ABSTRACT
Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.
Subject(s)
Interleukin-18 , Tumor Microenvironment , Animals , Humans , Interleukin-18/metabolism , Mice , Tumor Microenvironment/immunology , Tumor Microenvironment/drug effects , Cell Line, Tumor , Killer Cells, Natural/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Neoplasms/immunology , Neoplasms/drug therapy , Lymphocyte Activation/immunology , Lymphocyte Activation/drug effects , Female , Mice, Inbred C57BL , Intercellular Signaling Peptides and Proteins/metabolism , Xenograft Model Antitumor Assays , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
OBJECTIVES: Familial Mediterranean Fever (FMF) patients are required to adhere to a life-long treatment with colchicine, primarily for preventing amyloidosis. As some patients may be asymptomatic for long periods of time, it remains unclear whether it is possible to discontinue colchicine treatment in a selective group of patients. We aimed to identify predictive characteristics for a successful cessation of colchicine therapy. METHODS: Out of 646 FMF pediatric patients followed in our referral FMF clinic, colchicine treatment was discontinued in 51 patients. In this study we compared the genetic, demographic, and clinical characteristics between patients for whom a successful cessation of therapy was made (Group 1; n = 21) and patients for whom cessation of therapy was deemed a failure (Group 2; n = 30) and consequently had to resume colchicine therapy. RESULTS: Patients for whom a successful cessation of therapy was achieved had no biallelic pathogenic MEFV mutations, were less likely to have "severe attacks" (two or more FMF characteristic symptoms) (24% vs 80%; P = 0.000067) and did not require higher than 1 mg/day of colchicine, prior to the drug cessation. Remission duration under colchicine treatment was significantly higher in group 1 compared with group 2 (4.36 years ±2.12 vs 2.53 years ±2; P = 0.0036). CONCLUSION: This study supports the concept of colchicine free remission in a minority of FMF patients (3%). Holding treatment, under close monitoring, may be reasonable when selecting the appropriate patients.
Subject(s)
Amyloidosis , Colchicine , Familial Mediterranean Fever , Child , Humans , Amyloidosis/drug therapy , Amyloidosis/genetics , Colchicine/therapeutic use , Familial Mediterranean Fever/drug therapy , Familial Mediterranean Fever/genetics , Familial Mediterranean Fever/diagnosis , Pyrin/geneticsABSTRACT
Interest in the association between patient and therapist's motion synchrony and the working alliance has been growing in recent years. This interest is part of a larger effort in psychotherapy research to study how the working alliance, being central to the therapeutic process, develops over the course of therapy. However, while previous studies suggest that such an association between motion synchrony and the working alliance exists, there are mixed results regarding the direction of it. The present single-case study seeks to shed light on these mixed results with a multimodal perspective of nonverbal synchrony. That is, through an exploration of a single case, the present study explores physiological synchrony as an indicator of context in which motion synchrony is associated with the working alliance. For this aim, a single case was chosen from a randomized control trial investigating short-term psychodynamic treatment for major depressive disorder. Statistical analysis identified an interaction between physiological synchrony and motion synchrony in predicting working alliance levels. Findings show that in the context of an antiphase pattern of physiological synchrony (negative association between physiological measures of the two participants), there was a positive association between motion synchrony and the working alliance. This study emphasizes the potential of a multimodal approach, while suggesting a possible explanation for mixed results in current literature that focuses on the association between motion synchrony and the working alliance. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Subject(s)
Depressive Disorder, Major , Professional-Patient Relations , Humans , Depressive Disorder, Major/therapy , Psychotherapy/methods , Surveys and QuestionnairesABSTRACT
Numerous innovations within the field of plastic surgery have been developed in Israel over the last few decades. Many of these therapeutic devices and techniques have been established globally with demonstrable efficacy and respectable safety profiles. This article offers an overview of recent Israeli cutting-edge medical therapeutic solutions contributing to the global practice of plastic surgery.
