IGF-1 rs6218 polymorphisms modulate the susceptibility to age-related cataract.

Background: Single nucleotide polymorphisms (SNPs), as the most abundant form of DNA variation in the human genome, contribute to age-related cataracts (ARC) development. Apoptosis of lens epithelial cells (LECs) is closely related to ARC formation. Insulin-like growth factor 1 (IGF1) contributes to cell apoptosis regulation. Moreover, IGF1 was indicated to exhibit a close association with cataract formation. Afterward, an investigation was conducted to examine the correlation between polymorphisms in IGF1 and the susceptibility to ARC. Methods: The present investigation was a case-control study. Venous blood draws were collected from the participants for DNA genotyping. Lens capsule samples were collected to detect mRNA and apoptosis. TaqMan RT-PCR was used to detect IGF1 polymorphism genotypes and qRT PCR was used to detect IGF1 mRNA levels in LECs. LEC apoptosis was evaluated through flow cytometry. The chi-square test was used to compare differences between ARCs and controls of each SNP. Results: We found that the G allele frequency in the IGF1-rs6218 was higher in the ARCs than in the controls. Furthermore, it was observed that the rs6218 GG genotype exhibited a positive correlation to elevated levels of IGF1 mRNA in LECs. The IGF1 mRNA in the LECs and the apoptosis of LECs in nuclear type of ARCs (ARNC) was higher than the controls. Conclusion: The susceptibility to ARC was related to IGF1-rs6218 polymorphism, and this polymorphism is associated with IGF1 expression at the mRNA level. Moreover, apoptosis in LECs of ARNCs was found to be increased.

Discovery of novel antibacterial agent for the infected wound treatment: all-hydrocarbon stapling optimization of LL-37.

Rationale: Antimicrobial peptide LL-37 has been recognized as a favorable alternative to antibiotics due to its broad antibacterial spectrum, low resistance development and diverse biological activities. However, its high manufactory cost, poor proteolytic stability, and unpredictable cytotoxicity seriously hindered its medical translation. Methods: To push the frontiers of its clinical application, all-hydrocarbon stapling strategy was exploited here for the structural modification of KR-12, the core and minimal fragment of LL-37. Results: Based on a library of KR-12 derivatives that designed and synthesized to be stapled at positions of either i, i+4 or i, i+7, structure to activity relationship was investigated. Among them, KR-12(Q5, D9) with the glutamine and aspartic acid residues stapled displayed increased helical content and positive charge. The reinforced α-helical conformation not only protected it from proteolytic hydrolysis but also improved its antibacterial efficacy via effective membrane perturbation and anti-inflammatory efficacy via compact LPS binding. Besides, the increased positive charge endowed it with an enhanced therapeutic index. On infected wound mouse model, it was demonstrated to eliminate bacteria and promote wound closure and regeneration effectively. Conclusion: Overall, the all-hydrocarbon stapling was proven to lay the foundation for the future development of antibacterial agents. KR-12(Q5, D9) could serve as a lead compound for the clinical treatment of bacterial infections.

The causal effect of hypertension, intraocular pressure, and diabetic retinopathy: a Mendelian randomization study.

Background: Previous research has indicated a vital association between hypertension, intraocular pressure (IOP), and diabetic retinopathy (DR); however, the relationship has not been elucidated. In this study, we aim to investigate the causal association of hypertension, IOP, and DR. Methods: The genome-wide association study (GWAS) IDs for DR, hypertension, and IOP were identified from the Integrative Epidemiology Unit (IEU) Open GWAS database. There were 33,519,037 single-nucleotide polymorphisms (SNPs) and a sample size of 1,030,836 for DR. There were 16,380,466 SNPs and 218,754 participants in the hypertension experiment. There were 9,851,867 SNPs and a sample size of 97,465 for IOP. Univariable, multivariable, and bidirectional Mendelian randomization (MR) studies were conducted to estimate the risk of hypertension and IOP in DR. Moreover, causality was examined using the inverse variance weighted method, and MR results were verified by numerous sensitivity analyses. Results: A total of 62 SNPs at the genome-wide significance level were selected as instrumental variables (IVs) for hypertension-DR. The results of univariable MR analysis suggested a causal relationship between hypertension and DR and regarded hypertension as a risk factor for DR [p = 0.006, odds ratio (OR) = 1.080]. A total of 95 SNPs at the genome-wide significance level were selected as IVs for IOP-DR. Similarly, IOP was causally associated with DR and was a risk factor for DR (p = 0.029, OR = 1.090). The results of reverse MR analysis showed that DR was a risk factor for hypertension (p = 1.27×10-10, OR = 1.119), but there was no causal relationship between DR and IOP (p > 0.05). The results of multivariate MR analysis revealed that hypertension and IOP were risk factors for DR, which exhibited higher risk scores (p = 0.001, OR = 1.121 and p = 0.030, OR = 1.124, respectively) than those in univariable MR analysis. Therefore, hypertension remained a risk factor for DR after excluding the interference of IOP, and IOP was still a risk factor for DR after excluding the interference of hypertension. Conclusion: This study validated the potential causal relationship between hypertension, IOP, and DR using MR analysis, providing a reference for the targeted prevention of DR.

