Auswahl der wissenschaftlichen Literatur zum Thema „222/.506“

Objective. To study the prevalence of thrombosis allelic polymorphisms in patients with severe angina who have indications for myocardial revascularization. Design and methods. The study included 105 patients (87 men and 18 women) aged from 33 to 70 years who had angina III–IV functional class, with indications for myocardial revascularization. All the patients studied polymorphism of the inhibitor of tissue plasminogen activator I type (675 4G/5G) (PAI-I), mutations of the factor II-prothrombin (20210 G / A), mutations of the factor V Leiden (Arg 506 Gln) and polymorphism of the methylenetetrahydrofolate reductase (Ala 222 Val) (MTHFR). Results. The prevalence of these mutations and polymorphisms in patients with severe angina requiring revascularization of the myocardium in 3 times greater than in the group of healthy adolescents. Our data showed that the risk of severe angina is directly proportional, and the age of the clinical debut of CHD is inversely proportional to the number of studied genetic defects. Thrombophilic polymorphisms studied genes increases the effects of other cardiovascular risk factors such as male sex, smoking and leads to an earlier debut of clinical CHD. Conclusion. It is necessary to form the strategy of genetically-based population policy for the prevention of atherosclerosis, including coronary. Healthy persons with diagnosed thrombosis polymorphisms are need of active primary prevention of cardiovascular disease.

In the nineties, cattle stocks gradually decreased from 3 506 222 head of cattle in 1990 to 1 657 337 head in 1999. Skin testing of cattle was carried out annually using bovine tuberculin. Animals for sale were also simultaneously tested with avian tuberculin. In records from 1991 to 1999 a total of 14 611 393 bovine tuberculin skin tests and 611 405 simultaneous avian tuberculin skin tests are registered. A total of 1 457 (0.01%) animals reacted positively with bovine tuberculin and 1 790 (0.29%) with avian tuberculin. In the period monitored a total of 7 268 274 head of cattle were slaughtered and given veterinary hygienic examinations. Statistical data on the post-mortem detection of tuberculous lesions have been available for nine years since 1992 when tuberculous lesions were found in 1 186 (0.019%) out of 6 273 441 slaughtered animals. Mycobacteria were isolated from the organs of only 561 (17.5%) out of 3 202 culturally examined animals. M. bovis only was isolated from 48 (8.6%) animals originating from seven herds (two infected herds in 1991, 1992 and 1994 and one infected herd in 1995): four outbreaks were detected by annual skin testing, one outbreak by movement tuberculin skin testing and two outbreaks by the detection of tuberculous lesions at slaughter. M. avium complex strains of serotypes 1, 2 and 3 and of genotypes IS901+ and IS1245+ were isolated from 331 (59.0%) animals and strains of serotypes 4 to 6, 8 to 11 and 21 and of genotypes IS901- and IS1245+ were isolated from 132 (23.5%) animals. Potentially pathogenic bacteria of the M. chelonae, M. terrae, M. phlei and M. fortuitum species were isolated from 50 (8.9%) animals. Neither miliary nor generalised tuberculosis was found in any of the animals. Between 1996 and 1999, the proportion of cattle in which tuberculous lesions were recorded decreased.

