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1.
BMJ Mil Health ; 2024 May 20.
Article in English | MEDLINE | ID: mdl-38772623

ABSTRACT

INTRODUCTION: Combat boots are special shoes designed for soldiers to wear during activities in rough terrain, such as long marches or military training. Combat boots have been known to cause high plantar pressure and increase the injury rate of the lower extremities. Therefore, this study aimed to compare the difference in in-shoe plantar pressure between Korean combat boots and running shoes. We hypothesised that the newest Korean combat boots would have comparable plantar pressure distribution with running shoes. METHODS: We prospectively recruited 30 asymptomatic male participants, who are candidates for military services, from the local area. Two types of shoes (the newly developed Korean combat boots and running shoes) were examined. Pedobarographic measurements were collected using the pedar-X in-shoe pressure measurement system. Peak pressure (PP), pressure time integral (PTI), contact area and contact time were analysed. RESULTS: Both PP and PTI at the region of central and lateral forefeet (FF) were significantly higher in combat boots. The contact area of combat boots was significantly lower at the region of the hallux, second-fifth toes, medial FF, central FF and midfoot. Contact time at the region of central FF and medial heel was significantly higher in combat boots. CONCLUSIONS: Understanding the plantar pressure distribution of combat boots can be helpful for developing combat boots and preventing injury. Based on the results of our study, the next-generation Korean combat boots should be developed to increase contact area and distribute impulse under the head of the metatarsal bone.

2.
Clin Radiol ; 78(12): e1017-e1022, 2023 12.
Article in English | MEDLINE | ID: mdl-37813755

ABSTRACT

AIM: To explore the feasibility of a "triple-low" dose (low tube voltage, low tube current, and low contrast agent volume) bronchial artery computed tomography (CT) angiography (CTA) to replace routine dose bronchial artery CTA before bronchial artery embolisation (BAE). MATERIALS AND METHODS: CTA was obtained from 60 patients with body mass index (BMI) < 30 kg/m2 using a 256 multi-section iCT system, and they were divided into two groups: (1) group A: 100 kVp, 100 mAs, 50 ml contrast medium (CM); (2) group B: 120 kVp, automatic tube current modulation (ACTM), 80 ml CM. CT attenuation of the thoracic aorta, image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated, and subjective image quality scores and traceability scores assessed. The effective radiation dose was calculated. RESULTS: The radiation dose was reduced by 79.7% in group A compared to group B (p<0.05). The CT attenuation of the thoracic aorta was increased by approximately 13% in group A compared to group B (p<0.05). Higher image noise, lower SNR, and CNR were obtained in group A compared to group B (all p<0.05). Both subjective image quality scores and traceability scores did not differ between groups A and B (both p>0.05). CONCLUSION: It is feasible to use the "triple-low" dose CTA protocol for patients with a body mass index (BMI) < 30 kg/m2. The radiation dose was reduced by 79.7%, and the dose of contrast medium was reduced by 37.5% to ensure the diagnostic value.


Subject(s)
Bronchial Arteries , Computed Tomography Angiography , Humans , Feasibility Studies , Bronchial Arteries/diagnostic imaging , Tomography, X-Ray Computed , Angiography , Radiation Dosage , Contrast Media , Radiographic Image Interpretation, Computer-Assisted
3.
Pharmaceutics ; 15(8)2023 Aug 08.
Article in English | MEDLINE | ID: mdl-37631312

ABSTRACT

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.

5.
NPJ Microgravity ; 9(1): 28, 2023 Mar 31.
Article in English | MEDLINE | ID: mdl-37002218

ABSTRACT

Spaceflight associated neuro-ocular syndrome (SANS) is common amongst astronauts on long duration space missions and is associated with signs consistent with elevated cerebrospinal fluid (CSF) pressure. Additionally, CSF pressure has been found to be elevated in a significant proportion of astronauts in whom lumbar puncture was performed after successful mission completion. We have developed a retinal photoplethysmographic technique to measure retinal vein pulsation amplitudes. This technique has enabled the development of a non-invasive CSF pressure measurement apparatus. We tested the system on healthy volunteers in the sitting and supine posture to mimic the range of tilt table extremes and estimated the induced CSF pressure change using measurements from the CSF hydrostatic indifferent point. We found a significant relationship between pulsation amplitude change and estimated CSF pressure change (p < 0.0001) across a range from 2.7 to 7.1 mmHg. The increase in pulse amplitude was highest in the sitting posture with greater estimated CSF pressure increase (p < 0.0001), in keeping with physiologically predicted CSF pressure response. This technique may be useful for non-invasive measurement of CSF pressure fluctuations during long-term space voyages.

