Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation.

It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206-PD-L2-MHCII-UCP1+ phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni. The phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206- macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A-deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, which indicates that failure to convert macrophages from the F4/80intCD206+ phenotype to F4/80hiCD206- may lead to dysregulated inflammation during helminth infection.

Nuclear KRT19 is a transcriptional corepressor promoting histone deacetylation and liver tumorigenesis.

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 and REST corepressor 1, components of the corepressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing histone deacetylase 1 and REST corepressor 1 interaction, thus increasing the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha ( HNF4A ), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to histone deacetylase 1 inhibitors especially in combination with lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional corepressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.

Self-Assembled Micelles Based on Ginsenoside Rg5 for the Targeted Treatment of PTX-Resistant Tumors.

Paclitaxel (PTX) is one of the first-line drugs for prostate cancer (PC) treatment. However, the poor water solubility, inadequate specific targeting ability, multidrug resistance, and severe neurotoxicity are far from being fully resolved, despite diverse PTX formulations in the market, such as the gold-standard PTX albumin nanoparticle (Abraxane) and polymer micelles (Genexol-PM). Some studies attempting to solve the multiple problems of chemotherapy delivery fall into the trap of an extremely complicated formulation design and sacrifice druggability. To better address these issues, this study designed an efficient, toxicity-reduced paclitaxel-ginsenoside polymeric micelle (RPM). With the aid of the inherent amphiphilic molecular structure and pharmacological effects of ginsenoside Rg5, the prepared RPM enhances the water solubility and active targeting of PTX, inhibiting chemotherapy resistance in cancer cells. Moreover, the polymeric micelles demonstrated favorable anti-inflammatory and neuroprotective effects, providing ideas for the development of new clinical anti-PC preparations.

Current state of gene therapy in sickle cell disease.

Sickle cell disease (SCD) is a type of hemoglobinopathy due to an autosomal recessive genetic defect, causing significant red cell sickling, multi-organ damage and long-term severe morbidities. Due to its complicated care and the impact on quality of life, a curative treatment for SCD is highly desirable. In recent years, gene therapy is emerging as a curative option for SCD, where autologous haematopoietic stem cells are collected from SCD patients and genetically modified ex vivo to reduce its sickling tendency before reinfusion. Although still largely investigational, a limited number of gene therapy options have been recently granted approval for SCD patients. Published data are still currently limited, but early studies have so far demonstrated the intended outcomes of less vaso-occlusive crisis and haemolysis. Nonetheless, despite its curative potential, larger clinical trials and longer follow-up period are still necessary to evaluate the safety of this treatment option, especially the risk of unintended genetic modifications. Furthermore, SCD patients frequently have limited access to specialty care; hence, the issues of affordability and accessibility to SCD gene therapy must also be addressed for it to benefit the appropriate patient population.

Molecular phylogeny and morphology of Sporodiniella sinensis sp. nov. (Syzygitaceae, Mucorales), an invertebrate-associated species from Yunnan, China.

During investigations of invertebrate-associated fungi in Yunnan Province of China, a new species, Sporodiniella sinensis sp. nov., was collected. Morphologically, S. sinensis is similar to Sporodiniella umbellata; however, it is distinguished from S. umbellata by its greater number of sporangiophore branches, longer sporangiophores, larger sporangiospores, and columellae. The novel species exhibits similarities of 91.62 % for internal transcribed spacer (ITS), 98.66-99.10 % for ribosomal small subunit (nrSSU), and 96.36-98.22 % for ribosomal large subunit (nrLSU) sequences, respectively, compared to S. umbellata. Furthermore, phylogenetic analyses based on combined sequences of ITS, nrLSU and nrSSU show that it forms a separate clade in Sporodiniella, and clusters closely with S. umbellata with high statistical support. The phylogenetic and morphological evidence support S. sinensis as a distinct species. Here, it is formally described and illustrated, and compared with other relatives.

Design, synthesis and triglyceride-lowering activity of tricyclic matrine derivatives for the intervention of non-alcoholic fatty liver disease.

