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1.
Eur J Haematol ; 107(3): 301-310, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33973276

ABSTRACT

INTRODUCTION: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. METHODS: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131). RESULTS: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model. CONCLUSIONS: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Lymphoma, Mantle-Cell/therapy , Aged , Cyclophosphamide/therapeutic use , Dexamethasone/therapeutic use , Disease-Free Survival , Doxorubicin/therapeutic use , Female , Humans , Lymphoma, Mantle-Cell/mortality , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Proportional Hazards Models , Remission Induction/methods , Retrospective Studies , Time-to-Treatment , Transplantation, Autologous , Vincristine/therapeutic use
2.
Am J Hematol ; 96(11): 1374-1384, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34324220

ABSTRACT

Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Lymphoma, Mantle-Cell/drug therapy , Rituximab/therapeutic use , Age Factors , Aged , Female , Humans , Lymphoma, Mantle-Cell/epidemiology , Male , Middle Aged , Progression-Free Survival , Retrospective Studies , Survival Analysis , Treatment Outcome
3.
Genes Chromosomes Cancer ; 59(8): 484-494, 2020 08.
Article in English | MEDLINE | ID: mdl-32277542

ABSTRACT

Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.


Subject(s)
Chromothripsis , Cyclin-Dependent Kinase Inhibitor p15/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Genomic Instability , Lymphoma, Mantle-Cell/genetics , Tumor Suppressor Protein p53/genetics , Aged , Chromosomes, Human, Pair 17/genetics , Female , Humans , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Mutation
4.
Psychol Med ; 50(7): 1099-1109, 2020 05.
Article in English | MEDLINE | ID: mdl-31030696

ABSTRACT

BACKGROUND: Family education programs (FEPs) target caregiving-related psychological distress for carers of relatives/friends diagnosed with serious mental health conditions. While FEPs are efficacious in reducing distress, the mechanisms are not fully known. Peer group support and greater mental health knowledge are proposed to reduce carers' psychological distress by reducing stigmatising attitudes and self-blame, and strengthening carers' relationship with their relative. METHODS: Adult carers (n = 1016) who participated in Wellways Australia's FEP from 2009 to 2016 completed self-report questionnaires at the core program's start and end, during the consolidation period, and at a 6-month follow-up. Those who enrolled early completed questionnaires prior to a wait-list period. We used linear mixed-effects modelling to assess the program's effectiveness using a naturalistic wait-list control longitudinal design, and multivariate latent growth modelling to test a theory-based process change model. RESULTS: While there was no significant change over the wait-list period, psychological distress, self-blame and stigmatising attitudes significantly decreased, and communication and relationship quality/feelings increased from the core program's start to its end. Changes were maintained throughout the consolidation period and follow-up. Peer group support significantly predicted the declining trajectory of distress. Peer group support and greater knowledge significantly predicted declining levels of self-blame and stigmatising attitudes, and increasing levels of communication. CONCLUSIONS: This is the first study to quantitatively validate the mechanisms underlying the effect of FEPs on carers' psychological distress. Peer group support is key in modifying carers' appraisals of their friend/relatives' condition. Continued implementation of FEPs within mental health service systems is warranted.


Subject(s)
Caregivers/psychology , Health Education , Mental Disorders/nursing , Outcome and Process Assessment, Health Care , Stress, Psychological/therapy , Adaptation, Psychological , Adult , Aged , Australia , Female , Humans , Longitudinal Studies , Male , Mental Health Services , Middle Aged , Peer Group , Surveys and Questionnaires
5.
Heart Lung Circ ; 29(3): 401-404, 2020 Mar.
Article in English | MEDLINE | ID: mdl-30992243