Abstract MCL1 is an anti-apoptotic protein inhibiting cancer cell death. It is frequently amplified or overexpressed in cancer and confers resistance to relevant standard of care. Therefore, MCL1 is an attractive target to potentially re-sensitize tumors to conventional chemotherapy and targeted agents. Here we describe ANJ810 as a novel, potent, and selective MCL1 inhibitor which specifically induces apoptosis in cancer cells. ANJ810 potently and reversibly binds to the BH3-binding groove of human MCL1 (KD = 0.3 nM), thereby inhibiting the interaction with the BH3-only protein NOXA (IC50 = 0.4 nM). ANJ810 shows a 4-log-fold greater selectivity to MCL1 over other anti-apoptotic proteins like Bcl-xL or Bcl-2. In cells, ANJ810 treatment rapidly (< 15 min) disrupts the MCL1-BAK interaction with an IC50 < 10 nM, resulting in caspase-3 activation and cancer cell death. Knockout of BAK and BAX completely rescues cells from ANJ810 induced killing, indicating that initiation of cell death occurs through the intrinsic apoptotic pathway. Screening over 750 cell lines (PRISM), we found that ANJ810 induced anti-cancer activity in 222 cell lines with an IC50 < 1 μM across multiple solid and hematological cancers, including breast, lung, melanoma, sarcoma, lymphoma, and leukemia. The top genomic feature that correlates with sensitivity to ANJ810 treatment is the ratio of Bcl-xL/BAK expression. A key design principle of ANJ810 is its rapid systemic clearance to potentially minimize exposure-driven toxicities associated with MCL1 inhibition. ANJ810 induces efficient cancer cell killing within 4 hours in vitro but has no impact on cell viability or troponin I release in hiPSC-derived cardiomyocytes at supra-pharmacologic concentrations. In vivo, i.v. bolus injections of ANJ810 lead to short plasma residence time, yet are efficacious in xenograft models of multiple myeloma, DLBCL, NSCLC and HCC. ANJ810 will test the hypothesis in human clinical trials that short-term inhibition of MCL1 can overcome tumor resistance with an acceptable safety profile to improve current standard of care. Citation Format: Ulrike Rauh, Guo Wei, Michael Serrano-Wu, Georgios Kosmidis, Stefan Kaulfuss, Franziska Siegel, Kai Thede, James McFarland, Christopher Lemke, Nicolas Werbeck, Katrin Nowak-Reppel, Sabine Pillari, Stephan Menz, Matthias Ocker, Brian Hubbard, Virendar Kaushik, Karl Ziegelbauer, Todd Golub. ANJ810 is a highly selective novel MCL1 inhibitor with optimized in vivo clearance showing robust efficacy in preclinical solid and hematological tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 506.

