicle control, who were orally administered with normal saline for three weeks. Group III: MSG, who were orally administered with aqueous solution of MSG (2 mg/g b.w/day), for three weeks. Group IV: MSG+AA, who were administered with aqueous solution of MSG, and subsequently by ascorbic acid (100 mg/kg b.w/day) orally for three weeks. After the experimental period, all animals from all groups were first tested for anxiety followed by passive avoidance behavior.

RESULTS

MSG significantly altered the neurobehavioral performance in rats. The alteration manifested as less time spent on the open arm during the EPM test and shorter entrance latency to the dark compartment during the passive avoidance task. All behavioral changes were significantly prevented by simultaneous administration of ascorbic acid with MSG.

CONCLUSIONS

The present data point to the neuroprotective role of ascorbic acid. The ascorbic acid can be used as a therapeutic agent in various cognitive deficits (Fig. 5, Ref. 25). Full Text (Free, PDF) www.bmj.sk.

BACKGROUND

Low biocompatibility of peritoneal dialysis fluids (PDF) contributes to mesothelial injury. We investigated whether the heat shock proteins (HSP)-27, HSP-72, and HSP-90 are differentially induced upon exposure of mesothelial cells to PDF and whether this was affected by selective modulation of the physicochemical properties of PDF.

METHODS

Human mesothelial cells (Met5A and primary human mesothelial cells) were exposed to acidic lactate and glucose-monomer based PDF (CAPD2 and CAPD3), to control culture media, or to a neutral lactate and glucose-monomer-based PDF with reduced levels of glucose degradation products (BALANCE). Expression of HSP-27, HSP-72, and HSP-90 and cellular distribution of HSP-72 were assessed by Western blotting and immunocytochemistry.

RESULTS

Mesothelial cells exhibited strong constitutive expression of HSP-27 and to a lesser extent HSP-72 and HSP-90. Exposure of the cells to CAPD2 and CAPD3 resulted in strong up-regulation of HSP-72. HSP-27 levels were slightly increased, but HSP-90 levels were unchanged upon exposure to CAPD2 or CAPD3. In contrast, exposure of the cells to BALANCE did not affect HSP-27 or HSP-72 expression. The acidic pH and glucose degradation products were found to be principal in mediating increased HSP-72 expression upon exposure to PDF.

CONCLUSIONS

Analysis of HSP expression represents a novel tool to assess biocompatibility of PDF. Among the HSP investigated, HSP-72 is the most predictive and accurate parameter to assess mesothelial cell injury in the early phase of exposure to PDF.

OBJECTIVE

This collaborative study, based on data collected by the network of Italian association of cancer registries (AIRTUM), provides updated estimates on the incidence risk of multiple primary cancer (MP). The objective is to highlight and quantify the bidirectional associations between different oncological diseases. The quantification of the excess or decreased risk of further cancers in cancer patients, in comparison with the general population, may contribute to understand the aetiology of cancer and to address clinical follow-up.

METHODS

Data herein presented were provided by AIRTUM population-based cancer registries, which cover nowadays 48% of the Italian population. This monograph utilizes the AIRTUM database (December 2012), considering all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to ICD-O-3. Non-melanoma skin cancer cases, cases based on death certificate only, cases based on autopsy only, and cases with follow-up time equal to zero were excluded. To define multiple primaries, IARC-IACR rules were adopted (http://www.iacr.com.fr/MPrules_july2004.pdf). Data were subjected to standard quality control procedures (described in the AIRTUM data management protocol) and specific quality control checks defined for the present study. A cohort of cancer patients was followed over time from first cancer diagnosis until the date of second cancer diagnosis, death, or the end of follow-up, to evaluate whether the number of observed second cancer cases was greater than expected. Person years at risk (PY) were computed by first cancer site, geographic area (North, Centre, South and Islands), attained age, and attained calendar-year group. All second cancers diagnosed in the cohort's patients were included in the observed numbers of cases. The expected number of cancer cases was computed multiplying the accumulated PY by the expected rates, calculated from the AIRTUM database stratified by cancer site, geographic area, age, and calendar-year group. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cancer cases. The Excess Absolute Risk (EAR) beyond the expected amount were calculated subtracting the expected number of subsequent cancers from the observed number of cancer cases; the difference was then divided by the PY and the number of cancer cases in excess (or deficit) was expressed per 1,000 PY. Confidence intervals were stated at 95%. The two months (60 days) after first cancer diagnosis were defined as "synchronicity period", and in the main analysis observed and expected cases during this period were excluded. It was estimated the excess risk in the period after first diagnosis (≥ 0 months), excluding the synchronicity period (≥ 2 months), and during the following periods: 2-11, 12-59, 60-119 and 120 months after diagnosis. First-cancer-site-and-gender-specific sheets are presented, reporting both SIRs and EARs.