Massive transfusion protocol reactivation as a novel marker of physician team under-triage after injury.

BACKGROUND: Large trauma centers have protocols for the assessment of injury and triaging of care with attempts to over-triage to ensure adequate care for all patients. We noted that a significant number of patients undergo a second massive transfusion protocol (MTP) activation in the first 24 h of care and conducted a retrospective cohort study of patients involved over a 3-year period. METHODS: Transfusion service records of MTP activations 2019-2021 were linked to Trauma Registry records and divided into cohorts receiving a single versus a reactivation of the MTP. Time of activation and amounts of blood products issued were linked to demographic, injury severity, and outcome data. Categorical and continuous data were compared between cohorts with chi-squared, Fisher's, and Wilcoxan tests as appropriate, and multivariable regression models were used to seek interactions (p < .05). RESULTS: MTP activation was recorded for 1884 acute trauma patients over our 3-year study period, 142 of whom (7.5%) had reactivation. Factors associated with reactivation included older age (46 vs. 40 years), higher injury severity score (ISS, 27 vs. 22), leg injuries, and presentation during morning shift change (5-7 a.m., 3.3% vs. 7.7%). Patients undergoing MTP reactivation used more RBCs (5 U vs. 2 U) and had more ICU days (3 vs. 2). CONCLUSIONS: Older patients and those presenting during shift change are at risk for failure to recognize their complex injury patterns and under-triage for trauma care. The fidelity and granularity of transfusion service records can provide unique opportunities for quality assessment and improvement in trauma care.

A responsive hydrogel modulates innate immune cascade fibrosis to promote ocular surface reconstruction after chemical injury.

Following an ocular chemical injury, the release of neutrophil extracellular traps (NETs) triggers an innate immune cascade fibrotic effect involving macrophages (Mø), which limits corneal repair. However, the interplay and mechanisms between NETs and macrophages, as well as the coordination between the innate immunity and corneal repair, remain challenging issues. Using a co-culture system, we report that chemical stimulation exacerbates the accumulation of reactive oxygen species (ROS) within the polymorphonuclear neutrophils, leading to NET formation and the activation of M2 macrophages, ultimately inducing pathological fibrosis of the ocular surface through the IL-10/STAT3/TGF-ß1/Smad2 axis. Inspired by the locally formed acidic microenvironment mediated by innate acute inflammatory stimulation, we further integrate sericin with oxidized chitosan nanoparticles loaded with black phosphorus quantum dots (BPQDs) using Schiff base chemistry to construct a functional pH-responsive hydrogel. Following corneal injury, the hydrogel selectively releases BPQDs in response to the acidic environment, inhibiting the innate immune cascade fibrosis triggered by the PMN-ROS-NETs. Thus, corneal pathological fibrosis is alleviated and reshaping of the ocular surface takes place. These results represent a refinement of the mechanism of inherent immune effector cell interactions, and provide new research ideas for the construction of nano biomaterials that regulate pathological fibrosis.

Efficacy of four anti-vascular endothelial growth factor agents and laser treatment for retinopathy of prematurity: A network meta-analysis.