Thirty new tricyclicmatrinic derivatives were successively synthesized and evaluated for their inhibitory activity on the accumulation of triglycerides (TG) in AML12 cells, using 12 N-m-trifluoromethylbenzenesulfonyl matrine (1) as the hit compound. Among the analogues, compound 7n possessing 11-trimethylbutylamine quaternary exerted the highest in vitro TG-lowering potency, as well as a good safety profile. 7n significantly attenuated the hepatic injury and steatosis, and ameliorated dyslipidemia and dysglycemia in the mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Primary mechanism study revealed that upregulation of peroxisome proliferator-activated receptors α (PPARα)-carnitine palmitoyltransferase 1A (CPT1A) pathway mediated the efficacy of 7n. Our study provides powerful information for developing this kind of compound into a new class of anti-NAFLD candidates, and compound 7n is worthy of further investigation as an ideal lead compound.

Prevalence and risk factors for obstructive pulmonary dysfunction caused by silica dust exposure: a multicenter cross-sectional study.

OBJECTIVE: To understand the prevalence rate of obstructive pulmonary dysfunction in workers exposed to silica dust and analyze its risk factors, so as to provide reference for the formulation of diagnostic criteria for chronic obstructive pulmonary disease caused by occupational dust. METHODS: Data collection and structured questionnaire were used to collect the data of 2064 workers exposed to silica dust who underwent health examination in Hunan Occupational Disease Prevention and Control Hospital and Yuanling Second People's Hospital from January 1, 2021 to June 30, 2022. The prevalence rate of obstructive pulmonary ventilation dysfunction was analyzed and the risk factors were analyzed. RESULTS: The prevalence rate of obstructive pulmonary ventilation dysfunction (FEV1/FVC < 70%) was 2.3% in 2064 silica dust exposed workers. The prevalence of restrictive pulmonary ventilation dysfunction (FVC/Pre < 80%) was 8.1%. The prevalence of obstructive pulmonary ventilation dysfunction in the high level exposure group was higher than that in the low level exposure group, 8.2 vs0.9% (P < 0.05). The rate of obstructive pulmonary ventilation dysfunction in female group was higher than that in male group (5.3% vs. 1.7%, p = 0.00). Workers with obstructive pulmonary dysfunction were older and worked longer than workers without obstructive pulmonary dysfunction, but there was no statistical difference. Multivariate regression analysis showed that high exposure level was a risk factor for obstructive pulmonary ventilation dysfunction in silica dust exposed workers (P < 0.05). Females were the risk factors for obstructive pulmonary ventilation dysfunction (P < 0.05). CONCLUSION: Silica dust exposure can cause obstructive pulmonary ventilation dysfunction and lead to chronic obstructive pulmonary disease. High level of exposure is a risk factor for obstructive pulmonary ventilation dysfunction. Women exposed to dust are more prone to obstructive pulmonary ventilation dysfunction than men. Early diagnosis of chronic obstructive pulmonary disease caused by silica dust and timely intervention measures are very important to delay the decline of lung function and protect the health of workers.

Synthesis of selenophene-containing flavonols and 2-styrylchromones: Evaluation of their activities compared with selenophene-containing chalcones as potential anticancer agents.

Previously, we documented the synthesis and assessed the biological effects of chalcones containing selenium against HT-29 human colorectal adenocarcinoma cells, demonstrating their significant potential. As research on selenium-containing flavonoids remains limited, this article outlines our design and synthesis of three selenium-based flavonols and three 2-styrylchromones. We conducted evaluations of these compounds to determine their impact on human lung cancer cells (A549, H1975, CL1-0, and CL1-5) and their influence on normal lung fibroblast MRC5 cells. Additionally, we included selenium-based chalcones in our testing for comparative purposes. Our findings highlight that the simplest compound, designated as compound 1, exhibited the most promising performance among the tested molecules.

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Ginsenoside 3ß-O-Glc-DM (C3DM) suppressed glioma tumor growth by downregulating the EGFR/PI3K/AKT/mTOR signaling pathway and modulating the tumor microenvironment.