ABSTRACT
Objective: Accumulating research demonstrates the importance of utilizing supportive techniques in psychotherapy; however, little is known about therapeutic processes that are set in motion following the use of supportive techniques. The present study examined the effects of supportive techniques on nonverbal synchrony, both at the sample level and at the individual differences level.Method: The sample consisted of 86 patients from a randomized controlled trial for treatment of depression. Supportive techniques were rated by patients and therapists after every session, and nonverbal synchrony was quantified by motion energy analysis (MEA) for each session. The ability of supportive techniques to predict subsequent nonverbal synchrony was examined using polynomial regression and response surface analysis.Results: The findings suggest that, at the sample level, greater use of supportive techniques was a significant predictor of subsequent higher levels of nonverbal synchrony. At the individual differences level, this effect was significant for patients with low levels of depression severity and personality disorders, yet not significant for patients with high levels.Conclusion: The present study demonstrates that greater use of supportive techniques in treatment may facilitate a process that manifests as higher levels of synchrony, especially for patients with lower levels of personality disorders and depression.
Subject(s)
Depression , Psychotherapy , Depression/therapy , Humans , Psychotherapy/methods , Treatment OutcomeABSTRACT
Findings from the past 5 decades of empirical research on the working alliance suggest its importance in psychotherapy. Recent studies have sought to identify markers of the alliance, of which one of the most promising candidates is nonverbal synchrony. Delving into processes that constitute the alliance, such as alliance ruptures, may shed light on underlying mechanisms of the association between nonverbal synchrony and the therapeutic relationship. The present study examines whether nonverbal synchrony can serve as a marker of alliance ruptures. To achieve this aim, 418 sessions of 75 therapeutic dyads were coded for ruptures, using the Rupture Resolution Rating System, and for nonverbal synchrony, using motion energy analysis. A mixed-method analysis, integrating multilevel nested models with a case study analysis, was implemented. The results of the multilevel nested models suggest that nonverbal synchrony is significantly associated with confrontational ruptures, whereas withdrawal ruptures showed no such association. The findings of the case analysis suggest that moments of especially high nonverbal synchrony during a rupture are those in which the therapist made great efforts to be attentive to the patient when the patient acted in a confrontational manner. The findings of the present study demonstrate the potential of nonverbal synchrony to serve as a marker of confrontational ruptures. The findings support the social glue assumption, according to which therapists may seek higher levels of nonverbal synchrony with patients to maintain a strong alliance in the face of difficulties. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Subject(s)
Therapeutic Alliance , Antisocial Personality Disorder , Humans , Professional-Patient Relations , PsychotherapyABSTRACT
The h-index has been proven in the US and Canada to be a solid tool to assess the quality and impact of individual scientific work in the field of plastic surgery. M-quotient is an additional metric that mitigates the h-index's inherent bias toward more seasoned researchers. The objective of this study was evaluating the relationship between h-index and M-quotient and research productivity among plastic surgeons in the state of Israel. METHODS: A list of all Israeli board-certified plastic surgeons registered in the Israeli Society of Plastic and Aesthetic Surgery was obtained from the organization's website. Relevant demographic and academic factors of each surgeon were retrieved. The Scopus database was queried to determine each surgeon's h-index and M-quotient, among other bibliometric parameters. RESULTS: Our study included 173 plastic surgeons, 90% of whom were men. In total, 49.7% were working in academically affiliated hospitals; 14.4% of the surgeons had an academic rank. The mean h-index was 6.13; mean M-quotient was 0.27. Statistical analysis demonstrated a positive correlation between total number of publications (P < 0.0001), total number of citations (P < 0.0001), the surgeon's seniority (P < 0.0001), academic rank (P = 0.007), appointed as past/present plastic surgery department director (P < 0.0001), and working in an academic affiliated hospital (P < 0.025). The same parameters were found to have a positive correlation with M-quotient. CONCLUSIONS: The h-index is an effective measure to compare plastic surgeons' research productivity in Israel. M-quotient is an ancillary tool for the assessment of research productivity among plastic surgeons, with the advent of neutralizing the surgeon's seniority.