This study undertakes a comprehensive comparison of five different interventions for the treatment of type-1 retinopathy of prematurity (ROP) and aggressive posterior retinopathy of prematurity (APROP), offering insights into their relative efficacies and contributing to better clinical decision-making. The aim of this study was to compare the efficacy of intravitreal aflibercept (IVA), intravitreal bevacizumab (IVB), intravitreal conbercept (IVC), intravitreal ranibizumab (IVR), and laser therapy in treating these conditions. We conducted a search for relevant randomized controlled trials (RCTs) in databases, namely PubMed, Embase, Cochrane Library, Web of Science, and Ovid, focusing on these five treatment modalities for ROP. The quality of included studies was evaluated using the Cochrane Risk of Bias Assessment Tool, and data analysis was performed using STATA software. The results from our network meta-analysis (NMA) indicated that IVA significantly prolonged the interval between initial treatment and relapse in patients, with a surface under the cumulative ranking cruve (SUCRA) value of 99.1%. Additionally, patients in the IVB group had a significantly higher spherical equivalent refraction (SER) after surgery, with a SUCRA value of 84.4%. Furthermore, IVR was the most effective in reducing the duration of peripheral retinal vascularization, with a SUCRA value of 95.6%. However, no statistically significant differences were found in relapse rates among the five treatment options. Our analysis concludes that intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drug monotherapy generally offer better outcomes than laser treatment for ROP. Nonetheless, additional RCTs are necessary to further evaluate the safety of anti-VEGF agents.

The protective effect of DNase I in retinal vein occlusion.

Retinal vein occlusion (RVO) ranks as the second most prevalent retinal vascular disease, following diabetic retinopathy. Neutrophil extracellular traps (NETs) play an important role in vascular diseases. This study aimed to elucidate the relationship between NETs and RVO, and to discern the potential role of deoxyribonuclease I (DNase I) in the prevention and treatment of RVO through the modulation of NETs. We analyzed circulating NETs biomarkers, namely cell-free DNA (cf-DNA), myeloperoxidase (MPO)-DNA, and neutrophil elastase (NE), in 30 RVO patients and 30 healthy individuals. We established an RVO mouse model using a retinal laser, and the mice were categorized into two groups: the DNase I group and the control group. Retinal images were taken at predetermined time points, and the state of the retinal vessels was assessed. Both tissue and blood samples were harvested for analysis of NETs expression through methods such as western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Our finding indicate an increase in circulating NETs biomarkers in human and mouse RVO cases, while also verifying the presence of NETs in the retinal thrombus of the RVO model. Both in vitro and in vivo tests revealed that DNase I attenuated NETs formation. Moreover, DNase I injections led to diminished NETs biomarker levels and a reduced duration of the thrombus after the RVO model establishment. Consequently, DNase I, a well-established modulator of NETs formation, might exhibit protective properties in the prevention and treatment of RVO.

Age, admission platelet count, and mortality in severe isolated traumatic brain injury: A retrospective cohort study.

BACKGROUND: We asked whether patients >50 years of age with acute traumatic brain injury (TBI) present with lower platelet counts and whether lower platelet counts are independently associated with mortality. METHODS: We combined trauma registry and laboratory data on a retrospective cohort of all patients ≥18 years of age admitted to our Level 1 US regional trauma center 2015-2021 with severe (Head Abbreviated Injury Score [AIS] ≥3), isolated (all other AIS <3) TBI who had a first platelet count within 1 h of arrival. Age and platelet count were assessed continuously and as groups (age 18-50 vs. >50, platelet normals, and at conventional transfusion thresholds). Outcomes such as mean admission platelet counts and in-hospital mortality were assessed categorically and with logistic regression. RESULTS: Of 44,056 patients, 1298 (3%, median age: 52 [IQR 33,68], 76.1% male) met all inclusion criteria with no differences between younger and older age groups for (ISS; 18 [14,26] vs. 17 [14,26], p = .22), New ISS (NISS; 29 [19,50] vs. 28 [17,50], p = .36), or AIS-Head (4 [3,5] vs. 4 [3,5]; p = .87). Patients aged >50 had lower admission platelet counts (219,000 ± 93,000 vs. 242,000 ± 76,000/µL; p < .001) and greater in-hospital mortality (24.5% vs. 15.6%, p < .001) than those 18-50. In multivariable regression, firearms injuries (OR9.08), increasing age (OR1.004), NISS (OR1.007), and AIS-Head (OR1.05), and decreasing admission platelet counts (OR0.998) were independently associated with mortality (p < .001-.041). Platelet transfusion in the first 4 h of care was more frequent among older patients (p < .001). CONCLUSIONS: Older patients with TBI had lower admission platelet counts, which were independently associated with greater mortality.

