Development of an alarm symptom-based risk prediction score for localized oesophagogastric adenocarcinoma (VIOLA score).

BACKGROUND: Gastroesophageal adenocarcinoma is a major contributor to global disease burden with poor prognosis even in resectable, regionally limited stages. Feasible prognostic tools are crucial to improve patient management, yet scarce. PATIENTS AND METHODS: Disease-related symptoms, patient, tumour, treatment as well as laboratory parameters at initial diagnosis and overall survival (OS) of patients with stage II and III gastroesophageal adenocarcinoma, who were treated between 1990 and 2020 at the Medical University of Vienna, were evaluated in a cross-validation model to develop a feasible risk prediction score. RESULTS: In total, 628 patients were included in this single-centre analysis. The final score ranked from 0 to 10 and included the factors sex (female +1), age, years (30-59 +1, >60 +2), underweight classified by body mass index (+2), location of the tumour (stomach +1), stage (III +2), stenosis in endoscopy (+1) and weight loss (+1). The score was grouped into low- (0-3), medium- (4-6) and high-risk (7+) subgroups. The median OS were 70.3 [95% confidence interval (CI) 51.2-111.8], 23.4 (95% CI 21.2-26.7) and 12.6 (7.0-16.1) months, respectively. The 1-year survival probabilities were 0.88 (95% CI 0.83-0.93), 0.75 (95% CI 0.70-0.79) and 0.54 (95% CI 0.39-0.74), whereas the 5-year survival probabilities were 0.57 (95% CI 0.49-0.66), 0.24 (95% CI 0.20-0.28) and 0.09 (95% CI 0.03-0.28), respectively. CONCLUSIONS: The VIennese risk prediction score for Oesophagogastric Localized Adenocarcinoma (VIOLA) risk prediction score poses a feasible tool for the estimation of OS in patients with regionally limited gastroesophageal adenocarcinoma and, thus, may improve patient management in clinical routine. Prospective analyses should be carried out to confirm our findings.

First-line daratumumab shows high efficacy and tolerability even in advanced AL amyloidosis: the real-world experience.

BACKGROUND: Daratumumab was the first monoclonal CD38 antibody with single-agent activity approved for the treatment of multiple myeloma. Moreover, daratumumab demonstrated high response rates in relapsed immunoglobulin light-chain (AL) amyloidosis. PATIENTS AND METHODS: In our single-center retrospective real-life case series, we analyzed the efficacy and safety of daratumumab as first-line treatment. Daratumumab was administered with low-dose dexamethasone alone or in combination with other multiple myeloma therapeutics RESULTS: Fourteen patients were eligible, including nine patients with cardiac stage IIIa or IIIb. Overall hematologic response rate was 100%, with 64.3% achieving complete response after a median of 16 cycles of treatment. Median time to hematologic response was 1.4 months. Organ response rates were 45.5% after a median of 4.0 months and 66.7% after a median of 10.0 months, for heart and kidney involvement, respectively. After a median follow-up of 20.5 months, two patients underwent successful autologous stem cell transplantation (ASCT), while another three patients were in preparation for ASCT. Three patients remained on daratumumab at the last follow-up. There were no unexpected toxicities and no grade III or IV adverse events, although more than half of our patients were in stage IIIa or IIIb. CONCLUSION: Daratumumab proved to be highly effective in newly diagnosed AL amyloidosis with excellent hematologic and organ response rates, a remarkable safety profile, and good tolerability even in patients with advanced stage of disease.

[Magnetic resonance imaging and active cardiac implants]. / Magnetresonanztomographie und aktive kardiale Implantate.