Abstract Background In the recent International Prognostic Score for Thrombosis in essential thrombocythemia (IPSET-thrombosis), age and history of thrombosis were confirmed as independent risk factors for future thrombosis and the study also identified independent prothrombotic role for cardiovascular (CV) risk factors and JAK2 V617F mutation (Barbui et al. Blood 2012). Methods In the current study, we re-analyzed the original IPSET-thrombosis data in 1019 patients with WHO-defined ET in whom JAK2 mutational status was available, in order to quantify the individual contributions of JAK2 mutations and CV risk factors in conventionally-assigned low and high risk ET, as well as in age- versus thrombosis-defined high risk status. Results After a median follow-up of 6.8 and 5.0 years in conventionally-assigned low- and high-risk patients, respectively, the overall annual rate of total thrombosis (108 events) in conventionally-assigned low- and high-risk patients was 1.11%-pt/y (CI 0.81-1.52) and 2.46%-pt/y (CI 1.94-3.11) respectively (p=0.001), and the difference was mainly due to a higher frequency of arterial thrombosis in high-risk patients (p<0.001).The influence of JAK2 mutational status and CV-risk factors on the rate of thrombosis in conventionally assigned low- and high-risk groups is presented in the table. Table 1. Additional risk factors N (%) Event Rate % pts/yr (95% CI) P-value P-value P-value trend Low risk 506 (50) 39 1.11 (0.81-1.52) None 200 (40) 7 0.44 (0.21-0.92) ref Cardiovascular risk factor 36 (7) 3 1.05 (0.34-3.25) 0.220 0.227 JAK2V617F 213 (43) 21 1.59 (1.04-2.44) 0.001 0.217 Both 52 (10) 8 2.57 (1.29-5.15) <0.001 ref <0.001 High risk 513 (50) 69 2.46 (1.94-3.11) None 111 (22) 10 1.44 (0.78-2.68) ref Cardiovascular risk factor 44 (9) 4 1.64 (0.62-4.37) 0.909 0.067 JAK2V617F 222 (43) 30 2.36 (1.65-3.38) 0.168 0.082 Both 136 (27) 25 4.17 (2.82-6.17) 0.011 ref 0.005 The number of major arterial and venous thrombosis was reported as rates per 100 patient-years and the difference among groups was assessed by Mantel Cox log-rank test i) Conventionally-assigned low-risk group. Amongst 506 patients, 200 (40%) displayed neither JAK2 mutation nor CV risk factors and their annual rate of thrombosis was 0.44%, as opposed to 1.05% in the presence of CV risk factors (P=NS), 1.59% in the presence of JAK2 mutation (p=0.001) and 2.57% in the presence of both CV risk factors and JAK2 mutation (P<0.001). There was no significant difference when low-risk patients with both JAK2 mutation and CV risk factors were compared with either those with CV risk factors only (p=0.227) or those with JAK2 mutation only (p=0.217). ii) Conventionally assigned high-risk group: The absence or presence of one or both of the aforementioned additional risk factors for thrombosis were documented in 111 (22%), 44 (9%), 222 (43%) and 136 (27%) patients, respectively, with corresponding annual rates of thrombosis at 1.44%, 1.64%, 2.36% and 4.17% (Table). High-risk patients with both risk factors had a significantly higher risk of thrombosis compared to their counterparts with the absence of JAK2 mutations and CV risk factors (p=0.011). Additional analysis revealed limited enhancement of thrombosis risk by either JAK2 mutations or CV risk factors or both in patients whose high-risk status was defined by the presence of thrombosis history, regardless of age (P=NS). In contrast, the presence of JAK2 mutations, with or without CV risk factors, might have affected thrombosis risk in patients where high-risk status was defined by age alone (p=0.05). Conclusions The current study suggests the possibility of considering four risk categories in ET: "very low risk" group (age ≤60 years and without thrombosis history, JAK2 mutations or CV risk factors); "low risk" (age ≤60 years and without thrombosis history but with JAK2 mutations or CV risk factors); "intermediate risk" (age>60 years but without thrombosis history or JAK2 mutations); and "high risk" (thrombosis history at any age or JAK2 -mutated patients who are older than 60 years of age). Treatment recommendations for each one of the above-mentioned new risk categories should be examined in the context of prospective controlled studies. Disclosures Barbui: Novartis: Speakers Bureau. Vannucchi:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Buxhofer-Ausch:AOP Orphan: Research Funding. De Stefano:Novartis: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding; Shire: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Bruno Farmaceutici: Research Funding; Roche: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Gisslinger:Janssen Cilag: Honoraria, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Abstract Background: Many factors influence the choice of salvage therapy in relapsed/refractory multiple myeloma (RRMM), including various disease characteristics such as light chain and heavy chain subtypes. Patients with light chain only myeloma are a biologically and phenotypically distinct subset of patients from those with IgG, IgA, IgM, or IgD disease. Evidence exists that the presence of different paraprotein heavy and light chain subtypes may affect treatment outcomes. We investigated the effect of the presence of paraprotein heavy and light chain types on the efficacy and safety of pegylated liposomal doxorubicin (PLD) + bortezomib (B) versus B alone based on the phase III randomized trial of PLD+B vs. B alone in RRMM, which demonstrated improved time to progression (TTP) with PLD+B (Orlowski, JCO 2007). Methods: Eligible patients were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n=322) or to the same B regimen plus IV PLD 30 mg/m2 on day 4 (n=324) of each cycle. The subsets of patients with light chain and heavy chain multiple myeloma subtypes were analyzed retrospectively. Results: The presence of light chain myeloma was observed in 77 patients. Few patients had IgM/IgD subtype myeloma (4 and 6 patients, respectively), while the majority of patients had IgG (n=379) or IgA (n=265) subtypes. Time to disease progression (TTP) and complete response (CR) + partial response (PR) rates for PLD+B vs B alone in patients with light chain, IgG, and IgA myeloma subtypes are listed in the table. PLD+B B P valueb Hazard Ratioc a. Based on Kaplan-Meier product-limit estimates. b. Based on stratified Log-rank test. c. A hazard ratio &gt;1 indicates an advantage for PLD+B. d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment. Light chain, N 40 37 TTP, Median days (95% CI)a 276 (171, n/a) 117 (85, 173) .003 3.09 (1.42, 6.73) Total CR+PR, n/evaluable (%) 22/39 (56) 10/33 (30) .030d IgG subtype, N 182 197 TTP 282 (221, 331) 199 (170, 222) .002 1.67 (1.20, 2.31) Total CR+PR 70/173 (41) 81/194 (42) .915d IgA subtype, N 88 77 TTP 250 (218, n/a) 205 (177, 236) .506 1.22 (0.68, 2.18) Total CR+PR 46/79 (58) 39/72 (54) .723d Results showed that the combination of PLD+B had significant benefit over B alone in TTP (PLD+B led to longer TTP than B alone) for IgG paraprotein and light chain subtypes. Safety profiles for the 2 regimens in these subsets of patients with heavy or light chain myeloma were consistent with the known toxicities of the 2 agents used. Conclusions: These data demonstrate that the combination of PLD+B is an important treatment option in patients with RRMM. Patients with light chain only disease had the largest incremental benefit from the addition of PLD with an absolute increase in TTP of 159 days as well as an increase in the overall response rate from 30% to 56%.