ABSTRACT

BACKGROUND: Depression is common in cardiovascular disease (CVD). Clinical practice guidelines recommend routine depression screening by cardiologists. The aim of the study was to undertake a national survey of Australian cardiologists' clinical practice behaviours in relation to depression screening, referral, and treatment. METHODS: The Cardiovascular Disease and Depression Questionnaire was sent to 827 eligible cardiologist members of Cardiac Society of Australia and New Zealand, of which a total of 524 were returned (63%). RESULTS: Most Australian cardiologists do not routinely ask their patients about depression and only 3% routinely use depression screening instruments. Most cardiologists (>70%) think that General Practitioners (Primary Care Physicians) are primarily responsible for identifying and treating depression in CVD. Cardiologists, who understand the prognostic risks of depression in CVD and feel confident to identify and treat depression, were more likely to screen, refer and/or treat patients for depression. CONCLUSIONS: Australian cardiologists rarely use validated depression screening measures. Several brief instruments are available for use and can be easily integrated into routine patient care without taking additional consultation time.


Subject(s)
Attitude of Health Personnel , Cardiologists , Cardiovascular Diseases , Depression , Referral and Consultation , Surveys and Questionnaires , Adult , Australia , Cardiovascular Diseases/psychology , Cardiovascular Diseases/therapy , Depression/etiology , Depression/psychology , Depression/therapy , Female , Humans , Male , Middle Aged
6.
Appl Environ Microbiol ; 85(15)2019 08 01.
Article in English | MEDLINE | ID: mdl-31126942

ABSTRACT

Agrobacterium tumefaciens is a rhizosphere bacterium that can infect wound sites on plants. The bacterium transfers a segment of DNA (T-DNA) from the Ti plasmid to the plant host cell via a type IV secretion system where the DNA becomes integrated into the host cell chromosomes. The expression of T-DNA in the plant results in tumor formation. Although the binding of the bacteria to plant surfaces has been studied previously, there is little work on possible interactions of the bacteria with the plant cell wall. Seven of the 48 genes encoding putative glycoside hydrolases (Atu2295, Atu2371, Atu3104, Atu3129, Atu4560, Atu4561, and Atu4665) in the genome of A. tumefaciens C58 were found to play a role in virulence on tomato and Bryophyllum daigremontiana Two of these genes (pglA and pglB; Atu3129 and Atu4560) encode enzymes capable of digesting polygalacturonic acid and, thus, may play a role in the digestion of pectin. One gene (arfA; Atu3104) encodes an arabinosylfuranosidase, which could remove arabinose from the ends of polysaccharide chains. Two genes (bglA and bglB; Atu2295 and Atu4561) encode proteins with ß-glycosidase activity and could digest a variety of plant cell wall oligosaccharides and polysaccharides. One gene (xynA; Atu2371) encodes a putative xylanase, which may play a role in the digestion of xylan. Another gene (melA; Atu4665) encodes a protein with α-galactosidase activity and may be involved in the breakdown of arabinogalactans. Limited digestion of the plant cell wall by A. tumefaciens may be involved in tumor formation on tomato and B. daigremontianaIMPORTANCEA. tumefaciens is used in the construction of genetically engineered plants, as it is able to transfer DNA to plant hosts. Knowledge of the mechanisms of DNA transfer and the genes required will aid in the understanding of this process. Manipulation of glycoside hydrolases may increase transformation and widen the host range of the bacterium. A. tumefaciens also causes disease (crown gall tumors) on a variety of plants, including stone fruit trees, grapes, and grafted ornamentals such as roses. It is possible that compounds that inhibit glycoside hydrolases could be used to control crown gall disease caused by A. tumefaciens.


