Postmortem Study of Organ-Specific Toxicity in Glioblastoma Patients Treated with a Combination of Temozolomide, Irinotecan and Bevacizumab

Purpose Systemic monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as Irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma. Most patients tolerated these regimens well with well-established sides effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ-specific toxicities have never been examined by postmortem studies. Methods Postmortem tissues (from all major organs) were prospectively collected and examined by standard institution autopsy and brain cutting procedures from 76 decedents, including gliomas (N=68, 44/M, and 24/F) and brain metastases (N=8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs and brain samples harvested. Electronic microscopic (EM) study was carried on selected subjects kidney samples per standard EM protocol. Results Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at glioma recurrence. Exposure to IRI significantly increased the frequency of CM (p=0.05). No unexpected adverse events were detected clinically or permenant end-organ damage by postmortem examination among subjects who received TIB compared to subjects who received standard of care (SOC) therapies. Among glioma decedents, the most common causes of death (COD) were tumor progression (63.2%, N=43), followed by aspiration pneumonia (48.5%, N=33). No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. Conclusion IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. There is no permanent organ-specific toxicity among glioma decedents who received prolonged BEV, TMZ or TIB regimen based chemotherapies except expected occasional myelosuppresson. COD are most commonly resulted from glioma tumor progression and aspiration pneumonia.

BECN1 F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner

Autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer-lived Becn1F121A mutant mice. However, both autophagic and lysosomal activity have been described to decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1F121A mice is unknown. Here we demonstrate that old wild type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1F121A mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1F121A mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.

Functional status, mood state, and physical activity among women with post-acute COVID-19 syndrome

Objectives: While organ-specific pathophysiology has been well-described in SARS-CoV-2 infection, less is known about the attendant effects on functional status, mood state and leisure-time physical activity (PA) in post-acute COVID-19 syndrome. Methods: A case-control design was employed to recruit 32 women (n = 17 SARS-CoV-2; n = 15 controls) matched on age (54 +/- 12 years), body mass index (27 +/- 6 kg/m2), smoking status, and history of cardiopulmonary disease. Participants completed a series of assessments including the Modified Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M), Profile of Mood States (POMS), and Godin-Shephard Leisure-Time PA. Results: SARS-CoV-2 participants exhibited poorer functional status (p = 0.008) and reduced leisure-time PA (p = 0.004) compared to controls. Significant between-group differences were also detected for the POMS total mood disturbance with sub-scale analyses revealing elevated tension, confusion, and lower vigor among SARS-CoV-2 participants (all p-values < 0.05). The number of SARS-CoV-2 symptoms (e.g.,loss of taste / smell, muscle aches etc.) were associated (r = 0.620, p = 0.008) with confusion. Conclusion: The sequela of persistent SARS-CoV-2 symptoms elicit clear disturbances in functional status, mood state, and leisure-time PA among women with post-acute COVID-19 syndrome.

The Presence of Non-organ-specific Autoantibodies in Chronic Hepatitis C Treatment-naive Patients

Background: In the patients with hepatitis C virus (HCV) various immune mediated phenomena are described, and non organ specific autoantibodies (NOSAs) in particular are common. The aim of the present study was to investigate the NOSAs prevalence in chronic hepatitis C treatment naive patients. Patients and Methods: Sera of 76 consecutive HCV treatment naive patients were considered to be eligible for this study for evaluation of Antinuclear, antismooth muscle, antimitochondrial, antineutrophil cytoplasmatic and antiliver kidney microsomal antibodies. Criteria of eligibility were serum antiHCV antibody and HCV RNA positivity, chronic inflammation revealed by histological analysis of the liver, genotyping, treatment naive patients, and no have the diagnosis of probable or definite autoimmune hepatitis. Results: Mean chronological age for the 76 patients (44 females and 32 males) was 51.3 years (range: 20 to 67 years). Nineteen patients (25.0%) infected with HCV had detectable levels of NOSAs at before combined antiviral treatment. SMA was present in 16 (21.0%) of 76 patients, ANA in 2 patients (2.6%), and pANCA (perinuclear ANCA) in 1 patients (1.3%). No patient had specimens reactive to AMA, LMK, or cANCA (cytoplasmic ANCA). Conclusions: In this study, we show the NOSAs positivity in chronic hepatitis c treatment naive patients. Assigned to high prevalence of SMA positivity is associated with high METAVIR score, and HCV genotype 1 and 1b, may reflect a release of intracellular antigens at the time of hepatocellular injury triggering immune responses in the form of autoantibody production or a direct infection of immunocytes by the HCV. Keywords: hepatitis C, treatment naive, non organ specific antibodies, chronic liver disease

Xanthomonas campestris pv. musacearum bacterial infection induces organ-specific callose and hydrogen peroxide production in banana

