Scientific and Regulatory Policy Committee (SRPC) Review*: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment

Increased cell proliferation is a central key event in the mode of action for many non-genotoxic carcinogens, and quantitative cell proliferation data play an important role in the cancer risk assessment of many pharmaceutical and environmental compounds. Currently, there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here, we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment frameworks. As the regulatory environment moves toward more prospective evaluations based on quantitative pathway-based models, standardiza- tion of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies

As a Matter of Factions: The Budgetary Implications of Shifting Factional Control in Japan’s LDP

For 38 years, the Liberal Democratic Party (LDP) maintained single-party control over the Japanese government. This lack of partisan turnover in government has frustrated attempts to explain Japanese government policy changes using political variables. In this paper, we look for intraparty changes that may have led to changes in Japanese budgetary policy. Using a simple model of agenda-setting, we hypothesize that changes in which intraparty factions “control” the LDP affect the party’s decisions over spending priorities systematically. This runs contrary to the received wisdom in the voluminous literature on LDP factions, which asserts that factions, whatever their raison d’être, do not exhibit different policy preferences. We find that strong correlations do exist between which factions comprise the agenda-setting party “mainstream” and how the government allocates spending across pork-barrel and public goods items

Epidemiology of Clavibacter michiganensis subsp. sepedonicus in potato under European conditions: population development and yield reduction

The population development of Clavibacter michiganensis subsp, sepedonicus (Cms) using fluidal strain (NCPPB 4053) and non-mucoid strain (NCPPB 3898) were monitored by IF cell staining method in potato cultivars 'Hansa' and 'Desiree' under field conditions in Denmark and Finland. The influence of Cms on potato yield in 'Hansa' was also examined under field conditions in Finland. Population development was generally similar in potato fields in Denmark and Finland, but a higher bacterial density and a higher number of symptomatic plants were found in Finland than in Denmark. Inoculation of potato tubers with the fluidal Cms strain NCPPB 4053 resulted in higher densities of Cms in plants during the growing season than inoculation with the non-mucoid strain NCPPB 3898. Population densities of the fluidal Cms strain (4053) increased rapidly in the beginning of the seasons, and reached its maximum ca. 80-100 days from planting in susceptible 'Hansa'. Lower levels of Cms were found in tubers of the more resistant 'Desiree' than in those of the susceptible 'Hansa'. Tuber and stem symptoms emerged 80-100 days after planting in 'Hansa', but no visual symptoms were observed in 'Desiree'. Severe infection reduced the tuber yield of 'Hansa' by 41-56% in Finland

Transient trimethylaminuria related to menstruation

BACKGROUND: Trimethylaminuria, or fish odor syndrome, includes a transient or mild malodor caused by an excessive amount of malodorous trimethylamine as a result of body secretions. Herein, we describe data to support the proposal that menses can be an additional factor causing transient trimethylaminuria in self-reported subjects suffering from malodor and even in healthy women harboring functionally active flavin-containing monooxygenase 3 (FMO3). METHODS: FMO3 metabolic capacity (conversion of trimethylamine to trimethylamine N-oxide) was defined as the urinary ratio of trimethylamine N-oxide to total trimethylamine. RESULTS: Self-reported Case (A) that was homozygous for inactive Arg500stop FMO3, showed decreased metabolic capacity of FMO3 (i.e., ~10% the unaffected metabolic capacity) during 120 days of observation. For Case (B) that was homozygous for common [Glu158Lys; Glu308Gly] FMO3 polymorphisms, metabolic capacity of FMO3 was almost ~90%, except for a few days surrounding menstruation showing < 40% metabolic capacity. In comparison, three healthy control subjects that harbored heterozygous polymorphisms for [Glu158Lys; Glu308Gly] FMO3 or homozygous for wild FMO3 showed normal (> 90%) metabolic capacity, however, on days around menstruation the FMO3 metabolic capacity was decreased to ~60–70%. CONCLUSION: Together, these results indicate that abnormal FMO3 capacity is caused by menstruation particularly in the presence, in homozygous form, of mild genetic variants such as [Glu158Lys; Glu308Gly] that cause a reduced FMO3 function