ABSTRACT
Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Kupffer Cells/metabolism , Animals , Antigens, Ly/immunology , Antigens, Ly/metabolism , Cell Differentiation/genetics , Cell Survival , Hematopoiesis , Inflammasomes/metabolism , Inflammation/pathology , Intracellular Signaling Peptides and Proteins/genetics , Kupffer Cells/physiology , Liver/cytology , Liver/injuries , Male , Mice , Mice, Inbred C57BL , Monocytes/metabolismABSTRACT
The COVID-19 pandemic has presented unique challenges to the plastic surgery field. Substantial changes have been incorporated in hospital and practice protocols in all branches of medicine. Organic medical teams were placed on scheduled shifts to prevent cross-infection, and some working teams were discontinued. Remote technology consultations and deliberations were instituted in hospitals and community medical services to maintain the flow of information on patient status. Several mitigation strategies were implemented during these times throughout medical facilities. We present those implemented in our facility to ensure adequate labor, resources, and facilities along with proper protocols for patient selection and management according to predetermined risk assessment criteria with the hope to assist the healthcare staff to minimize mortality risks.
ABSTRACT
BACKGROUND: Patient-reported outcome (PRO) studies are essential in the assessment of surgical procedures in plastic surgery. One accepted and validated questionnaire is the BREAST-Q. OBJECTIVES: The aim of this study was to assess the quality of PRO studies in plastic surgery utilizing the BREAST-Q questionnaire. METHODS: This study involved 2 steps: (1) a systematic review of 23 key criteria assessing the quality of survey research in studies utilizing the BREAST-Q that were published between 2015 and 2018; (2) a review of current guidance for survey research in journals related to plastic surgery and breast surgery which were included in the systematic review. RESULTS: Seventy-nine studies were included in the systematic review. Many key criteria were poorly reported: 51.9% of the studies did not provide a defined response rate and almost 90% did not provide a method for analysis of nonresponse error; 67.1% lacked a description of the sample's representativeness of the population of interest, and 82.3% did not present a sample size calculation. The methods used to analyze data were not described in 11.4% of the papers; in 27.8% the data analysis presented could not allow replication of the results. Of the 16 journals in the fields of plastic surgery and breast surgery for which the "instructions to authors" were reviewed, 15 (93.7%) did not provide any guidance for survey reporting. CONCLUSIONS: The majority of key criteria are underreported by authors publishing their survey research in peer-reviewed journals in the fields of plastic and breast surgery. There is an urgent need to construct well-developed reporting guidelines for survey research in plastic surgery, and particularly in breast surgery.
Subject(s)
Plastic Surgery Procedures , Surgery, Plastic , Humans , Patient Reported Outcome Measures , Research Design , Surveys and QuestionnairesABSTRACT
Low bone mass and an increased risk of fracture are predictors of osteoporosis. Individuals who share the same bone-mineral density (BMD) vary in their fracture risk, suggesting that microstructural architecture is an important determinant of skeletal strength. Here, we utilized the rich diversity of the Collaborative Cross mice to identify putative causal genes that contribute to the risk of fractures. Using microcomputed tomography, we examined key structural features that pertain to bone quality in the femoral cortical and trabecular compartments of male and female mice. We estimated the broad-sense heritability to be 50-60% for all examined traits, and we identified five quantitative trait loci (QTL) significantly associated with six traits. We refined each QTL by combining information inferred from the ancestry of the mice, ranging from RNA-Seq data and published literature to shortlist candidate genes. We found strong evidence for new candidate genes, particularly Rhbdf2, whose close association with the trabecular bone volume fraction and number was strongly suggested by our analyses. We confirmed our findings with mRNA expression assays of Rhbdf2 in extreme-phenotype mice, and by phenotyping bones of Rhbdf2 knockout mice. Our results indicate that Rhbdf2 plays a decisive role in bone mass accrual and microarchitecture.