Subject(s)
Agrobacterium tumefaciens/genetics , Bacterial Proteins/genetics , Crassulaceae/microbiology , Glycoside Hydrolases/genetics , Plant Diseases/microbiology , Plant Tumors/microbiology , Solanum lycopersicum/microbiology , Agrobacterium tumefaciens/pathogenicity , Bacterial Proteins/metabolism , Genes, Bacterial , Glycoside Hydrolases/metabolism , Virulence/genetics
7.
Future Oncol ; 15(34): 3977-3986, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31724885

ABSTRACT

Background: Mucosal melanomas (MM) arise within the lining of the gastrointestinal (GI), genitourinary (GU) and head and neck (HN) systems. Method: A retrospective analysis of the National Comprehensive Database identified 4,961 MM patients. Primary objective was to compare survival outcomes across the different locations. Results: Overall survival for GI melanomas was significantly shorter than HN and GU melanomas. Median survival (95% confidence interval) was 19.5 (18.0-21.5), 26.4 (24.9-28.3), and 43.9 (38.8-47.8), months for GI, HN and GU cases, respectively (p<0.0001). Conclusion: This is the largest study of MM in a US based population, demonstrating worse overall survival for GI MM in comparison to HN and GU melanomas.


Subject(s)
Gastrointestinal Neoplasms/mortality , Head and Neck Neoplasms/mortality , Melanoma/mortality , Mucous Membrane/pathology , Urogenital Neoplasms/mortality , Aged , Aged, 80 and over , Female , Follow-Up Studies , Gastrointestinal Neoplasms/pathology , Gastrointestinal Neoplasms/therapy , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Humans , Kaplan-Meier Estimate , Male , Melanoma/pathology , Melanoma/therapy , Middle Aged , Sex Factors , Survival Rate , Treatment Outcome , United States/epidemiology , Urogenital Neoplasms/pathology , Urogenital Neoplasms/therapy
8.
Clin Lab ; 65(9)2019 Sep 01.
Article in English | MEDLINE | ID: mdl-31532106

ABSTRACT

BACKGROUND: Bone marrow core biopsy is a routine component of comprehensive marrow evaluation, and adequacy criteria have been recommended. However, the effectiveness of these adequacy criteria for diagnostic bone marrow evaluation needs to be reassessed in the current era of extensive ancillary testing. We aimed to determine the impact of core biopsy length and intertrabecular area of evaluable bone marrow on overall adequacy for diagnostic marrow evaluation at our tertiary care institution. METHODS: Five hundred sequential cases of iliac crest bone marrow sampling were identified by retrospective re-view at our tertiary care institution. In this cohort, 470 core biopsies were obtained for histologic evaluation. Data including gross core biopsy length, number of intertrabecular 40x high power fields of evaluable marrow, and other pathologic/clinical parameters were compiled. RESULTS: The mean core biopsy length was 1.2 cm, and only 23% measured the recommended ≥ 1.5 cm. However, 96% of the core biopsies were interpretable and contributed to the comprehensive bone marrow evaluation. Notably, 100% of biopsies with ≥ 5.5 intertrabecular areas were contributory. Ancillary testing including immunophenotypic, cytogenetic, and/or molecular studies were performed in > 99% of cases. CONCLUSIONS: When histology was integrated with ancillary testing, the overall diagnosis was substantially limited in only 0.4% of cases and material deemed entirely insufficient in 0.4%. The number of intertrabecular 40x areas of evaluable marrow is a better predictor of adequacy than core biopsy length, and adequacy criteria should be revised in this era of extensive ancillary testing.


Subject(s)
Bone Marrow Examination/methods , Hematologic Diseases/diagnosis , Hematologic Neoplasms/diagnosis , Tertiary Care Centers , Adolescent , Adult , Aged , Aged, 80 and over , Bone Marrow/pathology , Bone Marrow Examination/standards , Child , Child, Preschool , Female , Hematologic Diseases/blood , Hematologic Neoplasms/blood , Humans , Infant , Male , Middle Aged , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity , Young Adult
9.
Cancer ; 124(11): 2306-2315, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29579328