6.
Asian J Psychiatr ; 83: 103546, 2023 May.
Article in English | MEDLINE | ID: mdl-36958139

ABSTRACT

The suicide rate in Guam, a United States (U.S.) territory, is markedly higher than the suicide rate within the U.S. There are also important differences in who is most at risk for suicide in Guam, relative to within the general U.S. Understanding these distinctions is important for implementing effective suicide prevention initiatives in this region. In the current article, we discuss considerations for preventing suicide in Guam, including distinctions in suicide risk, relative to within the general U.S. For example, suicide rates in Guam are highest for those who are Pacific Islander, young, or male. Further, suicide in Guam more commonly involves hanging and less commonly involves firearms, a pattern that differs from suicide methods used within the general U.S. Additional considerations include the large military and Veteran population in Guam, as well as cultural and religious beliefs regarding suicide. Finally, given the geographic isolation of Guam, access to healthcare is likely an important facet of suicide risk. Considering these characteristics, it is imperative to develop and implement culturally-sensitive suicide prevention interventions for individuals residing in this region. We conclude by discussing future research avenues to address critical knowledge gaps to prevent suicide in Guam.


Subject(s)
Suicide , Humans , Male , United States/epidemiology , Guam/epidemiology , Violence , Suicide Prevention
7.
PLoS One ; 18(2): e0280431, 2023.
Article in English | MEDLINE | ID: mdl-36763646

ABSTRACT

AIMS: Firearm purchasing increased within the U.S. during the coronavirus disease 2019 pandemic. While rates of firearm ownership and suicide are elevated among women Veterans compared to women non-Veterans, no studies have examined if and how firearm beliefs and behaviors changed among women Veterans during the pandemic. We examined women Veterans' changes in firearm beliefs and engagement in firearm behaviors during the early pandemic era. METHOD: 3,000 post-9/11 era women Veterans were invited to participate in a survey. 501 respondents (May-December 2020) comprised the sample for this concurrent nested mixed-method analysis. Thematic analysis and log-binomial regression were used. RESULTS: 13.88% (n = 69) of women Veterans in our sample reported changes in their firearm beliefs; 22.15% (n = 109) reported engaging in firearm behaviors. The most prevalent reported behaviors were making household firearms more accessible (16.13%) and purchasing ammunition (11.97%). Smaller percentages reported carrying a firearm more frequently (6.71%), loading previously unloaded firearms (5.69%), or purchasing a firearm (4.24%). Thematic analysis suggested firearm behaviors were likely driven by a perceived increased need to protect oneself, family, and property due to: (1) uncertainties brought on by the pandemic; (2) pandemic-related threats necessitating self-defense, preparedness, and self-sufficiency; (3) political, social, and racial unrest and protests. PTSD symptom severity and military sexual assault history were associated with higher prevalence of changes in firearm beliefs and engagement in firearm behaviors during the pandemic. DISCUSSION: Consideration of women Veterans' prior experiences and pandemic-related factors may be necessary to contextualize firearm discussions and inform future research. Given associations of military sexual assault and PTSD symptoms with firearm beliefs and behaviors, it may be crucial to ensure that such discussion are trauma-informed.


Subject(s)
COVID-19 , Military Personnel , Sex Offenses , Stress Disorders, Post-Traumatic , Veterans , Humans , Female , Stress Disorders, Post-Traumatic/diagnosis , Pandemics , COVID-19/epidemiology , COVID-19/complications
8.
Microbiology (Reading) ; 169(1)2023 01.
Article in English | MEDLINE | ID: mdl-36748549