Xanthomonas campestris pv. musacearum (Xcm) bacteria cause banana Xanthomonas wilt (BXW), the most destructive disease of bananas in East and Central Africa. During early stages of infection in susceptible banana cultivars, incomplete systemic movement of Xcm limits bacterial colonization in the upper organs. Mechanistic basis of this delayed movement is unknown. We hypothesized that Xcm infection triggers basal pattern triggered immune (PTI) responses whose spatial and temporal variability along banana’s anatomical structure accounts for initially limiting Xcm in upper organs. Hence, we examined PTI responses such as callose deposition and hydrogen peroxide (H2O2) production in different organs in response to Xcm infection in BXW susceptible Kayinja and Mbwazirume banana cultivars and wild resistant progenitor Musa balbisiana. Xcm-induced callose increased and peaked at 14 days post inoculation (dpi) and 28dpi as assessed by fluorescence microscopy and enzyme-linked immunosorbent assays, respectively. The levels of Xcm-induced H2O2 and callose were highest in the pseudostems and corms, respectively, and were independent of host susceptibility or resistance to BXW. H2O2 production showed a biphasic transient pattern with an initial increase at 1-hour post Xcm-inoculation (hpi), followed by a decline 3-6hpi and then a second increase by 12hpi. Our findings point to organ-specific responses to Xcm infection in bananas. The corm which doubles as a subterranean parenating organ and interface between mother plants and lateral shoots, was the most responsive organ in callose production while the pseudostem was the most responsive organ in H2O2 production, suggesting the significance of these organs in banana response to BXW.

Emerging Insights Into the Role of Epigenetics and Gut Microbiome in the Pathogenesis of Graves’ Ophthalmopathy

Graves’ Ophthalmopathy (GO) is an organ-specific autoimmune disease that is often characterized by infiltration of orbital tissues and is considered as the most common extra-thyroid manifestation of Graves’ disease (GD). Although genetic susceptibility has been found to be critical for the phenotype of GO, the associated risk alleles in a single gene are generally insufficient to cause the disease. Accruing evidence has shown that epigenetic disorders can act as the potentially missing link between genetic risk and clinically significant disease development. Abnormal epigenetic modifications can lead to pro-inflammatory cascades and activation of orbital fibroblasts (OFs) by promoting the various inflammatory response pathways and regulating the diverse signaling molecules that are involved in the fibrogenesis and adipogenesis, thereby leading to the significant expansion of orbital tissues, fibrosis and inflammation infiltration. Additionally, emerging evidence has shown that the gut microbiome can possibly drive the pathogenesis of GO by influencing the secretion of Thyrotropin receptor antibody (TRAb) and T-helper 17 (Th17)/regulatory T cells (Treg) imbalance. This paper describes the latest epigenetic research evidence and progress made in comprehending the mechanisms of GO development, such as DNA methylation, histone modification, non-coding RNAs, and the gut microbiome.

Genetics, Epigenetics, Cellular Immunology, and Gut Microbiota: Emerging Links With Graves’ Disease

Graves’ disease (GD) is a well-known organ-specific autoimmune disease characterized by hyperthyroidism, goiter, and exophthalmos. The incidence of GD is approximately 2.0–3.0% in China and 0.5–2.0% in Western countries. Due to the complex pathogenesis and etiology of GD, current treatment methods have great side effects that seriously endanger human health. Therefore, it is particularly important to understand the pathogenesis of GD. Various studies have shown that genetics, epigenetics, cellular immunology, and gut microbiota are all involved in the development of GD. Genetically, CD25 gene and VDR gene polymorphisms are involved in the development of GD by increasing the ratio of Th17/Treg cells. Epigenetically, miR-23a-3p and lncRNA-MEG3 lead to Th17/Treg imbalance and participate in the progression of GD. Moreover, commensal microbe deletion can disrupt Th17/Treg balance and participate in the occurrence of GD. The imbalance of Th17/Treg cells induced by genetics, epigenetics, and gut microbiota plays a vital role in the pathogenesis of GD. Therefore, this article reviews the role of genetics, epigenetics, cellular immunology, and gut microbiota in the pathogenic mechanism of GD. This may lead to the development of novel therapeutic strategies and providing promising therapeutic targets.

Genome-Wide Prediction, Functional Divergence, and Characterization of Stress-Responsive BZR Transcription Factors in B. napus

BRASSINAZOLE RESISTANT (BZR) are transcriptional factors that bind to the DNA of targeted genes to regulate several plant growth and physiological processes in response to abiotic and biotic stresses. However, information on such genes in Brassica napus is minimal. Furthermore, the new reference Brassica napus genome offers an excellent opportunity to systematically characterize this gene family in B. napus. In our study, 21 BnaBZR genes were distributed across 19 chromosomes of B. napus and clustered into four subgroups based on Arabidopsis thaliana orthologs. Functional divergence analysis among these groups evident the shifting of evolutionary rate after the duplication events. In terms of structural analysis, the BnaBZR genes within each subgroup are highly conserved but are distinctive within groups. Organ-specific expression analyses of BnaBZR genes using RNA-seq data and quantitative real-time polymerase chain reaction (qRT-PCR) revealed complex expression patterns in plant tissues during stress conditions. In which genes belonging to subgroups III and IV were identified to play central roles in plant tolerance to salt, drought, and Sclerotinia sclerotiorum stress. The insights from this study enrich our understanding of the B. napus BZR gene family and lay a foundation for future research in improving rape seed environmental adaptability.