ABSTRACT

BACKGROUND: Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki-67 proliferative index. Single-center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy. METHODS: The authors retrospectively reviewed 483 patients from 5 academic centers in the United States and described the effect of a CK on survival outcomes in individuals with MCL. RESULTS: A CK was found to be associated with inferior overall survival (OS) (4.5 vs 11.6 years; P<.01) and progression-free survival (PFS) (1.9 vs 4.4 years; P<.01). In patients who underwent high-intensity induction followed by autologous stem cell transplantation (ASCT) in first remission, a CK was associated with poor OS (5.1 vs 11.6 years; P = .04) and PFS (3.6 vs 7.8 years; P<.01). Among patients with a CK, high-intensity induction had no effect on OS (4.5 vs 3.8 years; P = .77) nor PFS (2.3 vs 1.5 years; P = .46). Similarly, ASCT in first remission did not improve PFS (3.5 vs 1.2 years; P = .12) nor OS (5.1 vs 4.0 years; P = .27). On multivariable analyses with Ki-67 and MIPI, only CK was found to be predictive of OS (hazard ratio [HR], 1.98; 95% confidence interval [95% CI], 1.12-3.49 [P = .02]), whereas both CK (HR, 1.91; 95% CI, 1.17-3.12 [P = .01]) and Ki-67 >30% (HR, 1.86; 95% CI, 1.06-3.28 [P = .03]) were associated with inferior PFS. Multivariable analysis did not identify any specific cytogenetic abnormalities associated with inferior survival. CONCLUSIONS: CK appears to be independently associated with inferior outcomes in patients with MCL regardless of the intensity of induction therapy and receipt of ASCT. Cytogenetics should be incorporated into the workup of a new diagnosis of MCL and novel therapeutic approaches should be investigated for patients with CK. Cancer 2018;124:2306-15. © 2018 American Cancer Society.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosome Aberrations , Hematopoietic Stem Cell Transplantation , Lymphoma, Mantle-Cell/therapy , Remission Induction/methods , Adult , Aged , Aged, 80 and over , Combined Modality Therapy/methods , Female , Follow-Up Studies , Genetic Testing/methods , Humans , Karyotype , Karyotyping/methods , Ki-67 Antigen/analysis , Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/mortality , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Predictive Value of Tests , Prognosis , Progression-Free Survival , Retrospective Studies , Risk Assessment/methods , Transplantation, Autologous , United States/epidemiology
10.
Histopathology ; 70(7): 1166-1170, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28008656

ABSTRACT

AIMS: Lymphadenopathy, haematological abnormalities and constitutional symptoms are among the non-specific manifestations seen in drug rash with eosinophilia and systemic symptoms (DRESS), an uncommon but potentially fatal cutaneous adverse drug reaction. The ubiquitous human herpesvirus 6 (HHV-6) plays a unique role in the pathogenesis of DRESS, with emerging data suggesting that reactivation occurs in most cases and contributes to the clinical manifestations, including lymphadenopathy. Further, in the appropriate clinical context, demonstration of HHV-6 reactivation may lend support to a diagnosis of DRESS. The histopathology of DRESS-associated HHV-6 lymphadenitis is reported rarely, with morphologic and immunophenotypic characteristics concerning for T cell lymphoma. The aim is to characterize the histopathology of HHV-6 lymphadenitis in the context of DRESS and to highlight this as an important cause of lymphadenopathy that may be a clinical, morphologic and immunophenotypic mimic of lymphoma. METHODS AND RESULTS: We describe a case of lymphoma-mimicking lymphadenitis in which the histopathological demonstration of reactivation of HHV-6 infection lent support to the clinical diagnosis of DRESS. CONCLUSION: Lymph node biopsies concerning for T cell lymphoma should be evaluated for HHV-6 involvement in a clinical context suggestive of DRESS.