The combination of magnetic resonance imaging (MRI) and active cardiac implants, such as pacemakers and implantable cardioverter defibrillators (ICD) has been a challenge for electrophysiologists and imaging for many years. Diagnostic and therapeutic possibilities on the one hand and technical hazards on the other hand highlight the need for improvements and algorithms that enable a safe approach to these challenges. The advent of so-called MRI conditional implants provides safe procedures for at least some of the patients with an implant and the need for MRI. Recently published data encourage clinicians not to completely excluded an imaging modality as promising as MRI in clinically urgent cases in the presence of conventional implants. The interdisciplinary consensus paper of the German Society of Cardiology and the German Society of Radiology provides recommendations for these situations. This review article discusses these recommendations and provides an overview of the most recent publications with a focus on the long-term course of device parameters.

MR safety: fast T1 thermometry of the RF-induced heating of medical devices.

Determining the MR compatibility of medical implants and devices is becoming increasingly relevant. In most cases, the heating of conductive implants due to radiefrequency (RF) excitation pulses is measured by fluoroptic temperature sensors in relevant tests for approval. Another common method to determine these heating effects is MR thermometry using the proton resonance frequency. This method gives good results in homogeneous phantoms. However in many cases, technical shortcomings such as susceptibility artifacts prohibit exact proton resonance frequency thermometry near medical implants. Therefore, this work aimed at developing a fast T1-based method which allows controlled MR-related heating of a medical implant while simultaneously quantifying the spatial and temporal temperature distribution. To this end, an inversion recovery snapshot Fast Low-Angle Shot (FLASH) sequence was modified with additional off-resonant heating pulses. With an accelerated imaging method and a sliding-window technique, every 7.6 s a new temperature map could be generated with a spatial in-plane resolution of 2 mm. The temperature deviation from calculated temperature values to reference fluoroptic probe was found to be smaller than 1 K.

First observation of electrorheological plasmas.

We report the experimental discovery of "electrorheological (ER) complex plasmas," where the control of the interparticle interaction by an externally applied electric field is due to distortion of the Debye spheres that surround microparticles (dust) in a plasma. We show that interactions in ER plasmas under weak ac fields are mathematically equivalent to those in conventional ER fluids. Microgravity experiments, as well as molecular dynamics simulations, show a phase transition from an isotropic to an anisotropic (string) plasma state as the electric field is increased.

Redox regulation of calcineurin in T-lymphocytes.

To explore whether the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin is subject to redox regulation in vivo, we used a luciferase reporter gene construct whose expression was controlled by the transcription factor NF-AT (the nuclear factor of activated T-cells) to monitor intracellular calcineurin activity following redox state perturbations. The NF-AT reporter construct was transfected into Jurkat cells, and luciferase activity was assessed following treatment with phorbol ester and ionomycin in the presence of either hydrogen peroxide or dithiothreitol (DTT). While DTT had no effect, H(2)O(2) completely abrogated NF-AT transactivation in response to stimulation. The inhibitory effect was specific for NF-AT as comparable levels of H(2)O(2) had only minor effects on constitutive transcription factors while an analogous construct under AP-1 control showed a 5-fold stimulation in transactivation in the presence of H(2)O(2). The inhibitory effect of H(2)O(2) was observed up to approximately 3 h following mitogen stimulation, a time point where NF-AT activity begins to increase under normal conditions. Protein serine/threonine phosphatase activities from Jurkat lysate indicated that calcineurin activity was inhibited not only by H(2)O(2) but also by high concentrations of DTT. These results indicate that calcineurin activity is subject to redox regulation in vivo and are discussed in the context of redox reactions involving active site metal ions.

2D-finite element analyses and histomorphology of lag screws with and without a biconcave washer.