Subject(s)
Bone Density , Carrier Proteins/genetics , Genome-Wide Association Study , Osteoporosis/genetics , Animals , Computer Simulation , Female , Fractures, Bone/genetics , Genotype , Homeostasis , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Quantitative Trait Loci , RNA-Seq , X-Ray MicrotomographyABSTRACT
Focusing attention on one speaker on the background of other irrelevant speech can be a challenging feat. A longstanding question in attention research is whether and how frequently individuals shift their attention towards task-irrelevant speech, arguably leading to occasional detection of words in a so-called unattended message. However, this has been difficult to gauge empirically, particularly when participants attend to continuous natural speech, due to the lack of appropriate metrics for detecting shifts in internal attention. Here we introduce a new experimental platform for studying the dynamic deployment of attention among concurrent speakers, utilizing a unique combination of Virtual Reality (VR) and Eye-Tracking technology. We created a Virtual Café in which participants sit across from and attend to the narrative of a target speaker. We manipulated the number and location of distractor speakers by placing additional characters throughout the Virtual Café. By monitoring participant's eye-gaze dynamics, we studied the patterns of overt attention-shifts among concurrent speakers as well as the consequences of these shifts on speech comprehension. Our results reveal important individual differences in the gaze-pattern displayed during selective attention to speech. While some participants stayed fixated on a target speaker throughout the entire experiment, approximately 30% of participants frequently shifted their gaze toward distractor speakers or other locations in the environment, regardless of the severity of audiovisual distraction. Critically, preforming frequent gaze-shifts negatively impacted the comprehension of target speech, and participants made more mistakes when looking away from the target speaker. We also found that gaze-shifts occurred primarily during gaps in the acoustic input, suggesting that momentary reductions in acoustic masking prompt attention-shifts between competing speakers, in line with "glimpsing" theories of processing speech in noise. These results open a new window into understanding the dynamics of attention as they wax and wane over time, and the different listening patterns employed for dealing with the influx of sensory input in multisensory environments. Moreover, the novel approach developed here for tracking the locus of momentary attention in a naturalistic virtual-reality environment holds high promise for extending the study of human behavior and cognition and bridging the gap between the laboratory and real-life.
ABSTRACT
Staphylococcus aureus is a major cause of infectious disease. Liver Kupffer cells (KCs) are responsible for sequestering and destroying S. aureus through the phagolysosomal pathway. Proteins belonging to the COMMD family emerge as key intracellular regulators of protein trafficking, but the role of COMMD10 in macrophage-mediated S. aureus eradication is unknown. Here we report that COMMD10 in macrophages was necessary for its timely elimination, as demonstrated with two different S. aureus subspecies. In vivo, COMMD10-deficient liver KCs exhibited impaired clearance of systemic S. aureus infection. S. aureus-infected COMMD10-deficient macrophages exhibited impaired activation of the transcription factor EB, resulting in reduced lysosomal biogenesis. Moreover, S. aureus-initiated phagolysosomal maturation and function were significantly attenuated in COMMD10-deficient macrophages. Finally, expression of COMMD/CCDC22/CCDC93 complex, linked to phagolysosomal maturation, was reduced by COMMD10 deficiency. Collectively, these results support an important role for COMMD10 in instructing macrophage phagolysosomal biogenesis and maturation during S. aureus infection.
ABSTRACT
AIM: Despite research suggesting increased anxiety and depressive symptoms after a perinatal loss and during future pregnancies, little knowledge exists to guide clinicians treating pregnant women after perinatal loss. This case study explores processes that facilitated therapeutic change for a pregnant patient with major depressive disorder (MDD) and posttraumatic stress disorder after perinatal losses. METHOD: The study integrated quantitative and narrative analyses in a single case derived from the pilot phase of a randomized controlled trial on supportive-expressive therapy for MDD. RESULTS: The quantitative and narrative analyses suggest that an improvement in maladaptive interpersonal patterns toward the therapist, in the form of attachment avoidance, made it possible to form a strong alliance, which in turn led to a successful outcome. CONCLUSIONS: The findings highlight the importance of improving maladaptive interpersonal patterns as a prerequisite to enable patients after pregnancy losses to develop and maintain a corrective therapeutic experience.