Subject(s)
Drug Hypersensitivity Syndrome/diagnosis , Lymphadenitis/virology , Lymphoma, T-Cell/diagnosis , Roseolovirus Infections/complications , Adult , Diagnosis, Differential , Drug Hypersensitivity Syndrome/virology , Female , Herpesvirus 6, Human , Humans
11.
Hepatology ; 61(4): 1357-69, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25477000

ABSTRACT

UNLABELLED: Innate immune mechanisms leading to liver injury subsequent to chronic alcohol ingestion are poorly understood. Natural killer T (NKT) cells, enriched in the liver and comprised of at least two distinct subsets, type I and II, recognize different lipid antigens presented by CD1d molecules. We have investigated whether differential activation of NKT cell subsets orchestrates inflammatory events leading to alcoholic liver disease (ALD). We found that after chronic plus binge feeding of Lieber-DeCarli liquid diet in male C57BL/6 mice, type I, but not type II, NKT cells are activated, leading to recruitment of inflammatory Gr-1(high) CD11b(+) cells into the liver. A central finding is that liver injury after alcohol feeding is dependent upon type I NKT cells. Thus, liver injury is significantly inhibited in Jα18(-/-) mice deficient in type I NKT cells as well as after their inactivation by sulfatide-mediated activation of type II NKT cells. Furthermore, we have identified a novel pathway involving all-trans retinoic acid (ATRA) and its receptor (RARγ) signaling that inhibits type I NKT cells and, consequently, ALD. A semiquantitative polymerase chain reaction analysis of hepatic gene expression of some of the key proinflammatory molecules shared in human disease indicated that their up-regulation in ALD is dependent upon type I NKT cells. CONCLUSIONS: Type I, but not type II, NKT cells become activated after alcohol feeding. Type I NKT cell-induced inflammation and neutrophil recruitment results in liver tissue damage whereas type II NKT cells protect from injury in ALD. Inhibition of type I NKT cells by retinoids or by sulfatide prevents ALD. Given that the CD1d pathway is highly conserved between mice and humans, NKT cell subsets might be targeted for potential therapeutic intervention in ALD.


Subject(s)
Liver Diseases, Alcoholic/immunology , Liver Diseases, Alcoholic/prevention & control , Natural Killer T-Cells/drug effects , Natural Killer T-Cells/physiology , Retinoids/pharmacology , Retinoids/therapeutic use , Sulfoglycosphingolipids/pharmacology , Sulfoglycosphingolipids/therapeutic use , Animals , Male , Mice , Mice, Inbred C57BL , Natural Killer T-Cells/classification
12.
Appl Microbiol Biotechnol ; 99(7): 2939-54, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25722022

ABSTRACT

Lignocellulose is a term for plant materials that are composed of matrices of cellulose, hemicellulose, and lignin. Lignocellulose is a renewable feedstock for many industries. Lignocellulosic materials are used for the production of paper, fuels, and chemicals. Typically, industry focuses on transforming the polysaccharides present in lignocellulose into products resulting in the incomplete use of this resource. The materials that are not completely used make up the underutilized streams of materials that contain cellulose, hemicellulose, and lignin. These underutilized streams have potential for conversion into valuable products. Treatment of these lignocellulosic streams with bacteria, which specifically degrade lignocellulose through the action of enzymes, offers a low-energy and low-cost method for biodegradation and bioconversion. This review describes lignocellulosic streams and summarizes different aspects of biological treatments including the bacteria isolated from lignocellulose-containing environments and enzymes which may be used for bioconversion. The chemicals produced during bioconversion can be used for a variety of products including adhesives, plastics, resins, food additives, and petrochemical replacements.


Subject(s)
Bacteria/metabolism , Biotechnology/methods , Industrial Waste , Lignin/metabolism , Bacteria/growth & development , Biodegradation, Environmental , Cellulose/chemistry , Cellulose/metabolism , Enzymes/genetics , Enzymes/metabolism , Fungi/metabolism , Lignin/chemistry , Polysaccharides/chemistry , Polysaccharides/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Waste Management/methods
13.
Am J Physiol Gastrointest Liver Physiol ; 306(10): G819-23, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24699333

ABSTRACT

Over the last four decades, chronic ethanol feeding studies in rodents using either ad libitum feeding or intragastric infusion models have significantly enhanced our understanding of the pathogenesis of alcoholic liver disease (ALD). Recently, we developed a chronic plus binge alcohol feeding model in mice that is similar to the drinking patterns of many alcoholic hepatitis patients: a history of chronic drinking and recent excessive alcohol consumption. Chronic+binge ethanol feeding synergistically induced steatosis, liver injury, and neutrophil infiltration in mice, which may be useful for the study of early alcoholic liver injury and inflammation. Using this chronic+binge model, researchers have begun to identify novel mechanisms that participate in the pathogenesis of alcoholic liver injury, thereby revealing novel therapeutic targets. In this review article, we briefly discuss several mouse models of ALD with a focus on the chronic+binge ethanol feeding model.