For osteosynthesis and for bone transplant fixation in particular, a lag screw with a biconcave washer, the so called "Anchor Screw" (AS) has been introduced in maxillo-facial surgery. Using 2D-finite element analysis (FEA), the v. Mises and the circumferential stresses induced in underlying bone by this AS are analysed and compared to those under a conventional lag screw. The stress distributions below the biconcave washer of the AS were correlated with histomorphological bone reactions after AS osteosynthesis in two tumor patients, retrieved 12 weeks and 19 months after tumor surgery, respectively. Depending on the thickness of cortical bone, the v. Mises stress concentrations below the biconcave washer were lower than under the head of the conventional lag screw (CLS), but with a higher stress maximum concentrated around the rim of the washer. The circumferential stresses were only half as high around the AS, and thus the deformation of bone was reduced. As predicted by FEA, histology showed microcrack formation, but then after minimal resorption, remodelling of bone below the biconcave washer. Stable osteosynthesis could be demonstrated by bony union already after 12 weeks, and, while bone remodelling continued in the healed osteotomy, it had decreased around the screws after 19 months. It can be concluded from the biomechanical principles and the histomorphological findings that the AS appears superior to the CLS.

Working aboard the Mir space station.

For more than ten years, the Mir station has been the World's only permanently manned laboratory in low earth orbit. With an orbital inclination of 51.6 degrees, its ground track covers more than 85% of the Earth's surface, where approximately 95% of the population lives. For the transfer of up to three crew members per trip to and from Mir, the 6.9 t Soyuz spacecraft is used. In general, the station's crew is changed every six months, with an overlap during the exchange of between one and two weeks. A Progress spacecraft (an unmanned derivative of the Soyuz vehicle) visits the station every three months to resupply it, with up to 2.1 t of payload, and to reboost it to maintain its nominal orbital altitude. The station's core module, injected into orbit in February 1986, contains the central control post for most onboard systems, the computer for attitude control, and the telemetry and communications system. It also contains the station's largest work space, which is 7.0 m long and varies in width between 1.5 and 2.5 m.

Finite element analysis of the stress distributions in the proximal end of the femur after stabilization of a pertrochanteric model fracture: a comparison of two implants.

The study investigated the influence of two different implants--the dynamic hip screw (AOR) 135 degrees with 2-hole-plate and the 135 degrees gamma-nail (HowmedicaR)--on the resulting stress and strain distributions in the proximal femur after stabilization of an idealized trochanteric fracture under typical physiological loading conditions. Data recorded for the uninjured femur were used for comparison. Two-dimensional plane stress finite element models of the femur and the implants were used for the calculations. The three-dimensional nature of this problem was approximated by an appropriate distribution of element thickness according to the real geometry in combination with an overlay technique, superimposing special finite element layers for each constituent of the bone-implant system (i.e. steel, cortical and cancellous bone). Three variations of the idealized fracture were introduced, i.e. free, with callous and bony bridging, the screw being modelled in a movable ('dynamic') as well as in a locked state. As far as the resulting stress distributions are concerned, neither of the two implants proved to be significantly superior to the other for stabilization of the idealized fracture selected.

Cell-cycle-dependent expression of DNA primase activity.

Protein extracts were prepared at various times after serum stimulation of growth-arrested mouse 3T3 fibroblasts. The extracts were fractionated by sucrose gradient centrifugation and used to determine the activities of DNA polymerase alpha and DNA primase. We found that polymerase and primase appeared in close association in one homogeneous 8.2-S peak. Neither polymerase, free of associated primase, nor primase, free of polymerase, could be detected at any time after serum stimulation. The activities of both enzymes started to increase concomitantly at the beginning of the DNA replication phase of the cell cycle. We found five to six times more DNA primase activity in replicating than in resting 3T3 cells. Besides DNA primase, a second additional priming activity could be detected. This activity sedimented at 12.5 S and corresponded most probably to RNA polymerase I.

Synthesis of DNA polymerase alpha analyzed by immunoprecipitation from synchronously proliferating cells.