RESULTS

For 5,979,338 person-years a cohort of 1,635,060 cancer patients (880,361 males and 754,699 females) diagnosed between 1976 and 2010 was followed. The mean follow-up length was 14 years. Overall, 85,399 metachronous (latency ≥2 months) cancers were observed, while 77,813 were expected during the study period: SIR: 1.10 (95%CI 1.09-1.10), EAR: 1.32 x 1,000 person-years (95%CI 1.19 - 1.46). The SIR was 1.08 (95%CI 1.08-1.09) for men (54,518 observed and 50,260 expected) and 1.12 (95%CI 1.11-1.13) for women (30,881/27,553), and the EAR 1.61 (95%CI 1.37-1.84) and 1.08 x 1,000 person-years (95%CI 0.93-1.24), respectively.Moreover, during the first two months after first cancer diagnosis (synchronous period) 14,807 cancers were observed while 3,536 were expected (SIR: 4.16; 95%CI 4.09-4.22); the SIR was 4.08 (95%CI 4.00-4.16) for men and 4.32 (95%CI 4.20-4.45) for women.The mean age of patients at first cancer diagnosis was 67.0 years among males and 65.8 among females.The risk of MP was related to age being higher for younger patients and lower for older ones. In relation to the time of first cancer diagnosis, the SIR was very high at the beginning and then decreased, although remaining constantly over 1, and then rose over time. No strong differences were evident across the different incidence periods, which all showed an increased MP risk.Women had higher SIRs than expected for 18 cancer sites, men for 12. The statistically significantly SIRs lower than 1 were 2 and 8, respectively. Increased overall MP risk was observed for patients of both sexes with a first primary in the oral cavity (SIR men: 1.93; SIR women: 1.48), pharynx (SIR men: 2.13; SIR women: 1.99), larynx (SIR men: 1.57; SIR women: 1.79), oesophagus (SIR men: 1.45; SIR women: 1.41), lung (SIR men: 1.09; SIR women: 1.13), kidney (SIR men: 1.14; SIR women: 1.15), urinary bladder (SIR men: 1.29; SIR women: 1.22), thyroid (SIR: 1.22 in both sexes), Hodgkin lymphoma (SIR men: 1.59; SIR women: 1.94), and non-Hodgkin lymphoma (SIR men: 1.13; SIR women: 1.12), and for the heterogeneous group "other sites" (SIR men: 1.09; SIR women: 1.07). Moreover, men had a higher MP risk if the first cancer was in the testis (SIR: 1.24), while the same was true for women with gallbladder (SIR: 1.21), skin melanoma (SIR: 1.17), bone (SIR: 1.41), breast (SIR: 1.12), cervix uteri (SIR: 1.23) and corpus uteri (SIR: 1.23), and ovarian cancer (SIR: 1.18). On the contrary, a first liver or pancreas cancer were associated with a decreased MP risk in both sexes (liver SIR: 0.86 and 0.81 for men and women, respectively; pancreas SIR: 0.70 and 0.78 for men and women, respectively), as were those of colon (SIR: 0.93), rectum (SIR: 0.83), gallbladder (SIR: 0.80), prostate (SIR: 0.93), mesothelioma (SIR: 0.65), and central nervous system (SIR: 0.82) among men. Among the cancers for which the EAR is statistically significant, those with higher Excess Absolute Risk of MP were those of the oral cavity (EAR: 16.0 x 1,000 person-years in men and 5.4 in women), pharynx (17.6 and 9.1), larynx (11.4 and 8.8), and oesophagus (8.5 and 4.8).

CONCLUSIONS

This descriptive study provides quantitative information on the risk of developing a second cancer in an Italian population-based cohort of approximately 1.65 million cancer patients, compared to the risk of the general population. During the follow-up time (on average 14 years) cancer patients had an MP risk that was 10% higher in comparison to the general population and an Excess Absolute Risk of 1.32 x 1,000 person-years. Study of MPs and their risk measures are dependent on methods used in the calculation. The definition of MP is not univocal and using different rules can greatly change the number of cancers in a patient with MPs. However, the AIRTUM cancer registries adopt the same recommendations for MP definition. This monograph was therefore made possible by the shared rules and standards used by AIRTUM registries. The cancer site-specific sheets, which represent the core of the monograph, can be useful to highlight and quantify the bidirectional associations among different diseases and therefore provide indications for clinical follow-up. Lifestyle changes in more healthful directions can have a positive effect in the cancer patient population and should always be recommended.