Subject(s)
Depressive Disorder, Major/therapy , Perinatal Death , Professional-Patient Relations , Psychotherapeutic Processes , Adult , Female , Humans , Infant, Newborn , PregnancyABSTRACT
Enteroendocrine cells relay energy-derived signals to immune cells to signal states of nutrient abundance and control immunometabolism. Emerging data suggest that the gut-derived nutrient-induced incretin glucose-dependent insulinotropic polypeptide (GIP) operates at the interface of metabolism and inflammation. Here we show that high-fat diet (HFD)-fed mice with immune cell-targeted GIP receptor (GIPR) deficiency exhibit greater weight gain, insulin resistance, hepatic steatosis and significant myelopoiesis concomitantly with impaired energy expenditure and inguinal white adipose tissue (WAT) beiging. Expression of the S100 calcium-binding protein S100A8 was increased in the WAT of mice with immune cell-targeted GIPR deficiency and co-deletion of GIPR and the heterodimer S100A8/A9 in immune cells ameliorated the aggravated metabolic and inflammatory phenotype following a HFD. Specific GIPR deletion in myeloid cells identified this lineage as the target of GIP effects. Furthermore, GIP directly downregulated S100A8 expression in adipose tissue macrophages. Collectively, our results identify a myeloid-GIPR-S100A8/A9 signalling axis coupling nutrient signals to the control of inflammation and adaptive thermogenesis.
Subject(s)
Body Weight , Calgranulin A/metabolism , Calgranulin B/metabolism , Gastric Inhibitory Polypeptide/metabolism , Inflammation/etiology , Inflammation/metabolism , Myeloid Cells/metabolism , Animals , Bone Marrow/metabolism , Bone Marrow/pathology , Calgranulin A/genetics , Calgranulin B/genetics , Immunity , Immunohistochemistry , Inflammation/pathology , Insulin Resistance/genetics , Mice , Myelopoiesis/genetics , Phenotype , Receptors, Gastrointestinal Hormone/deficiency , Receptors, Gastrointestinal Hormone/metabolismABSTRACT
Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1ß production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1ß production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD.
Subject(s)
Colitis/immunology , Inflammasomes/metabolism , Inflammation/immunology , Inflammatory Bowel Diseases/immunology , Intestinal Mucosa/pathology , Intracellular Signaling Peptides and Proteins/metabolism , Monocytes/immunology , Animals , Antigens, Ly/metabolism , Colitis/chemically induced , Dextran Sulfate , Disease Models, Animal , Humans , Intracellular Signaling Peptides and Proteins/genetics , Lipopolysaccharides/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction , Tight JunctionsABSTRACT
BACKGROUND: Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (DM2) are all linked to diabetic cardiomyopathy that lead to heart failure. Cardiomyopathy is initially characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and fibrosis, both of which are aggravated by angiotensin. Caloric restriction (CR) is cardioprotective in animal models of heart disease through its catabolic activity and activation of the expression of adaptive genes. We hypothesized that in the diabetic heart; this effect involves antioxidant defenses and is mediated by SIRT1 and the transcriptional coactivator PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator). METHODS: Obese Leptin resistant (db/db) mice characterized by DM2 were treated with angiotensin II (AT) for 4 weeks to enhance the development of cardiomyopathy. Mice were concomitantly either on a CR diet or fed ad libitum. Cardiomyocytes were exposed to high levels of glucose and were treated with EX-527 (SIRT1 inhibitor). Cardiac structure and function, gene and protein expression and oxidative stress parameters were analyzed. RESULTS: AT treated db/db mice developed cardiomyopathy manifested by elevated levels of serum glucose, cholesterol and cardiac hypertrophy. Leukocyte infiltration, fibrosis and an increase in an inflammatory marker (TNFα) and natriuretic peptides (ANP, BNP) gene expression were also observed. Oxidative stress was manifested by low SOD and PGC-1α levels and an increase in ROS and MDA. DM2 resulted in ERK1/2 activation. CR attenuated all these deleterious perturbations and prevented the development of cardiomyopathy. ERK1/2 phosphorylation was reduced in CR mice (p = 0.008). Concomitantly CR prevented the reduction in SIRT activity and PGC-1α (p < 0.04). Inhibition of SIRT1 activity in cardiomyocytes led to a marked reduction in both SIRT1 and PGC-1α. ROS levels were significantly (p < 0.03) increased by glucose and SIRT1 inhibition. CONCLUSION: In the current study we present evidence of the cardioprotective effects of CR operating through SIRT1 and PGC-1 α, thereby decreasing oxidative stress, fibrosis and inflammation. Our results suggest that increasing SIRT1 and PGC-1α levels offer new therapeutic approaches for the protection of the diabetic heart.