Synchronously proliferating TC7 monkey and 3T3 mouse cells were pulse labeled with [35S]methionine. Radioactively labeled DNA polymerase alpha was immunoprecipitated with polymerase-specific monoclonal antibodies. The precipitated polypeptides were identified by gel electrophoresis and fluorography. The increase in DNA polymerase alpha activity during S phase was accompanied by an increased synthesis of the enzyme. Some DNA polymerase alpha was synthesized in growth-arrested TC7 cells whereas the synthesis of the large polymerase subunit in 3T3 cells was strictly coupled to the replicative phase of the cell cycle. We also found that DNA polymerase alpha was more prone to proteolysis in TC7 cells than in 3T3 cells. In 3T3 cells, a polymerase subunit with an apparent molecular weight of 186 000 was observed; this subunit was most probably associated with two smaller subunits of Mr 74 000 and 52 000. Synthesis of these three polymerase-associated polypeptides appeared to be regulated differently.

Shape-dependent regulation of cytoskeletal protein synthesis in anchorage-dependent and anchorage-independent cells.

We examine changes in protein synthesis that accompany suspension (i.e. shape alteration) of anchorage-dependent and anchorage-independent cells using a newly developed cell fractionation procedure based on detergent extraction. Using this procedure, a cell can be divided into four distinct and independent fractions: soluble, cytoskeleton, chromatin and nuclear matrix-intermediate filament. This fractionation procedure is used to investigate protein synthetic events associated with the release from anchorage-dependent growth, characteristic of transformed cells. Suspension results in several unexpected events in both anchorage-dependent (3T3) cells and anchorage-independent (SVPy 3T3) cells. Suspension of 3T3 cells results in a reduction of total protein synthesis; however, two proteins are enhanced in their amount of synthesis. Suspension of SVPy 3T3 results in about 20 proteins proceeding through short and long-term alterations in the rate of synthesis. The synthesis of some of these proteins is inhibited, others undergo a transient decrease in synthesis upon suspension and then increase above their rate in the anchored state, while the synthesis of others steadily increases after suspension. Suspension of anchorage-dependent cells results in a fraction specific shift in the rates of protein synthesis. Possible roles for these fraction-specific proteins are considered.

"Prompt" heat shock proteins: translationally regulated synthesis of new proteins associated with the nuclear matrix-intermediate filaments as an early response to heat shock.

The response of mammalian cells, such as HeLa cells, to prolong exposure to increased temperature (termed heat shock) has been well characterized. In these studies new mRNA is synthesized for several proteins whose translation is best seen after a return to 37 degrees C. We show here another response to increased temperature of a distinctively different character. A set of at least 50 newly detectable proteins, exclusively associated with the nuclear matrix-intermediate filaments (NM-IF) fraction, is synthesized immediately upon exposure to high temperature. These are of very low abundance or nonexistent in the unstressed cell and none appear to correspond to the "classic" heat shock proteins produced after new transcription. Prior treatment with actinomycin D has little effect on these "prompt" proteins, and they appear to be made from preexisting mRNAs that are activated at the increased temperature. The protein synthesis in the soluble, cytoskeletal, and chromatin fractions is strongly reduced by the increased temperature, while the labeling of the prompt proteins associated with NM-IF complex rapidly rises severalfold above that in control cells. Additionally these results suggest that the four cell fractions are not arbitrary cell divisions; rather they represent physiologically significant compartments in the cell.

Initiation of adenovirus DNA replication.

In an attempt to study the mechanism of initiation of adenovirus DNA replication, an assay was developed to investigate the pattern of DNA synthesis in early replicative intermediates of adenovirus DNA. By using wild-type virus-infected cells, it was possible to place the origin of adenovirus type 2 DNA replication within the terminal 350 to 500 base pairs from either of the two molecular termini. In addition, a variety of parameters characteristic of adenovirus DNA replication were compared with those obtained in a soluble nuclear extract competent for viral DNA replication. It was observed that in vitro DNA replication, which is dependent on the exogenously added viral DNA-protein complex as its optimal template, occurs in a manner apparently indistinguishable from the situation in virus-infected cells. This includes the presence of proteinaceous material on the molecular termini of newly initiated viral DNA.