ABSTRACT

While recent efforts to catalogue Earth's microbial diversity have focused upon surface and marine habitats, 12-20 % of Earth's biomass is suggested to exist in the terrestrial deep subsurface, compared to ~1.8 % in the deep subseafloor. Metagenomic studies of the terrestrial deep subsurface have yielded a trove of divergent and functionally important microbiomes from a range of localities. However, a wider perspective of microbial diversity and its relationship to environmental conditions within the terrestrial deep subsurface is still required. Our meta-analysis reveals that terrestrial deep subsurface microbiota are dominated by Betaproteobacteria, Gammaproteobacteria and Firmicutes, probably as a function of the diverse metabolic strategies of these taxa. Evidence was also found for a common small consortium of prevalent Betaproteobacteria and Gammaproteobacteria operational taxonomic units across the localities. This implies a core terrestrial deep subsurface community, irrespective of aquifer lithology, depth and other variables, that may play an important role in colonizing and sustaining microbial habitats in the deep terrestrial subsurface. An in silico contamination-aware approach to analysing this dataset underscores the importance of downstream methods for assuring that robust conclusions can be reached from deep subsurface-derived sequencing data. Understanding the global panorama of microbial diversity and ecological dynamics in the deep terrestrial subsurface provides a first step towards understanding the role of microbes in global subsurface element and nutrient cycling.


Subject(s)
Gammaproteobacteria , Microbiota , Water Microbiology , Bacteria/genetics , Microbiota/genetics , Biomass , Metagenomics , RNA, Ribosomal, 16S
9.
J Physiol Pharmacol ; 73(2)2022 Apr.
Article in English | MEDLINE | ID: mdl-36193969

ABSTRACT

The present study aimed to screen out the proteins with significantly differential expression through the proteomics study of Tianxiangdan intervention in rats with myocardial ischemia as well as elucidate the mechanism of the intervention. In total, 54 Wistar rats (male, 6-8 weeks old) were randomly divided into the blank group, sham operation group, and model group, with 6 rats in each, together with the model + low dose group, model + medium-dose group, and model + high dose group, with 12 rats in each. Upon successful construction of the ischemic model, low, medium, and high doses, respectively, of Tianxiangdan were administered in the groups. The rat model of coronary heart disease (CHD) with myocardial ischemia was prepared by ligating the coronary artery. The tandem mass tag-labeled quantitative proteomics technology was adopted to observe the differentially expressed proteins in the myocardium of the model rats under the action of Tianxiangdan to find the target proteins for the treatment of myocardial ischemia in CHD. A total of 3122 proteins were identified. Combined with the references, tropomyosin alpha-3 chain (TPM3), protein kinase C delta (PRKCD), myosin heavy chain 10 (MYH10), MYH6, G protein subunit alpha i2 (GNAI2), and other proteins were screened out. Western blotting was adopted for the proteomics validation, and it was found that compared with the sham operation group, the expression levels of the GNAI2, TPM3, and MYH10 proteins were upregulated in the myocardial ischemia model group but downregulated after the administration of Tianxiangdan; the differences were statistically significant (p<0.05). We conclude that Tianxiangdan could improve myocardial ischemia by downregulating the proteins, including GNAI2, TPM3, and MYH10, which might be potential targets of Tianxiangdan in the treatment of myocardial infarction.


Subject(s)
Myocardial Ischemia , Tropomyosin , Animals , Male , Rats , GTP-Binding Protein alpha Subunit, Gi2 , Myocardial Ischemia/drug therapy , Myocardium , Myosin Heavy Chains , Protein Kinase C-delta , Proteomics , Rats, Wistar
10.
J Trauma Dissociation ; : 1-19, 2022 Sep 07.
Article in English | MEDLINE | ID: mdl-36069509

ABSTRACT

Institutional betrayal is defined as harm caused by an institution to an individual in the context of trust and dependence. High institutional betrayal is associated with poorer health outcomes, and high levels of trust, dependence, or identification with the institution (institutional closeness) may exacerbate the negative effects of institutional betrayal. While military sexual trauma is prevalent among women Veterans and associated with high rates of institutional betrayal, studies of the impact of military sexual trauma-related institutional betrayal have been limited in size and scope and have not examined the potential role of institutional closeness. We conducted a secondary analysis of national survey data collected from women Veterans who screened positive for military sexual trauma (n = 229). Hierarchical logistic and linear regression were used to examine associations between predictor variables (institutional betrayal, institutional closeness, and their interaction) and outcomes of interest and adjusted for age, education, and military sexual assault history. Institutional betrayal was associated with increased odds of suicidal ideation and suicide attempt during or following military service, as well as more severe symptoms of depression and posttraumatic stress disorder (PTSD). Institutional betrayal was not associated with non-suicidal self-injury or lifetime substance misuse. Counter to hypotheses, institutional closeness did not moderate relationships between institutional betrayal and mental health symptoms or self-directed violence. Results underscore the necessity of preventing and addressing institutional betrayal among women Veterans who experience military sexual trauma.