Subject(s)
Alcohol Drinking/pathology , Binge Drinking/pathology , Liver Diseases, Alcoholic/etiology , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Binge Drinking/physiopathology , Dietary Fats, Unsaturated/administration & dosage , Disease Models, Animal , Disease Progression , Intubation, Gastrointestinal , Liver Cirrhosis, Alcoholic/pathology , Mice , Rats
15.
J Gastroenterol Hepatol ; 28 Suppl 1: 56-60, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23855297

ABSTRACT

Interleukin-22 (IL-22) plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces by binding to the receptors IL-22R1, which is generally thought to be expressed exclusively in epithelial cells, and IL-10R2. Our laboratory previously demonstrated that IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22R1 and IL-10R2. Recently, we have identified high expression levels of IL-22R1 and IL-10R2 in liver progenitor cells and hepatic stellate cells (HSCs). Overexpression of IL-22 in vivo or treatment with IL-22 in vitro promotes proliferation of liver progenitor cells via a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. IL-22 treatment also prevents HSC apoptosis in vitro and in vivo. Surprisingly, overexpression of IL-22, via either gene targeting or exogenous administration of adenovirus expressing IL-22, reduces liver fibrosis and accelerates the resolution of liver fibrosis during recovery. The anti-fibrotic effects of IL-22 are mediated via the activation of STAT3 in HSCs and subsequent induction of suppressor of cytokine signaling 3, which induces HSC senescence. Taken together, the hepatoprotective, mitogenic, and anti-fibrotic effects of IL-22 are beneficial in ameliorating alcoholic liver injury. Importantly, due to the restricted expression of IL-22R1, IL-22 therapy is expected to have few side effects, thus making IL-22 a potential candidate for treatment of alcoholic liver disease.


Subject(s)
Interleukins/physiology , Interleukins/therapeutic use , Liver Diseases, Alcoholic/drug therapy , Liver Diseases, Alcoholic/etiology , Molecular Targeted Therapy , Animals , Apoptosis/drug effects , Cell Proliferation , Gene Expression , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Hepatocytes/metabolism , Humans , Interleukins/metabolism , Interleukins/pharmacology , Liver/cytology , Liver Diseases, Alcoholic/genetics , Liver Diseases, Alcoholic/immunology , Receptors, Interleukin/metabolism , Receptors, Interleukin-10/metabolism , STAT3 Transcription Factor/physiology , Stem Cells/metabolism , Interleukin-22
16.
Int J Exerc Sci ; 16(6): 242-251, 2023.
Article in English | MEDLINE | ID: mdl-37114116

ABSTRACT

Cortisol is a hormone that corresponds to physiological and emotional stress. The purpose of this study was to 1) evaluate the changes in cortisol in female Division I collegiate lacrosse players (n = 15) throughout the competitive season, and 2) evaluate the correlation between cortisol and athlete wellness and workload. Salivary cortisol samples were collected weekly in the morning throughout the entirety of the 2021 competitive season (12 weeks). Subjective athlete total wellness scores and sub-scores (muscle soreness, sleep quality, fatigue, and stress) were taken on the same days. Objective total weekly Athlete Load (AL, an amalgam workload metric) were tabulated from the previous training week. A significant effect of time was found on wellness (p < 0.001) and AL (p < 0.001) over the twelve weeks with weekly differences, such as weeks with more than one game, weeks with no games, weeks with students in quarantine (not competing), or weeks with academic stressors such as final exams. There were no weekly differences in cortisol (p = 0.058). Cortisol had negligible correlations with wellness (r = -0.010, p = 0.889) and AL (r = 0.083, p = 0.272) during the competitive season. These findings suggest that cortisol changed little for athletes throughout the season although training volume and wellness did. Thus, assessing acute responses of cortisol may prove to be more beneficial to evaluating athletes' stress.