Ultramassive Transfusion for Trauma in the Age of Hemostatic Resuscitation: A Retrospective Single-Center Cohort From a Large US Level-1 Trauma Center, 2011-2021.

BACKGROUND: Uncontrolled bleeding is a leading cause of death in trauma. In the last 40 years, ultramassive transfusion (UMT; ≥20 units of red blood cells [RBCs]/24 hours) for trauma has been associated with 50% to 80% mortality; the question remains as to whether the increasing number of units transfused in urgent resuscitation is a marker of futility. We asked whether the frequency and outcomes of UMT have changed in the era of hemostatic resuscitation. METHODS: We performed a retrospective cohort study of all UMTs in the first 24 hours of care over an 11-year period at a major US level-1 adult and pediatric trauma center. UMT patients were identified, and a dataset was built by linking blood bank and trauma registry data, then reviewing individual electronic health records. Success in achieving hemostatic proportions of blood products was estimated as (units of plasma + apheresis-platelets-in-plasma + cryoprecipitate-pools + whole blood]/[all units given] ≥0.5. Demographics, injury type (blunt or penetrating), severity (Injury Severity Score [ISS]), severity pattern (Abbreviated Injury Scale score for head [AIS-Head] ≥4), admitting laboratory, transfusion, selected emergency department interventions, and discharge status were assessed using χ2 tests of categorical association, the Student t-test of means, and multivariable logistic regression. P <.05 was considered significant. RESULTS: Among 66,734 trauma admissions from April 6, 2011 to December 31, 2021, we identified 6288 (9.4%) who received any blood products in the first 24 hours, 159 of whom received UMT (0.23%; 154 aged 18-90 + 5 aged 9-17), 81% in hemostatic proportions. Overall mortality was 65% (n = 103); mean ISS = 40; median time to death, 6.1 hours. In univariate analyses, death was not associated with age, sex, or more RBC units transfused beyond 20 but was associated with blunt injury, increasing injury severity, severe head injury, and failure to receive hemostatic blood product ratios. Mortality was also associated with decreased pH and evidence of coagulopathy at admission, especially hypofibrinogenemia. Multivariable logistic regression showed severe head injury, admission hypofibrinogenemia and not receiving a hemostatic resuscitation proportion of blood products as independently associated with death. CONCLUSIONS: One in 420 acute trauma patients at our center received UMT, a historically low rate. A third of these patients lived, and UMT was not itself a marker of futility. Early identification of coagulopathy was possible, and failure to give blood components in hemostatic ratios was associated with excess mortality.

Drivers of blood use in paediatric trauma: A retrospective cohort study.

OBJECTIVES: We asked whether age or injury severity drives blood use patterns in paediatric trauma. BACKGROUND: Transfusion for paediatric trauma care is complicated by known developmental differences in coagulation and injury patterns. METHODS/MATERIALS: We linked 10 years of Trauma Registry and blood bank data, 2011-2020, for all acute trauma patients aged <18 treated at a large US Level 1 adult and paediatric trauma centre. We assessed age, injury severity and mechanism for association with any blood use, use within the first 4 h of care, and resuscitation balance, using grouped-age Chi-square and multivariable regression models. RESULTS: Of 60 066 acute trauma arrivals at our centre in the study period, 7979 (13.3%) met inclusion criteria. Median age (IQR) was (7.6[2.4-14.5]); 6230(78.1%) were < 15 years old; 590(7.4%) received any blood products; and 128(1.6%) died. Among the 5842(73.2%) patients with impact-related injury, 2023(34.6%) met standards for severe injury (New Injury Severity Score [NISS] ≥ 16); 541(9.3%) were transfused, 171(31.6%) in the first 4 h and 72(13.3%) using ≥3 units of products in the first hour. Firearms injuries were the most severe, most likely to be transfused urgently, using balanced resuscitation, and to die (p < 0.001 for all). Multivariable logistic regression showed any blood use as strongly associated with NISS (Odds Ratio 1.124832; p < 0.0001; 95% CI 1.11-1.13) but not with age (OR 0.98; p = 0.07; 95% CI 0.96-1.00). CONCLUSION: Transfusion in the care of acute paediatric trauma is uncommon (<10% of injured minors in our cohorts received any blood products), and injury severity, particularly firearms injury-not age-drove transfusion.