Ginsenosides are the main bioactive constituents of Panax ginseng, which have been broadly studied in cancer treatment. Our previous studies have demonstrated that 3ß-O-Glc-DM (C3DM), a biosynthetic ginsenoside, exhibited antitumor effects in several cancer cell lines with anti-colon cancer activity superior to ginsenoside 20(R)-Rg3 in vivo. However, the efficacy of C3DM on glioma has not been proved yet. In this study, the antitumor activities and underlying mechanisms of C3DM on glioma were investigated in vitro and in vivo. Cell viability, apoptosis, migration, FCM, IHC, RT-qPCR, quantitative proteomics, and western blotting were conducted to evaluate the effect of C3DM on glioma cells. ADP-Glo™ kinase assay was used to validate the interaction between C3DM and EGFR. Co-cultured assays, lactic acid kit, and spatially resolved metabolomics were performed to study the function of C3DM in regulating glioma microenvironment. Both subcutaneously transplanted syngeneic models and orthotopic models of glioma were used to determine the effect of C3DM on tumor growth in vivo. We found that C3DM dose-dependently induced apoptosis, and inhibited the proliferation, migration and angiogenesis of glioma cells. C3DM significantly inhibited tumor growth in both subcutaneous and orthotopic mouse glioma models. Moreover, C3DM attenuated the acidified glioma microenvironment and enhanced T-cell function. Additionally, C3DM inhibited the kinase activity of EGFR and influenced the EGFR/PI3K/AKT/mTOR signaling pathway in glioma. Overall, C3DM might be a promising candidate for glioma prevention and treatment.

Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus.

Nod2 has been extensively characterized as a bacterial sensor that induces an antimicrobial and inflammatory gene expression program. Therefore, it is unclear why Nod2 mutations that disrupt bacterial recognition are paradoxically among the highest risk factors for Crohn's disease, which involves an exaggerated immune response directed at intestinal bacteria. Here, we identified several abnormalities in the small-intestinal epithelium of Nod2(-/-) mice including inflammatory gene expression and goblet cell dysfunction, which were associated with excess interferon-γ production by intraepithelial lymphocytes and Myd88 activity. Remarkably, these abnormalities were dependent on the expansion of a common member of the intestinal microbiota Bacteroides vulgatus, which also mediated exacerbated inflammation in Nod2(-/-) mice upon small-intestinal injury. These results indicate that Nod2 prevents inflammatory pathologies by controlling the microbiota and support a multihit disease model involving specific gene-microbe interactions.

The highly exothermic hydrogen abstraction reaction H2Te + OH → H2O + TeH: comparison with analogous reactions for H2Se and H2S.

The "gold standard" CCSD(T) method is adopted along with the correlation consistent basis sets up to aug-cc-pV5Z-PP to study the mechanism of the hydrogen abstraction reaction H2Te + OH. The predicted geometries and vibrational frequencies for reactants and products are in good agreement with the available experimental results. With the ZPVE corrections, the transition state in the favorable pathway of this reaction energetically lies 1.2 kcal mol-1 below the reactants, which is lower than the analogous relative energies for the H2Se + OH reaction (-0.7 kcal mol-1), the H2S + OH reaction (+0.8 kcal mol-1) and the H2O + OH reaction (+9.0 kcal mol-1). Accordingly, the exothermic reaction energies for these related reactions are predicted to be 47.8 (H2Te), 37.7 (H2Se), 27.1 (H2S), and 0.0 (H2O) kcal mol-1, respectively. Geometrically, the low-lying reactant complexes for H2Te + OH and H2Se + OH are two-center three-electron hemibonded structures, whereas those for H2S + OH and H2O + OH are hydrogen-bonded. With ZPVE and spin-orbit coupling corrections, the relative energies for the reactant complex, transition state, product complex, and the products for the H2Te + OH reaction are estimated to be -13.1, -1.0, -52.0, and -52.6 kcal mol-1, respectively. Finally, twenty-eight DFT functionals have been tested systematically to assess their ability in describing the potential energy surface of the H2Te + OH reaction. The best of these functionals for the corresponding energtics are -9.9, -1.4, -46.4, and -45.4 kcal mol-1 (MPWB1K), or -13.1, -2.4, -57.1, and -54.6 kcal mol-1 (M06-2X), respectively.