BACKGROUND

The respiratory related target motion and setup error will lead to a large margin in the gastric radiotherapy. The purpose of this study is to investigate the dosimetric benefit and the possibility of incorporating the breath-hold (BH) technique with online image-guided radiotherapy in the adjuvant gastric cancer radiotherapy.

METHODS

Setup errors and target motions of 22 post-operative gastric cancer patients with surgical clips were analyzed. Clips movement was recorded using the digital fluoroscopics and the probability distribution functions (pdf) of the target motions were created for both the free breathing (FB) and BH treatment. For dosimetric comparisons, two intensity-modulated radiotherapy (IMRT) treatment plans, i.e. the free breathing treatment plan (IMRT(FB)) and the image-guided BH treatment plan (IMRT(IGBH)) using the same beam parameters were performed among 6 randomly selected patients. Different margins for FB and BH plans were derived. The plan dose map was convoluted with various pdfs of the setup errors and the target motions. Target coverage and dose to organs at risk were compared and the dose-escalation probability was assessed.

RESULTS

The mean setup errors were 1.2 mm in the superior-inferior (SI), 0.0 mm in the left-right (LR), and 1.4 mm in the anterior-posterior (AP) directions. The mean target motion for the free breathing (vs. BH) was 11.1 mm (vs. 2.2 mm), 1.9 mm (vs. 1.1 mm), and 5.5 mm (vs. 1.7 mm) in the SI, LR, and AP direction, respectively. The target coverage was comparable for all the original plans. IMRT(IGBH) showed lower dose to the liver compared with IMRT(FB) (p = 0.01) but no significant difference in the kidneys. Convolved IMRTIGBH showed better sparing in kidneys (p < 0.01) and similar in liver (p = 0.08).

CONCLUSIONS

Combining BH technique with online image guided IMRT can minimize the organ motion and improve the setup accuracy. The dosimetric comparison showed the dose could be escalated to 54 Gy without increasing the critical organs toxicities, although further clinical data is needed.

1. There are certainly two, and probably three, stages in the development of B. megaterium from the spore to inception of cell division. The rapid increase in rate of respiration during the initial 10 minutes on glucose-peptone-yeast extract medium coincides with decrease in optical density and with increase in stainability. From about 10 to 100 minutes, the rate increases linearly, coinciding with swelling of the spores and ending at approximately the time of rupture of the spore case. From about 100 to 180 minutes, there is a second and steeper linear increase in respiration rate coinciding with cell elongation. These physiological and morphological phenomena are discussed as criteria for germination. 2. The rate of respiration of M. verrucaria spores also increases linearly up to about 300 minutes in sucrose-yeast extract medium. No breaks in the curves are observed during formation of the germ tubes. 3. Oxygen uptake follows the parabolic curve See PDF for Equation within the limits of experimental error for both types of spores. 4. It is postulated that metabolism during these stages of linear increase may be regulated by processes occurring at cellular or intracellular surfaces or by synthesis of a limiting enzyme at constant rate.

Capillary endothelial surface charge was investigated by perfusing the intestinal circulation of anesthetized rats in situ with 0.1 or 10 mg/ml native ferritin (NF, pI = 3.8-4.2) or with 0.1 mg/ml cationized ferritin (CF, pI greater than 10.0) for 5 min, with or without 5% Dextran 40. Ferritin binding was quantified by electron microscopy. All electron micrographs of capillaries perfused with NF showed some NF binding. Mean NF particle densities (particles/microns) were significantly greater at vesicle necks (PDv) than elsewhere on the endothelial surface (PD). Capillaries perfused with CF showed binding in only 60% of the transverse sections examined. The binding was very marked in a large proportion of these vessels. Mean CF particle densities were significantly greater at fenestrae (PDf) than elsewhere. These results demonstrate that mucosal capillaries have a variable negative electrostatic charge on the endothelial surface and support the hypothesis that some vesicle diaphragms act as preferential attractors for anionic macromolecules. Such structures could promote transendothelial vesicular transport of albumin. Dextran significantly decreased PD for NF from 25.4 +/- 2.4 (SEM) to 13.1 +/- 0.9 and PD, PDv, and PDf for CF from 45.9 +/- 4.6 to 31.0 +/- 2.7, from 62.1 +/- 6.2 to 43.6 +/- 5.4, and from 152.9 +/- 15.5 to 114.5 +/- 8.6, respectively. The above responses result from dextran's weak interaction with the endothelial surface. Dextran reduces access of ferritin molecules to the cell surface by steric hindrance and/or electrostatic shielding of the glycocalyx.