Erratum: Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors.

[This corrects the article DOI: 10.1016/j.omtm.2021.12.003.].

Blood product availability in the Washington state trauma system.

BACKGROUND: Early transfusion can prolong life in injured patients awaiting definitive hemorrhage control. We conducted a community resources assessment of blood product availability at hospitals within the Washington State (WA) Regional Trauma System, with the expectation that a minority of Level IV and V centers would have blood products routinely available for use in resuscitation. METHODS: We designed a questionnaire soliciting information on routinely available unit quantities of red blood cells (RBC), plasma, platelets, cryoprecipitate, and/or whole blood and submitted this questionnaire electronically to the 82 WA designated trauma centers (Levels I-V). Non-responders were contacted directly by telephone. The study was conducted in September and October 2021. US 2020 census data were used to correlate results with local population densities. RESULTS: First-round contact netted responses from 57 (70%) centers; the remaining centers provided information via telephone, for a 100% final response. Packed RBC were available in 79 of the 82 centers (96%; range 6-220 units); plasma, 62 centers (76%, range 1-100 units); platelets, 40 centers (49%, range 1-8 units); cryoprecipitate, 45 centers (55%, range 1-20 units). Whole blood was only available at the Level I center. Three Level V centers, located in 2 of the 8 WA state trauma regions, reported no routine blood availability. The two trauma regions affected represent 12% of the state's population and more than a third of its geographic area. CONCLUSIONS: Within the WA regional trauma system, blood products are wide, if unevenly, available. Large urban/rural disparities in availability exist that should be explored.

Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors.

We tested a new in vivo hematopoietic stem cell (HSC) transduction/selection approach in rhesus macaques using HSC-tropic, integrating, helper-dependent adenovirus vectors (HDAd5/35++) designed for the expression of human γ-globin in red blood cells (RBCs) to treat hemoglobinopathies. We show that HDAd5/35++ vectors preferentially transduce HSCs in vivo after intravenous injection into granulocyte colony-stimulating factor (G-CSF)/AMD3100-mobilized animals and that transduced cells return to the bone marrow and spleen. The approach was well tolerated, and the activation of proinflammatory cytokines that are usually associated with intravenous adenovirus vector injection was successfully blunted by pre-treatment with dexamethasone in combination with interleukin (IL)-1 and IL-6 receptor blockers. Using our MGMTP140K-based in vivo selection approach, γ-globin+ RBCs increased in all animals with levels up to 90%. After selection, the percentage of γ-globin+ RBCs declined, most likely due to an immune response against human transgene products. Our biodistribution data indicate that γ-globin+ RBCs in the periphery were mostly derived from mobilized HSCs that homed to the spleen. Integration site analysis revealed a polyclonal pattern and no genotoxicity related to transgene integrations. This is the first proof-of-concept study in nonhuman primates to show that in vivo HSC gene therapy could be feasible in humans without the need for high-dose chemotherapy conditioning and HSC transplantation.

Concussion symptoms and temporary accommodations using a student-centered return to learn care plan.

BACKGROUND: Many students return to school after concussion with symptoms but without formal support. OBJECTIVE: To examine concussion symptoms and temporary academic accommodations during school use of a four-week student-centered return to learn (RTL) care plan. METHODS: Five public high schools used the RTL care plan and contributed student-level data after student report of concussion. Data on concussion symptoms, temporary academic accommodations corresponding to reported symptoms, and accommodations provided during RTL care plan use were examined. RESULTS: Of 115 students, 55%used the RTL care plan for three (34%) or four (21%) weeks. Compared to students whose symptoms resolve within the first two weeks, students who used the RTL care plan for three or four weeks reported more unique symptoms (P = 0.038), higher total severity score (P = 0.005), and higher average severity per symptom (P = 0.007) at week one. Overall, 1,127 weekly accommodations were provided. While least reported, emotional symptoms received corresponding accommodations most often (127/155 reports: 82%of occurrences). CONCLUSIONS: Use of an RTL care plan can facilitate the RTL of students with a concussion and may aid in the identification of students who are in need of longer-term support.