Development and application of Adverse drug reactions reports QUality Algorithm (AQUA-12) score: a single-centre quality improvement initiative.

PURPOSE: To develop a reliable assessment tool to monitor the quality of adverse drug reaction (ADR) reports and evaluate its performance within a quaternary hospital setting. METHODS: Adverse drug reactions report QUality Algorithm (AQUA-12) was developed by a multidisciplinary team with the expertise in the management of ADRs. The design was based on data elements required to establish medication causality. Inter-rater reliability of AQUA-12 was evaluated over three rounds in two phases: development and prospective evaluation phases, by independent assessors both internal and external to the institutional ADR review processes. The characteristics and quality of ADR reports were subsequently assessed, and potential factors contributing to low-quality reports were identified. RESULTS: A total of 70 ADR reports were assessed, 20 in development and 50 in evaluation phases. The inter-rater reliability of AQUA-12 was found to be excellent in all three rounds (Cronbach's alpha of  ≥ 0.9, p < 0.001 for all). Approximately one in five reports concerned immediate hypersensitivity reactions while delayed hypersensitivity reactions constituted 60% of all reactions. AQUA-12 identified 18 (25.7%) reports as 'low-quality' with a score of  < 10. Identification of suspected medications (37.1%), description of index ADR (27.1%), and key events (ADR narrative, 35.7%) were the top data elements incomplete or missing from all reports. Univariable analyses identified the severity of the reaction as a factor associated with low quality of reports (p = 0.008). CONCLUSIONS: AQUA-12 is a practical and highly reliable assessment tool that can be utilised in hospital settings to regularly monitor the completeness of ADR reports to guide quality improvement initiatives.

The post-discharge coping difficulty of puerperal women in a middle and low-income tourist city during the COVID-19 pandemic.

BACKGROUND: Since the coronavirus disease 2019 (COVID-19) pandemic outbreak, the incidence of mental health problems in perinatal women has been high, and particularly prominent in China which was the first country affected by COVID-19. This paper aims to investigate the current situation and the related factors of maternal coping difficulties after discharge during COVID-19. METHODS: General information questionnaires (the Perinatal Maternal Health Literacy Scale, Postpartum Social Support Scale and Post-Discharge Coping Difficulty Scale-New Mother Form) were used to investigate 226 puerperal women in the third week of puerperium. The influencing factors were analyzed by single factor analysis, correlation and multiple linear regression. RESULTS: The total score of coping difficulties after discharge was 48.92 ± 12.05. At the third week after delivery, the scores of health literacy and social support were 21.34 ± 5.18 and 47.96 ± 12.71. There were negative correlations among health literacy, social support and coping difficulties after discharge (r = -0.34, r = -0.38, P < 0.001). Primipara, family income, health literacy and social support were the main factors influencing maternal coping difficulties after discharge. CONCLUSION: During the COVID-19 pandemic, puerperal women in a low- and middle-income city had moderate coping difficulties after discharge and were affected by many factors. To meet the different needs of parturients and improve their psychological coping ability, medical staff should perform adequate assessment of social resources relevant to parturients and their families when they are discharged, so they can smoothly adapt to the role of mothers.

Physiologically based pharmacokinetic model to predict drug-drug interactions with the antibody-drug conjugate enfortumab vedotin.