The proportion of mutants in a growing culture of organisms will depend upon (a) the rate at which the wild cells produce them (with or without growth), (b) the back mutation rate, and (c) the growth rates of the wild and mutant cells. If the mutation rate without growth and the back mutation rate are neglected, the growth of a mutant is expressed by See PDF for Equation and the ratio of the mutant to wild by See PDF for Equation in which lambda = mutation frequency rate constant, "mutation rate," A = growth rate constant of wild cells W, B = growth rate constant of mutant cells M. If the term [B - (1 - 2lambda)A] is positive, the proportion of mutants increases continuously. If it is negative, the proportion of mutants reaches a constant value See PDF for Equation If mutation is assumed to occur without growth at the rate C, then the corresponding equations are (11), (12), and (14). See PDF for Equation If (B + C - A) is negative and t = infinity, See PDF for Equation If C (< A, See PDF for Equation

The purpose of this study was to evaluate the therapeutic efficacy and limitations of alpha-particle-emitting radiolabeled compounds by means of 2-dimensional histological images and distribution of activity on a microscopic level.

METHODS

A microdosimetric approach based on histological images is used to analyze the therapeutic effectiveness of alpha-particle-emitting (211)At and (213)Bi conjugated to 201B monoclonal antibody (mAb), which is reactive with murine lung blood vessels for the treatment of EMT-6 lung tumor colonies in nude mice. Autoradiography images were used to define the tissue morphology and activity distribution within lung tissues. Two animal groups were studied: Group A consisted of animals bearing small tumors (<130 micro m) and group B consisted of larger tumors (<600 micro m). Probability density functions (pdf) described the variability in average absorbed dose and survival probability among normal and tumor target cells and, in turn, were used to assess the survival fraction of tumor and normal tissue.

RESULTS

The average absorbed dose to tumor cells per unit cumulated activity concentration for animals in group A was 1.10 x 10(-3) and 1.37 x 10(-3) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively, and for animals in group B was 3.8 x 10(-4) and 5.6 x 10(-4) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively. The fraction of tumor cells that received a zero absorbed dose for animals in group A was 0.04% for (213)Bi and 0.2% for (211)At and for animals in group B was 25% for (213)Bi and 31% for (211)At. Both (213)Bi- and (211)At-labeled 201B mAb were effective therapies for animals with small tumors, where predicted therapeutic effectiveness was consistent with experimental findings; however, they were ineffective for animals with larger tumors.

CONCLUSIONS

Microdosimetric methods based on knowledge of tissue morphology and activity distribution on a small-scale level can be a useful tool for evaluating a priori the therapeutic efficacy and limitations of targeted alpha-particle endoradiotherapeutic strategies.

1. No significant change with time (to 24 hours) in the cataphoretic velocity of certain mammalian red cells occurs when the cells are suspended in M/15 phosphate buffer at pH = 7.35. Neither successive washings nor standing effect a change. 2. In M/15 phosphate buffer at pH 7.35 +/- 0.03 the following order of red cell velocity has been obtained. The numbers in parenthesis are micro per second per volt per centimeter. See PDF for Structure The order, though not the absolute values, was the same in buffered isotonic dextrose. Human and rabbit cells showed similar differences when both were studied simultaneously in the serum of either. Under these conditions, there is no apparent relationship between zoological Order and cataphoretic velocity. 3. Cholesterol and quartz adsorb gelatin from dilute solution in the phosphate buffer. Red cells, on the other hand, even after 24 hours contact with gelatin solution, retain their previous velocity. 4. Pregnant and non-pregnant white female humans have the same red cell cataphoretic velocity. (The cells were not agglutinated.) 5. In a series of severe anemias no significant change in cataphoretic velocity was in general apparent, although marked changes in the morphology of the red cells were present.

Digital surface mesh models based on segmented datasets have become an integral part of studies on animal anatomy and functional morphology; usually, they are published as static images, movies or as interactive PDF files. We demonstrate the use of animated 3D models embedded in PDF documents, which combine the advantages of both movie and interactivity, based on the example of preserved Trigonopterus weevils. The method is particularly suitable to simulate joints with largely deterministic movements due to precise form closure. We illustrate the function of an individual screw-and-nut type hip joint and proceed to the complex movements of the entire insect attaining a defence position. This posture is achieved by a specific cascade of movements: Head and legs interlock mutually and with specific features of thorax and the first abdominal ventrite, presumably to increase the mechanical stability of the beetle and to maintain the defence position with minimal muscle activity. The deterministic interaction of accurately fitting body parts follows a defined sequence, which resembles a piece of engineering.