Anticancer Activity of New Na(I) Complex on Retinoblastoma Cells via Inhibiting PI3K/AKT/mTOR Pathway.

Here, through applying 2,6-bis(4'-carboxyl-phenyl)pyridine (H2L), a rigid ligand featuring both carboxylic acid and pyridine groups, a new coordination polymer containing Na(I) has been generated with the reaction between H2L ligand and NaNO3 in a water and DMF mixed solvent, and its chemical composition is [Na2L]n. Furthermore, the antiproliferative activity of Na(I) complex against the HXO-Rb44 retinoblastoma cells was detected with CCK-8 assay. Hoechst staining along with Annexin V-FITC/PI revealed that Na(I) complex induces the HXO-Rb44 retinoblastoma cells apoptosis. Flow cytometry analysis of reactive oxygen species (ROS) showed that Na(I) complex significantly increases the level of intracellular ROS. Importantly, western blot analysis revealed that Na(I) complex might induce apoptosis through inactivation of PI3K/AKT/mTOR pathway.

Blood component use and injury characteristics of acute trauma patients arriving from the scene of injury or as transfers to a large, mature US Level 1 trauma center serving a large, geographically diverse region.

BACKGROUND: Advanced trauma care demands the timely availability of hemostatic blood products, posing special challenges for regional systems in geographically diverse areas. We describe acute trauma blood use by transfer status and injury characteristics at a large regional Level 1 trauma center. STUDY DESIGN AND METHODS: We reviewed Harborview Medical Center (HMC) Trauma Registry, Transfusion Service, and electronic medical records on acute trauma patients for demographics, injury patterns, blood use, and in-hospital mortality, 2011-2019. RESULTS: Among 47,471 patients (mean age 45.2 ± 23.0 years; 68.3% male; Injury Severity Score 12.6 ± 11.1), 4.7% died and 8547 (18%) received at least one blood component through HMC. Firearms injuries were the most often transfused (690/2596, 26.6%) and the most urgently (39.9% ≥3 units in <1 h; 40.6% ≥5 units in <4 h), and had the highest mortality (case-fatality, 12.2%) (all p < .001). From-scene patients were younger than transfers (42.9 ± 21.0 vs. 47.2 ± 24.4), predominated among firearms injuries (68.2% from-scene vs. 31.8% transfers), were more likely to receive blood (18.5% vs. 17.6%) more urgently (≥3 units first hour, 24.4% vs. 7.7%; ≥5 units first 4 h: 25.6% vs. 8.2%), were more likely to die of hemorrhage (15.5% vs. 4.3%) and from firearms injuries (310/1360, 22.8%) (all p < .001). DISCUSSION: Early blood use, firearms injuries, and mortality were all greater among from-scene patients, and firearms injuries had worse outcomes despite greater and more urgent blood use, but the role of survivor bias for transfer patients must be clarified. Future research must identify strategies for providing local hemostatic transfusion support, particularly for firearms injuries.

Cold-stored whole blood and platelet counts in severe acute injury: A comparison of four retrospective cohorts.

BACKGROUND: Low-titer group O whole blood (LTOWB) is attractive for acute trauma care as it delivers concentrated and balanced hemostatic resuscitation in single large bags. Whether cold-stored LTOWB can sustain platelet counts is unclear. STUDY DESIGN AND METHODS: Four cohorts of trauma patients-three historic, one retrospective-were identified by their urgency of blood use. Admission and all subsequent platelet counts over the first 24 h of care were compared with t-tests. The cohorts were as follows: 1292 patients at Maryland Shock Trauma as described by Stansbury and colleagues in 2013; 35 patients enrolled locally in the 1:1:2 arm of the pragmatic randomized optimal plasma and platelet ratios (PROPPR) trial; 34 patients enrolled locally in the 1:1:1 arm of PROPPR; and 59 patients receiving more than 3 units of LTOWB enroute to or at our Level 1 trauma center, 2019-2020. RESULTS: Mean age of LTOWB units transfused was 9 ± 5 days and mean dose was 5 ± 2 units. All four cohorts were profoundly injured (mean Injury Severity Score ≥ 31), with mean first platelet counts 204-228 K/µ and subsequent counts approximately 100 k/µl lower. Through the first 24 h of care, mean platelet counts decreased least, 79 and 83 103 /µl, in the 1:1:1 PROPPR and LTOWB cohorts. Mean platelet counts in patients transfused with LTOWB remained stable after the third hour of care. DISCUSSION: LTOWB transfusion was associated with lesser mean decrease in platelet counts during the first 24 h after injury, similar to those observed among patients receiving components 1:1:1 component in the PROPPR study.