11.
Facts Views Vis Obgyn ; 14(1): 95-98, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35373555

ABSTRACT

Placenta accreta located in a caesarean section scar is difficult to remove. The Intrauterine Bigatti Shaver (IBS®) has already been proven to be effective in placental remnant removal. Our case report highlights that the IBS® is also a safe method to remove placental remnants attached to a previous caesarean section scar performed for a cervical pregnancy and associated with placenta accreta.

12.
Int J Hydrogen Energy ; 47(11): 7281-7288, 2022 Feb 05.
Article in English | MEDLINE | ID: mdl-33746342

ABSTRACT

COVID-19 is a disease caused by the SARS-CoV virus. It stands for severe acute respiratory syndrome, which affects the lungs. The process of replication and progression of the COVID-19 virus causes the formation of an excessive amount of reactive oxygen species and inflammation. Many studies have been carried out that have demonstrated that hydrogen has strong anti-inflammatory properties. It reduces hypotension and other symptoms by reducing inflammation and oxidative stress. Oxygen mixture, enriched with Hydrogen, - helps to reduce the resistance of the respiratory tract and frees up access to the pulmonary alveolus, which improves the penetration of oxygen into the lungs. Since hydrogen is an antioxidant, it helps to reduce the burden on the immune system, helps to maintain the body's health and its ability to quickly recover. When electrolysers are used to produce an oxygen-hydrogen mixture, alkaline mist and other impurities can enter the patient's lungs and cause poisoning and chemical burns. For this reason, the use of atomic hydrogen obtained from metal hydride sources for ventilation of the lungs will be more effective for treating COVID-19 than a molecular hydrogen-oxygen mixture from an electrolyzer. A functional diagram of a metal hydride source of atomic hydrogen to an artificial lung ventilator is shown. It is possible to create a series of hydrogen storage tanks of various capacities.

13.
Eur J Haematol ; 107(3): 343-353, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34053123

ABSTRACT

OBJECTIVES: This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics. METHODS: Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL-1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL-1-negative subpopulation of CLL-1 bimodal AML samples. RESULTS: The frequency of a bimodal pattern of CLL-1 expression of CD34+ blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL-1 expression was most prevalent in patients with MDS-related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia-associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL-1- subpopulation may consist of pre-B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)-leukemic mutations were detected in both CLL-1+ and CLL-1- subfractions of bimodal samples (N = 3). CONCLUSIONS: C-lectin-like molecule 1 bimodality occurs in about 25% of AML patients and the CLL-1- cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL-1-targeted therapies and warrant further investigation.


Subject(s)
Biomarkers, Tumor/genetics , Bone Marrow Cells/metabolism , Lectins, C-Type/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , Myeloid Cells/metabolism , Receptors, Mitogen/genetics , Antigens, CD34/genetics , Antigens, CD34/immunology , Biomarkers, Tumor/immunology , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , Cytogenetic Analysis , Female , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Leukemic , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Humans , Immunophenotyping , Lectins, C-Type/immunology , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Myeloid Cells/immunology , Myeloid Cells/pathology , Precursor Cells, B-Lymphoid/immunology , Precursor Cells, B-Lymphoid/metabolism , Precursor Cells, B-Lymphoid/pathology , Primary Cell Culture , Receptors, Mitogen/immunology
14.
Int J Cardiol Hypertens ; 8: 100079, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33598654

