Abstract
Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either
JAK2
or Calreticulin (
...CALR
) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First,
CALR
mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous
CALR
mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
Streptococcus salivarius
K12 is an oral probiotic known to contribute to protection against oral pathogenic bacteria in humans. Studies of immune responses to
S. salivarius
K12 have focused on the ...oral cavity, and systemic immune responses have not yet been reported. The aim of this study was to identify acute systemic immune responses to the commercial product,
S. salivarius
BLIS K12, in a double-blinded, placebo-controlled human clinical trial. It was hypothesised that consumption of
S. salivarius
BLIS K12 would induce an anti-inflammatory response and a decrease in pro-inflammatory cytokines. Blood samples were obtained from participants prior to a single dose of
S. salivarius
BLIS K12 or a placebo and then secondary blood samples were obtained 24 h and 7 days post-consumption. Samples were analysed using multi-parametric flow cytometry, to quantify immune cell frequency changes, and by a LEGENDplex assay of human inflammatory cytokines. Consumption of
S. salivarius
BLIS K12 was associated with increased levels of IL-8 at 24 h. The frequency of Tregs increased in samples taken 7 days after probiotic consumption, and IL-10 concentrations were higher at 7 days than 24 h after consumption. There was no difference in the frequency and/or activation of CD4
+
T cells, CD8
+
T cells, B cells and NK cells. Interestingly, there was an increase in IL-12, 7 days after the consumption of
S. salivarius
BLIS K12. Collectively, this research demonstrates that ingestion of the probiotic
S. salivarius
K12 can induce changes in the systemic immune response. The implications of the generation and type of immune response warrant further study to determine potential health benefits.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Streptococcus salivarius
BLIS K12 is a probiotic strain developed for application to the oral cavity. The strain was originally characterised for its in vitro antibacterial activity against the ...prominent oral pathogen
Streptococcus pyogenes.
More recent research has expanded its applications to include reducing halitosis, preventing otitis media and protecting against virus infections of the respiratory tract. A potential mechanism for this anti-viral activity could be the stimulation of salivary interferon gamma (IFN-γ) production in the oral cavity. The aim of this study was to investigate whether the ingestion of and oral cavity colonisation by
S. salivarius
BLIS K12 is associated with enhancement of IFN-γ levels in saliva. Application of ELISA demonstrated that consumption of
S. salivarius
BLIS K12 effected an increase in salivary IFN-γ, and this response was more consistent with use of viable cells than following ingestion of heat-killed
S. salivarius
BLIS K12. Interestingly, those subjects who more successfully colonised with
S. salivarius
BLIS K12 did not experience a relatively larger increase in their IFN-γ levels, indicating that the observed IFN-γ response occurs independently of colonisation efficacy. In summary, the consumption of
S. salivarius
BLIS K12 increases salivary levels of IFN-γ, an effect that may contribute to protection of the host against certain virus infections.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The National Beef Quality Audit (NBQA)-2016 used in-plant cooler assessments to benchmark the current status of the fed steer and heifer beef industry in the United States. In-plant cooler ...assessments ( = 9,106 carcasses) were conducted at 30 facilities, where approximately 10% of a single day's production were evaluated for USDA quality grade (QG) and yield grade (YG) factors. Frequencies of evaluated traits were 66.5% steer and 33.4% heifer sex classes and 82.9% native, 15.9% dairy-type, and 1.2% estimated breed types. Mean USDA YG factors were 1.42 cm for adjusted fat thickness, 89.5 cm for LM area, 390.3 kg for HCW, and 1.9% for KPH. Mean USDA YG was 3.1, with a frequency distribution of 9.6% YG 1, 36.7% YG 2, 39.2% YG 3, 12.0% YG 4, and 2.5% YG 5. Mean USDA QG traits were Small for marbling score, A for overall maturity, A55 for lean maturity, and A for skeletal maturity. Mean USDA QG was Select with a frequency distribution of QG of 3.8% Prime, 67.3% Choice, 23.2% Select, and 5.6% lower score. Lower score included dark cutter (1.9%), blood splash (0.1%), and hard bone, which are USDA overall maturity scores of C or older (1.8%). Marbling score distributions were 0.85% Slightly Abundant or greater, 7.63% Moderate, 23.54% Modest, 39.63% Small, 23.62% Slight, and 0.83% Traces or less. Carcasses that were Choice or Select and USDA YG 2 or 3 accounted for 70.7% of the carcasses evaluated. Compared with the previous NBQA, we found a numerical increase in mean USDA YG, USDA QG, adjusted fat thickness, HCW, LM area, and marbling score with an increase in dairy-type carcasses and percentage of carcasses grading USDA Prime and Choice as well as frequency of USDA YG 4 and 5. The findings from this study will be used by all segments of the industry to understand and improve the quality of fed steer and heifer beef that is being produced.