17.
Blood Adv ; 7(11): 2287-2296, 2023 06 13.
Article in English | MEDLINE | ID: mdl-36516079

ABSTRACT

The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.


Subject(s)
Lymphoma, Mantle-Cell , Adult , Humans , Lymphoma, Mantle-Cell/therapy , Lymphoma, Mantle-Cell/drug therapy , Risk Assessment , Prognosis , Combined Modality Therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
18.
Blood Adv ; 5(23): 5179-5189, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34516611

ABSTRACT

Although an expanding array of effective treatments has resulted in recent improvement in survival of patients with mantle cell lymphoma (MCL), outcomes remain heterogeneous, and identification of prognostic factors remains a priority. We assessed the prognostic impact of time to progression of disease (POD) after first-line therapy among 455 patients with relapsed MCL. Patients were categorized by duration of first remission as PRF/POD6, defined as progressive disease during induction or POD within 6 months of diagnosis (n = 65; 14%); POD6-24, defined as POD between 6 and 24 months after diagnosis (n = 153; 34%); and POD>24, defined as POD >24 months after diagnosis (n = 237; 53%). The median overall survival from POD (OS2) was 1.3 years (95% confidence interval [CI], 0.9-2.4) for patients with PRF/POD6, 3 years (95% CI, 2-6.8) for those with POD6-24, and 8 years (95% CI, 6.2-NR) for those with POD>24. Median OS2 was inferior in patients with early POD (defined as PRF/POD6 or POD6-24) after both intensive and less intensive frontline treatment. The prognostic performance of time until POD was replicated in an independent cohort of 245 patients with relapsed MCL, with median OS2 of 0.3 years (95% CI, 0.1-0.5) for PRF/POD6, 0.8 years (95% CI, 0.6-0.9) for POD6-24, and 2.4 years (95% CI 2.1-2.7) for POD>24. Early POD is associated with inferior OS2 in patients with relapsed MCL, identifying a high-risk population for future prospective studies.


Subject(s)
Lymphoma, Mantle-Cell , Adult , Humans , Lymphoma, Mantle-Cell/diagnosis , Lymphoma, Mantle-Cell/drug therapy , Prognosis , Prospective Studies , Recurrence , Treatment Outcome
20.
R Soc Open Sci ; 6(3): 180748, 2019 Mar.
Article in English | MEDLINE | ID: mdl-31031986

ABSTRACT

A citizen science project found that the greenhouse camel cricket (Diestrammena asynamora) is common in North American homes. Public response was to wonder 'what good are they anyway?' and ecology and evolution guided the search for potential benefit. We predicted that camel crickets and similar household species would likely host bacteria with the ability to degrade recalcitrant carbon compounds. Lignocellulose is particularly relevant as it is difficult to degrade yet is an important feedstock for pulp and paper, chemical and biofuel industries. We screened gut bacteria of greenhouse camel crickets and another household insect, the hide beetle (Dermestes maculatus) for the ability to grow on and degrade lignocellulose components as well as the lignocellulose-derived industrial waste product black liquor. From three greenhouse camel crickets and three hide beetles, 14 bacterial strains were identified that were capable of growth on lignocellulosic components, including lignin. Cedecea lapagei was selected for further study due to growth on most lignocellulose components. The C. lapagei secretome was identified using LC/MS/MS analysis. This work demonstrates a novel source of lignocellulose-degrading bacteria and introduces an effective workflow to identify bacterial enzymes for transforming industrial waste into value-added products. More generally, our research suggests the value of ecologically guided discovery of novel organisms.

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