Enfortumab vedotin is an antibody-drug conjugate (ADC) comprised of a Nectin-4-directed antibody and monomethyl auristatin E (MMAE), which is primarily eliminated through P-glycoprotein (P-gp)-mediated excretion and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. A physiologically based pharmacokinetic (PBPK) model was developed to predict effects of combined P-gp with CYP3A4 inhibitor/inducer (ketoconazole/rifampin) on MMAE exposure when coadministered with enfortumab vedotin and study enfortumab vedotin with CYP3A4 (midazolam) and P-gp (digoxin) substrate exposure. A PBPK model was built for enfortumab vedotin and unconjugated MMAE using the PBPK simulator ADC module. A similar model was developed with brentuximab vedotin, an ADC with the same valine-citrulline-MMAE linker as enfortumab vedotin, for MMAE drug-drug interaction (DDI) verification using clinical data. The DDI simulation predicted a less-than-2-fold increase in MMAE exposure with enfortumab vedotin plus ketoconazole (MMAE geometric mean ratio [GMR] for maximum concentration [Cmax], 1.15; GMR for area under the time-concentration curve from time 0 to last quantifiable concentration [AUClast], 1.38). Decreased MMAE exposure above 50% but below 80% was observed with enfortumab vedotin plus rifampin (MMAE GMR Cmax, 0.72; GMR AUClast, 0.47). No effect of enfortumab vedotin on midazolam or digoxin systemic exposure was predicted. Results suggest that combination enfortumab vedotin, P-gp, and a CYP3A4 inhibitor may result in increased MMAE exposure and patients should be monitored for potential adverse effects. Combination P-gp and a CYP3A4 inducer may result in decreased MMAE exposure. No exposure change is expected for CYP3A4 or P-gp substrates when combined with enfortumab vedotin.ClinicalTrials.gov identifier Not applicable.

Alcohol consumption, smoking, and invasive breast cancer risk after ductal carcinoma in situ.

PURPOSE: Alcohol is an established risk factor for invasive breast cancer, and women with a prior ductal carcinoma in situ diagnosis are at higher risk of invasive breast cancer than the general population. However, for women with a prior ductal carcinoma in situ diagnosis, few studies have evaluated the association between alcohol and smoking and risk of subsequent invasive breast cancer. METHODS: Utilizing a population-based case-control design nested among women diagnosed with a ductal carcinoma in situ between 1995 and 2013, we compared 243 cases diagnosed with a subsequent invasive breast cancer and 423 individually matched controls never diagnosed with a subsequent breast cancer. RESULTS: Compared with never to occasional drinkers, drinkers consuming at least 7 alcoholic drinks per week on average at ductal carcinoma in situ diagnosis had a higher risk of invasive breast cancer that was borderline significant (OR 1.79, 95% CI 1.01-3.17, P value = 0.04). Smoking was not significantly associated with risk of developing an invasive breast cancer after adjustment for alcohol consumption. CONCLUSIONS: These findings suggest that consuming at least one alcoholic drink per day on average is positively associated with invasive breast cancer for women with a prior ductal carcinoma in situ diagnosis. If confirmed, modulating alcohol consumption could be one strategy for women with a history of ductal carcinoma in situ to impact their risk of invasive breast cancer.

Association between antidepressant use and second breast cancer event after ductal carcinoma in situ diagnosis: a nested case-control study.

PURPOSE: Controversy exists regarding the potential relationship between antidepressant use and risk of breast cancer. No previous studies have evaluated the relationship between antidepressant use after diagnosis of ductal carcinoma in situ (DCIS) and risk of a subsequent breast cancer restricted to women with a history of DCIS. METHODS: We conducted a population-based, nested case-control study in western Washington State. Cases included 337 women diagnosed with DCIS and a subsequent breast cancer and they were compared to 592 individually matched controls (on age, year of DCIS diagnosis, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but not a subsequent breast cancer. Information on antidepressant use after DCIS diagnosis was obtained from comprehensive medical records reviews. Antidepressant use was defined as greater or equal to 3 months of duration. RESULTS: Antidepressant use after initial DCIS was associated with a 1.4-fold increased risk of a subsequent breast cancer event (adjusted OR 1.41, 95% CI 1.02, 1.95). Similar risks were observed when assessing individual antidepressant classes, however, there was no sufficient power across specific classes of antidepressants. CONCLUSIONS: Antidepressant use after DCIS diagnosis was associated with an increased risk of subsequent breast cancer in women. Further studies are needed to confirm the associations observed.

Potential of an endophytic bacteria Bacillus amyloliquefaciens 3-5 as biocontrol agent against potato scab.