Three groups of steers (A, B, C) were used to study the effect of temperament (Calm, Intermediate, and Excitable) on meat quality. Temperament was based on exit velocity, pen scores, and chute ...scores. Temperament traits were consistent across evaluations, and values decreased (
P
<
0.05) in magnitude over time. Increasing excitability was associated with higher (
P
<
0.05) serum cortisol concentrations. Carcasses from cattle with calm temperaments had higher (
P
<
0.05) 0.5
h postmortem pH values than those from Intermediate and Excitable cattle (0.1 and 0.2 units, respectively). Group C Excitable steers had higher (
P
<
0.05) WBS values than the calmer Group C steers. This trend was observed in Group A steers, although the values were not statistically different. Correlations were highest between temperament values and tenderness after 21
d. Temperament influences tenderness, although the mechanism is not clear.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The National Beef Quality Audit-2005 assessed the current status of quality and consistency of US fed steers and heifers. Hide colors or breed type were black (56.3%), red (18.6%), Holstein (7.9%), ...gray (6.0%), yellow (4.9%), brown (3.0%), white (2.3%), and brindle (1.0%). Identification method and frequency were lot visual tags (63.2%), individual visual tags (38.7%), metal-clip tags (11.8%), electronic tags (3.5%), bar-coded tags (0.3%), by other means (2.5%), and without identification (9.7%). Brand frequencies were no (61.3%), 1 (35.1%), and 2 or more (3.6%), and brands were located on the butt (26.5%), side (7.4%), and shoulder (1.2%). There were 22.3% of cattle without horns, and the majority of those with horns (52.2%) were between 2.54 and 12.7 cm in length. Percentages of animals with mud or manure on specific body locations were none (25.8%), legs (61.4%), belly (55.9%), side (22.6%), and top-line (10.0%). Permanent incisor number and occurrence were zero (82.2%), 1 (5.2%), 2 (9.9%), 3 (0.4%), 4 (1.2%), 5 (0.1%), 6 (0.3%), 7 (0.0%), and 8 (0.7%). Most carcasses (64.8%) were not bruised, 25.8% had one bruise, and 9.4% had multiple bruises. Bruise location and incidence were round (10.6%), loin (32.6%), rib (19.5%), chuck (27.0%), and brisket, flank, and plate (10.3%). Condemnation item and incidence were liver (24.7%), lungs (11.5%), tripe (11.6%), heads (6.0%), tongues (9.7%), and carcasses (0.0%). Carcass evaluation revealed these traits and frequencies: steer (63.7%), heifer (36.2%), bullock (0.05%), and cow (0.04%) sex classes; dark-cutters (1.9%); A (97.1%), B (1.7%), and C or older (1.2%) overall maturities; and native (90.9%), dairy-type (8.3%), and Bos indicus (0.8%) estimated breed types. Mean USDA yield grade (YG) traits were USDA YG (2.9), HCW (359.9 kg), adjusted fat thickness (1.3 cm), LM area (86.4 cm²), and KPH (2.3%). The USDA YG were YG 1 (16.5%), YG 2 (36.3%), YG 3 (33.1%), YG 4 (11.8%), and YG 5 (2.3%). Mean USDA quality grade traits were USDA quality grade (Select⁹⁰), marbling score (Small³²), overall maturity (A⁶⁴), lean maturity (A⁵⁷), and skeletal maturity (A⁶⁸). Marbling score distribution was Slightly Abundant or greater (2.7%), Moderate (4.3%), Modest (14.4%), Small (34.5%), Slight (41.2%), and Traces or less (2.9%). This information helps the beef industry measure progress and provides a benchmark for future educational and research activities.
Cluster randomised controlled trials (CRCTs) are increasingly used to evaluate the effectiveness of interventions for improving health. A key feature of CRCTs is that individuals in clusters are ...often more alike than individuals in different clusters, irrespective of treatment. This similarity within clusters needs to be taken into account when planning CRCTs to obtain adequate sample sizes, and when analysing clustered data to obtain correct estimates.