ABSTRACT

OBJECTIVES: This retrospective cohort study examines incidence, risk factors, and clinical outcomes of acute myocardial infarction (AMI) and acute ischemic stroke (AIS) within one year of gram-negative bloodstream infection (GN-BSI) based on predefined clinical criteria. METHODS: Hospitalized adults with GN-BSI at Prisma Health-Midlands hospitals in South Carolina, USA from 2010 through 2015 were identified. Kaplan-Meier analysis was used to determine incidence of AMI and AIS within one year after GN-BSI. Multivariate Cox proportional hazards regression models were used to examine risk factors for AMI or AIS and impact on 1-year mortality. RESULTS: Among 1292 patients with GN-BSI, 263 and 17 developed AMI and AIS within 1-year with incidences of 23.4% and 1.9%, respectively. Majority of AMI were type 2 (164; 62%); 99 patients had type 1 AMI with incidence of 8.9%. Age >65 years (hazard ratio [HR] 1.52, 95% CI: 1.17-1.99), prior coronary artery disease or stroke (HR 1.74, 95% CI: 1.34-2.25), hypertension (HR 1.55, 95% CI: 1.13-2.15), end-stage renal disease (HR 1.52, 95% CI: 1.09-2.08), and quick Pitt bacteremia score (HR 1.55 per point, 95% CI: 1.40-1.72) were predictors of AMI/AIS. Development of type 1 AMI or AIS after GN-BSI was independently associated with increased 1-year mortality (HR 1.47, 95% CI: 1.03-2.07). CONCLUSIONS: AMI and AIS occur frequently within one year of GN-BSI and have negative impact on 1-year survival. Future randomized clinical trials are needed to determine the most effective clinical interventions for prevention of AMI/AIS following BSI in high risk patients and improve survival after these events.

15.
Cancer Discov ; 11(1): 68-79, 2021 01.
Article in English | MEDLINE | ID: mdl-32887697

ABSTRACT

The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti-PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy. SIGNIFICANCE: The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency-approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.This article is highlighted in the In This Issue feature, p. 1.


Subject(s)
Immune Checkpoint Inhibitors , T-Lymphocytes , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Sulfonamides/pharmacology
16.
Clin Radiol ; 76(3): 236.e9-236.e19, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33272531

ABSTRACT

AIM: To assess the potential of texture analysis (TA) applied in T1 maps and extracellular volume (ECV) obtained using cardiac magnetic resonance (CMR) in the diagnosis of hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) compared with normal controls (NC). Strain parameters were analysed to compare with final TA models. MATERIALS AND METHODS: This retrospective study included 66 HCM patients, 39 HHD patients, and 41 NC. Step-wise dimension reduction and feature selection were performed by reproducibility, machine learning, collinearity, and multivariable regression analysis to select the texture features that enable diagnosis of and differentiation between HCM and HHD. Strain parameters were calculated by short-axis and three long-axis cine sequences. RESULTS: Independent features in T1 maps and ECV analysis allowed for the differentiation between patients (HCM and HHD) and NC. Of the best-calculated model, the areas under the receiver operating curve (AUCs) were as follows: 0.969 for T1 map and 0.964 for ECV. To distinguish HCM from HHD, two independent features were screened out for both T1 and ECV maps. The AUCs were as follows: 0.793 for T1 map and 0.894 for ECV. Radial, circumferential, and longitudinal strain parameters could differentiate patients from NC, but only longitudinal strain parameters was significantly different between HCM and HHD. CONCLUSIONS: Texture analysis of T1 maps and ECV shows high accuracy in differentiating hypertrophic myocardium from NC, and HCM from HHD. Strain parameters are able to demonstrate the difference between patients and NC, but were less impressive in differentiating HCM and HHD.


Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Hypertension/diagnosis , Magnetic Resonance Imaging/methods , Adult , Cardiomyopathy, Hypertrophic/pathology , Female , Heart/diagnostic imaging , Humans , Hypertension/pathology , Male , Middle Aged , Myocardium/pathology , Reproducibility of Results , Retrospective Studies
17.
Clin Lymphoma Myeloma Leuk ; 21(4): 267-278.e10, 2021 04.
Article in English | MEDLINE | ID: mdl-33303421

ABSTRACT

INTRODUCTION: The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts. PATIENTS AND METHODS: The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310). RESULTS: Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell-like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry). CONCLUSION: Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Lymphoma, Large B-Cell, Diffuse/mortality , Proto-Oncogene Proteins c-bcl-2/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biomarkers, Tumor/analysis , Clinical Trials, Phase III as Topic , Cohort Studies , Drug Resistance, Neoplasm/genetics , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Multicenter Studies as Topic , Prognosis , Progression-Free Survival , Proto-Oncogene Proteins c-bcl-2/analysis , Randomized Controlled Trials as Topic , Registries/statistics & numerical data , Young Adult
18.
Acta Virol ; 64(4): 427-432, 2020.
Article in English | MEDLINE | ID: mdl-33112640

ABSTRACT

The present paper describes first full genome sequence of the Garlic virus D (GarV-D) from northern India with a genome size of 8425 bp long ssRNA. The infected leaves and bulbs of garlic variety Yamuna Safed (G-282) plants suspected for GarV-D infection were collected with the aim to identify contagion virus during March, 2018. The total RNA was extracted from the pooled garlic plants using TRIzol reagent and sequenced using an Illumina HiSeq 2000 platform. BLASTn search in the NCBI database identified contagion as GarV-D (MK518067). It shared 83.63-85.83% nucleotide sequence identities with other (GarV-D) isolates from Argentina (KF550407, KF555653, KR819505) and 83.15% with isolates from China (MF795136, MF363012). Keywords: Allium sativum; Allexivirus; Garlic virus D; India.