To obtain a potential biocontrol agent for potato scab, 75 endophytic bacteria were isolated from the healthy potato tubers and strain 3-5 was selected as an optimal antagonistic bacterium against Streptomyces griseoplanus (Streptacidiphilus griseoplanus) causing potato scab. Strain 3-5 was identified as Bacillus amyloliquefaciens based on its morphological characteristics, 16S rDNA and gyrB gene sequence analysis. B. amyloliquefaciens 3-5 has biological functions of indole-3-acetic acid (IAA) production and nitrogen fixation. Polymerase chain reaction (PCR) detection revealed that B. amyloliquefaciens 3-5 had 6 diverse antibacterial substance synthesis genes, named bacD, bacAB, ituD, ituC, sfP and albF, which resulted in the production of bacilysin, iturin, surfactin and subtilosin. Field efficacy evaluation revealed that B. amyloliquefaciens 3-5 (solid fermentation) was successful in controlling potato scab with a 38.90 ± 3.2140% efficiency which is higher than other chemical bactericides except zhongshengmycin·oligosaccharins and kasugamycin·zhongshengmycin. The endophytic bacterium B. amyloliquefaciens 3-5 could be used as a biocontrol agent against potato scab due its control efficacy and environmental safety.

Transfusion outcomes between regular and low yield pathogen reduced platelets across different patient populations in a single institution.

BACKGROUND: Pathogen reduction technology (PRT) effectively mitigates bacterial contamination in platelets but is more likely to produce low yield units. Although low dose transfusion using conventional platelets has not been associated with increased bleeding, these findings have not been reproduced with PRT-treated platelets. STUDY DESIGN AND METHODS: Platelet transfusions in a tertiary adult hospital were retrospectively reviewed. Comparisons were made between PRT-treated regular (PRT-PR) and low (PRT-PL) yield platelets. Outcomes examined included the number of platelets and RBCs transfused, transfusion-free interval, and corrected count increment (CCI). Subgroup analyses were also performed on hematology-oncology inpatients and outpatients, as well as non-hematology-oncology patients. RESULTS: Platelet utilization per patient remained mostly unchanged (mean 2.9-4.3 units per patient per month) even when the frequency of PRT-PL transfusion increased. Among 1402 patients examined, the number of platelets and RBCs transfused was not significantly different between patients first transfused with PRT-PR versus PRT-PL (mean number of platelet units = 2.8 vs. 3.1, p = 0.38; mean number of RBC units = 4.8 vs. 4.3, p = 0.93). Among 10,257 platelet transfusions examined, the transfusion-free interval (hazard ratio = 1.05, 95% confidence interval 1.00-1.10) and CCI (10.2 vs. 11.0, p = 0.70) were comparable between PRT-PR and PRT-PL units. Similar findings were observed in all subgroups, except for shortened transfusion-free intervals among hematology-oncology inpatients. CONCLUSION: PRT-PR and PRT-PL units may be used in an equivalent manner to maintain an adequate platelet inventory, since there was only a minor difference in time between transfusions.

Alternative Activation of Macrophages Is Accompanied by Chromatin Remodeling Associated with Lineage-Dependent DNA Shape Features Flanking PU.1 Motifs.

IL-4 activates macrophages to adopt distinct phenotypes associated with clearance of helminth infections and tissue repair, but the phenotype depends on the cellular lineage of these macrophages. The molecular basis of chromatin remodeling in response to IL-4 stimulation in tissue-resident and monocyte-derived macrophages is not understood. In this study, we find that IL-4 activation of different lineages of peritoneal macrophages in mice is accompanied by lineage-specific chromatin remodeling in regions enriched with binding motifs of the pioneer transcription factor PU.1. PU.1 motif is similarly associated with both tissue-resident and monocyte-derived IL-4-induced accessible regions but has different lineage-specific DNA shape features and predicted cofactors. Mutation studies based on natural genetic variation between C57BL/6 and BALB/c mouse strains indicate that accessibility of these IL-4-induced regions can be regulated through differences in DNA shape without direct disruption of PU.1 motifs. We propose a model whereby DNA shape features of stimulation-dependent genomic elements contribute to differences in the accessible chromatin landscape of alternatively activated macrophages on different genetic backgrounds that may contribute to phenotypic variations in immune responses.