The ERK-1 function is required for HSV-1-mediated G1/S progression in HEP-2 cells and contributes to virus growth

The herpes simplex virus 1 is able to readdress different cellular pathways including cell cycle to facilitate its replication and spread. During infection, the progression of the cell cycle from G1 to S phase makes the cellular replication machinery accessible to viral DNA replication. In this work we established that HSV-1, in asynchronized HEp-2 cells, strictly controls cell cycle progression increasing S-phase population from 9 hours post infection until the end of HSV-1 replication. The G1/S phases progression depends on two important proteins, cyclin E and CDK2. We demonstrate that their phosphorylated status and then their activity during the infection is strongly correlated to viral replication events. In addition, HSV-1 is able to recruit and distribute ERK1/2 proteins in a spatio-temporal fashion, highlighting its downstream regulatory effects on cellular processes. According with this data, using chemical inhibitor U0126 and ERK dominant negative cells we found that the lack of ERK1 activity affects cyclin E protein accumulation, viral gene transcription and percentage of the cells in S phase, during the viral replication. These data suggested a complex interaction between ERK, cell cycle progression and HSV-1 replication

Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis

Objectives. The osteochondral junction can be a source of pain in both RA and OA. Growth of blood vessels and nerves from the subchondral bone into articular cartilage may mediate the association between joint pathology and symptoms. We have investigated associations between angiogenesis, inflammation and neurovascular growth factor expression at the osteochondral junction in human arthritis

Direct high-precision measurement of the mass difference of 77^{77}As-77^{77}Se related to neutrino mass determination

The first direct determination of the ground-state-to-ground-state ${\beta^{-}}$-decay $Q$-value of $^{77}$As to $^{77}$Se was performed by measuring their atomic mass difference utilizing the double Penning trap mass spectrometer, JYFLTRAP. The resulting $Q$-value is 684.463(70) keV, representing a remarkable 24-fold improvement in precision compared to the value reported in the most recent Atomic Mass Evaluation (AME2020). With the significant reduction of the uncertainty of the ground-state-to-ground-state $Q$-value and knowledge of the excitation energies in $^{77}$Se from $\gamma$-ray spectroscopy, the ground-state-to-excited-state $Q$-value of the transition $^{77}$As (3/2$^{-}$, ground state) $\rightarrow$ $^{77}$Se$^{*}$ (5/2$^{+}$, 680.1035(17) keV) was refined to be 4.360(70) keV. We confirm that this potential low $Q$-value ${\beta^{-}}$-decay transition for neutrino mass determination is energetically allowed at a confidence level of about 60$\sigma$. Nuclear shell-model calculations with two well-established effective Hamiltonians were used to estimate the partial half-life for the low $Q$-value transition. The half-life was found to be of the order of 10$^{9}$ years for this first-forbidden non-unique transition, which rules out this candidate a potential source for rare-event experiments searching for the electron antineutrino mass.Comment: 8 pages, 4 figure

Nuclear charge radius of 26m^{26m}Al and its implication for Vud_{ud} in the quark-mixing matrix

Collinear laser spectroscopy was performed on the isomer of the aluminium isotope $^{26m}$Al. The measured isotope shift to $^{27}$Al in the 3s^{2}3p\;^{2}\!P^\circ_{3/2} \rightarrow 3s^{2}4s\;^{2}\!S_{1/2} atomic transition enabled the first experimental determination of the nuclear charge radius of $^{26m}$Al, resulting in $R_c$=\qty{3.130\pm.015}{\femto\meter}. This differs by 4.5 standard deviations from the extrapolated value used to calculate the isospin-symmetry breaking corrections in the superallowed $\beta$ decay of $^{26m}$Al. Its corrected $\mathcal{F}t$ value, important for the estimation of $V_{ud}$ in the CKM matrix, is thus shifted by one standard deviation to \qty{3071.4\pm1.0}{\second}.Comment: 5 pages, 2 figures, submitted to Phys. Rev. Let