Subject(s)
Flexiviridae/genetics , Garlic/virology , Genome, Viral , Plant Diseases/virology , India , RNA, Viral/genetics
19.
Hum Brain Mapp ; 41(18): 5255-5281, 2020 12 15.
Article in English | MEDLINE | ID: mdl-32936989

ABSTRACT

Cognitive neuroscience research has provided foundational insights into aging, but has focused primarily on the cerebral cortex. However, the cerebellum is subject to the effects of aging. Given the importance of this structure in the performance of motor and cognitive tasks, cerebellar differences stand to provide critical insights into age differences in behavior. However, our understanding of cerebellar functional activation in aging is limited. Thus, we completed a meta-analysis of neuroimaging studies across task domains. Unlike in the cortex where an increase in bilateral activation is seen during cognitive task performance with advanced age, there is less overlap in cerebellar activation across tasks in older adults (OAs) relative to young. Conversely, we see an increase in activation overlap in OAs during motor tasks. We propose that this is due to inputs for comparator processing in the context of control theory (cortical and spinal) that may be differentially impacted in aging. These findings advance our understanding of the aging mind and brain.


Subject(s)
Aging/physiology , Cerebellum/diagnostic imaging , Cerebellum/physiology , Functional Neuroimaging , Memory/physiology , Motor Activity/physiology , Psychomotor Performance/physiology , Adult , Aged , Humans , Likelihood Functions , Middle Aged , Young Adult
20.
Clin Radiol ; 75(3): 237.e17-237.e25, 2020 03.
Article in English | MEDLINE | ID: mdl-31679817

ABSTRACT

AIM: To investigate the feasibility and prognostic value of biventricular strain analysis for patients with systemic lupus erythematosus (SLE) and relationship to left ventricular (LV) myocardial fibrosis, pulmonary hypertension (PAH), and right ventricular (RV) ejection fraction (RVEF). MATERIALS AND METHODS: A total of 50 SLE patients (47 women; 34.4±12 years) and 15 controls (13 women; 32.9±8.6 years) were imaged via echocardiography and a 3 T magnetic resonance imaging (MRI). Pulmonary artery systolic pressure (sPAP) was assessed using echocardiography. Biventricular global circumferential strain (GCS), global longitudinal strain (GLS), global circumferential strain rate (GCSR), and global longitudinal strain rate (GLSR) as well as LV myocardial extracellular volume (ECV) were derived for each subject. RESULTS: Elevated LV ECV was significantly associated with LV GCS (beta -0.428, p=0.000), GLS (beta 0.404, p=0.000), GCSR (beta -0.350, p=0.006), GLSR (beta -0.445, p=0.000) and RV GCS (beta -0.373, p=0.000), and the presence of reduced RVEF was significantly associated with LV GCS (beta -0.338, p=0.002), GLS (beta -0.465, p=0.000) and RV GCS (beta -0.465, p=0.000). Raised sPAP was significantly associated with RV GLS (beta 0.445, p=0.000) and GCSR (beta -0.387, p=0.001). Moreover, there were significantly correlations between LV and RV strain and strain rate. CONCLUSIONS: Biventricular strain analysis may be a better prognostic tool for patients with SLE as it allows greater comprehensive analysis and more definitive treatment planning compared to separate assessment of LV or RV contractility.


Subject(s)
Hypertension, Pulmonary/diagnostic imaging , Lupus Erythematosus, Systemic/physiopathology , Magnetic Resonance Imaging , Ventricular Dysfunction, Right/diagnostic imaging , Adult , Case-Control Studies , Contrast Media , Echocardiography , Feasibility Studies , Female , Gadolinium DTPA , Humans , Hypertension, Pulmonary/physiopathology , Image Interpretation, Computer-Assisted , Male , Prognosis , Prospective Studies , Stroke Volume , Ventricular Dysfunction, Right/physiopathology
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