Nationally representative data from 15 to 16 year olds were analysed, from 21 of the 35 countries that participated in the 2007 European School Survey Project on Alcohol and Other Drugs. Within country school level intra-class correlation coefficients (ICCs) were calculated for substance use (self-reported alcohol use, regular alcohol use, binge drinking, any smoking, regular smoking, and illicit drug use) and psychosocial health (depressive mood and self-esteem). Unadjusted and adjusted ICCs are presented. ICCs are adjusted for student sex and socioeconomic status.
ICCs ranged from 0.01 to 0.21, with the highest (0.21) reported for regular smoking. Within country school level ICCs varied substantially across health outcomes, and among countries for the same health outcomes. Estimated ICCs were consistently higher for substance use (range 0.01-0.21), than for psychosocial health (range 0.01-0.07). Within country ICCs for health outcomes varied by changes in the measurement of particular health outcomes, for example the ICCs for regular smoking (range 0.06-0.21) were higher than those for having smoked at all in the last month (range 0.03-0.17).
For school level ICCs to be effectively utilised in informing sample size requirements for CRCTs and adjusting estimates from meta-analyses, the school level ICCs need to be both country and outcome specific.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thalassemia, as the most common single-gene genetic disorder, is related to a defect in the synthesis of one or more hemoglobin chains. More than 200 mutations have been identified in the β-globin ...gene. Globally, every susceptible racial group has its own specific spectrum of the common mutations that are well-known to a particular geographic region. On the other hand, varying numbers of diverse rare mutations may occur.
The subjects of the study included 2113 heterozygote or homozygote β-thalassemia cases selected among couples who participated in the Iranian national thalassemia screening program from January 2011 to November 2019. Molecular characterization of the β-thalassemia mutation was initially carried out by the amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) technique for common mutations, followed by sequencing, Gap PCR, and Multiple ligation-dependent probe amplification (MLPA) methods - in cases not detected by the ARMS-PCR.
The existence of 39 rare and new point mutations and 4 large deletions were described in our cohort. Sicilian (-13,337bp) deletion, CD36/37 (-T), and CD15 TGG>TGA were encountered more often than the others in a decreasing order, in terms of frequency. The least frequent mutations/deletions were deletion from HBD exon 1 to HBB promoter, 619 bp deletion, Deletion from up HBBP1-Exon3 HBBP1 and up HBB-0.5Kb down HBB, CAP+8 C>A, CD37 (G>A), CD6 (-A), IVSI-2 (T>C), IVSII-705 T>G, and IVSII-772 (G>A). Each occurred once. Five mutations/variants were also determined which have not been reported previously in Iran.
According to the findings of the study, the Northwestern Iranian population displayed a wide variety of thalassemia allelic distributions. Identification of rare and new mutations in the β-thalassemia in the national population is beneficial for screening programs, genetic counseling, and prenatal diagnosis.
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IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UL, UM, UPUK
Understanding at a molecular level, the immunologic response of polyomavirus nephropathy (PVN), a critical cause of kidney graft loss, could lead to new targets for treatment and diagnosis. We ...undertook a transcriptional evaluation of kidney allograft biopsies from recipients with PVN or acute rejection (AR), as well as from recipients with stable allograft function (SF). In both the PVN and AR groups, Banff histologic scores and immunohistochemical analysis of inflammatory infiltrates were similar. Despite their different etiologies, the transcriptional profiles of PVN and AR were remarkably similar. However, transcription of genes previously linked to AR including CD8 (65.9 ± 18.8) and related molecules IFN‐γ(55.1 ± 17.0), CXCR3 (49.9 ± 12.8) and perforin (153.8 ± 50.4) were significantly higher in PVN compared to AR (30.9 ± 2.0, 14.0 ± 7.3, 12.1 ± 7.3 and 15.6 ± 3.8‐fold, respectively; p < 0.01). Importantly, transcription of molecules associated with graft fibrosis including matrix collagens, TGFβ, MMP2 and 9, as well as markers of epithelial‐mesenchymal transformation (EMT) were significantly higher in PVN than AR. Thus, renal allografts with PVN transcribe proinflammatory genes equal in character and larger in magnitude to that seen during acute cellular rejection. BK infection creates a transcriptional microenvironment that promotes graft fibrosis. These findings provide new insights into the intrarenal inflammation of BK infection that promotes graft loss.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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