Subject(s)
Caloric Restriction , Diabetes Mellitus, Type 2/diet therapy , Diabetic Cardiomyopathies/prevention & control , Myocardium/enzymology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Sirtuin 1/metabolism , Angiotensin II , Animals , Cells, Cultured , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/physiopathology , Diabetic Cardiomyopathies/enzymology , Diabetic Cardiomyopathies/etiology , Diabetic Cardiomyopathies/physiopathology , Disease Models, Animal , Fibrosis , Hypertension/chemically induced , Male , Mice, Inbred C57BL , Myocardium/pathology , Obesity/complications , Oxidative Stress , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Rats, Sprague-Dawley , Signal Transduction , Ventricular RemodelingABSTRACT
Unfortunately, after publication of this article [1], it was noticed that Table 1 contained errors introduced during the production process. In the WT + AT column, the FS value is 21 ± 7 and the Body Weight value is 25 ± 2. In the WT + AT + CR column, the FS value is 46 ± 14 and the Body Weight value is 19 ± 1. The original article has been updated to reflect this.
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Pancreatic Neoplasms/drug therapy , Platinum Compounds/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Animals , Carcinoma, Pancreatic Ductal/genetics , Disease Progression , Drug Resistance, Neoplasm , Genomic Instability , Homologous Recombination , Humans , Mice , Mutation , Neoplasm Metastasis , Neoplasm Transplantation , Pancreatic Neoplasms/genetics , Platinum Compounds/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Prognosis , Whole Genome SequencingABSTRACT
Bone marrow interstitial fluid (BMIF) has not been well characterized. BMIF was isolated from 60 patients including plasma cell dyscrasias (PCD, n = 33), other primary hematologic disorders (OHD, n = 15), and patients with secondary or nonhemtologic disorders (NHD, n = 12) and analyzed for an array of chemical constituents. These included total cholesterol, glucose, phosphate, creatinine, urea, total protein, albumin, globulins, total bilirubin, aspartate aminotransferase, lactate dehydrogenase, sodium, osmolarity, free triiodothyronine (free T3), total triiodothyronine (total T3), and free tetraiodothyronine (free T4). Levels of BMIF components were compared between patient groups and to plasma levels. Compared with plasma, total cholesterol, total protein, total bilirubin, sodium, and calculated osmolarity were lower in BMIF in all groups (P < 0.05). Calculated globulins and aspartate aminotransferase were lower in BMIF of PCD patients and patients with NHD. Albumin was lower in BMIF of patients with PCD and patients with OHD. Lastly, free T4 was significantly higher in BMIF of patients with PCD and patients with OHD. Similar results were demonstrated in a separate analysis performed in patients with multiple myeloma. To conclude, the chemical and thyroid hormone composition of BMIF differs significantly from plasma in several key constituents.