Ubiquitin specific peptidase 33 promotes cell proliferation and reduces apoptosis through regulation of the SP1/PI3K/AKT pathway in retinoblastoma.

Ubiquitin-specific protease 33 (USP33), a deubiquitinating enzyme (DUB), has been identified to serve as a tumor suppressor or an oncogene in different cancers. However, its role in retinoblastoma (RB) remains unknown. Here, we aimed to uncover USP33 expression profile and function in RB, and disclose the underlying mechanism. USP33 levels in RB tissues and cells were determined using RT-qPCR and western blotting assays. USP33 effects on cell growth, cycle, apoptosis and tumorigenesis were studied using MTT, Edu, cycle and western blotting and in vivo assays. The results showed that USP33 expression levels were elevated in RB tissues and cells as compared with normal retinal tissues and cells. Downregulation of USP33 in RB Y79 and WERI-RB1 cells leaded to significant increases in cell apoptosis, G1 phase arrest and tumorigenesis, and reductions in cell growth and G2 and S phase arrest, as well as inhibited the activation of the PI3K/AKT signaling. SP1 overexpression abolished the roles of USP33 downregulation in modulating the activation of PI3K/AKT signaling, cell growth, apoptosis, and cell cycle. This study uncovered that USP33 promoted the progression of RB through regulation of the SP1/PI3K/AKT pathway.

Study on the mechanism of PAMAM(DETA as the core) against silica scale.

Molecular simulation was performed to study the interaction between PAMAM(DETA as the core) with different generations and silicic acid molecules, and discussed the inhibition effect mechanism against silica scale through gyration radius and radial distribution function et al. The results showed that adsorption interactions between silicic acid molecules and the PAMAM with -NH2 terminated groups molecule (G1.0 and G2.0) were stronger than those and the PAMAM with -COOH terminated groups molecule (G0.5 and G1.5). The adsorption interactions were primarily divided into electrostatic interactions, vdW interactions as well as H-bond interactions, where electrostatic interaction was dominant. Molecular simulation results were consistent with our experimental results.

Single-dose MGTA-145/plerixafor leads to efficient mobilization and in vivo transduction of HSCs with thalassemia correction in mice.

We have developed an in vivo hemopoietic stem cell (HSC) gene therapy approach without the need for myelosuppressive conditioning and autologous HSC transplantation. It involves HSC mobilization and IV injection of a helper-dependent adenovirus HDAd5/35++ vector system. The current mobilization regimen consists of granulocyte colony-stimulating factor (G-CSF) injections over a 4-day period, followed by the administration of plerixafor/AMD3100. We tested a simpler, 2-hour, G-CSF-free mobilization regimen using truncated GRO-ß (MGTA-145; a CXCR2 agonist) and plerixafor in the context of in vivo HSC transduction in mice. The MGTA-145+plerixafor combination resulted in robust mobilization of HSCs. Importantly, compared with G-CSF+plerixafor, MGTA-145+plerixafor led to significantly less leukocytosis and no elevation of serum interleukin-6 levels and was thus likely to be less toxic. With both mobilization regimens, after in vivo selection with O6-benzylguanine (O6BG)/BCNU, stable GFP marking was achieved in >90% of peripheral blood mononuclear cells. Genome-wide analysis showed random, multiclonal vector integration. In vivo HSC transduction after mobilization with MGTA-145+plerixafor in a mouse model for thalassemia resulted in >95% human γ-globin+ erythrocytes at a level of 36% of mouse ß-globin. Phenotypic analyses showed a complete correction of thalassemia. The γ-globin marking percentage and level were maintained in secondary recipients, further demonstrating that MGTA145+plerixafor mobilizes long-term repopulating HSCs. Our study indicates that brief exposure to MGTA-145+plerixafor may be advantageous as a mobilization regimen for in vivo HSC gene therapy applications across diseases, including thalassemia and sickle cell disease.