Abstract Two novel spectrophotometric determination procedures based on retention of Allura Red onto Amberlite XAD-1180 and XAD-16 resins for its preconcentration, purification, and separation were developed. Analytical parameters of the methods including pH, eluent type, sample volume, and sample and eluent flow rates, were investigated and optimized. Interference effects of some cations, anions, and widely used food dyes were also investigated. Detection limits of the two methods were found to be 1.2 and 1.5 μg/L for XAD-1180 and XAD-16 columns, respectively, under optimum conditions. Linear calibration curve ranges of the methods were 0.4–8.0 and 0.5–6.0 μg/mL of Allura Red for XAD-1180 and XAD-16 resins, respectively. Preconcentration factors were found as 80 for both the XAD-1180 and XAD-16 columns using maximum sample volume and minimum eluent volume. RSDs of the methods were below 6% throughout all experiments. All absorbance measurements were performed at 506 nm. Validations of the methods were performed comparatively with determination of the Allura Red contents of some foodstuff, pharmaceutical, and energy drink samples. Allura Red concentrations in investigated solid and liquid samples ranged from 298 to 501 μg/g and 53.8 to 508 μg/mL, respectively. Satisfactory results were obtained from the real samples analysis. Allura Red contents of samples were determined to be highly similar using the two extraction methods. Comparisons of the methods were performed by analysis of Allura Red contents of the real samples. In addition to analytical parameters, adsorption isotherm studies were performed for the two kinds of Amberlite resins. It was observed that developed methods fit the linear form of the Freundlich adsorption isotherm model. All of the experimental results suggested that the developed SPE procedures are suitable for separation, preconcentration, and determination of Allura Red in solid and liquid matrixes.

In this study, heat transfer and fluid flow characteristics of nonboiling two-phase flow in microchannels were experimentally investigated. The effects of channel diameter (140, 222, 334, and 506 μm) on the Nusselt number and the pressure drop were considered. Air and water were used as the test fluids. Results were presented for the Nusselt number and the pressure drop over a wide range of gas superficial velocity (1.24–40.1 m/s), liquid superficial velocity (0.57–2.13 m/s), and wall heat flux (0.34–0.95 MW/m2). The results showed that the Nusselt number increased with increasing gas flow rate for the large channels of 506 and 334 μm, while the Nusselt number decreased with increasing gas flow for the small channels of 222 and 140 μm. Based on these experimental results, a new correlation for the forced convection Nusselt number was developed. In addition, the two-phase friction multiplier is shown to decrease as channel diameter decreases due to the influence of viscous and surface tension forces.

The heat transfer and fluid flow characteristics of non-boiling two-phase flow in microchannels were experimentally investigated. The effects of channel diameter (140, 222, 334, and 506 μm) on the Nusselt number were considered. Air and water were used as the working fluids. Results were presented for the Nusselt number over a wide range of gas superficial velocity (1.24–40.1 m/s), liquid superficial velocity (0.57–2.13 m/s), and wall heat flux (0.34–0.95 MW/m2). The results showed that the Nusselt number increased with increasing gas flow rate for the 506 μm and 334 μm channels, while the Nusselt number decreased with increasing gas flow for the 222 μm and 140 μm channels. Based on these experimental results, a transition channel diameter of about 235 μm to 260 μm, which distinguishes microchannels from minichannels, was suggested. By observing two-phase flow patterns within the microchannels, viscosity and surface tension were identified as the key factors that caused the heat transfer characteristics to change. In addition, new correlations for the forced convection Nusselt number were developed.