Cutaneous mastocytosis (CM) is a rare condition in young dogs characterized by multicentric cutaneous proliferation of neoplastic mast cells. Clinical data from 8 dogs that met inclusion criteria ...(age of onset less than 1.5 years, greater than 3 lesions) were obtained via a standardized survey. Biopsy samples were classified by the Kiupel/Patnaik grading systems and analyzed for c-KIT mutations. The median age of onset was 6 months (range: 2–17 months). Dogs had 5 to more than 50 lesions characterized as nodules, plaques, and papules. Seven dogs were pruritic. Clinical staging in 2 dogs did not reveal visceral involvement. No dogs had systemic illnesses at diagnosis. Histologically, CM was similar to cutaneous mast cell tumor (cMCT). Two dogs had neoplasms classified as high-grade/grade II while 6 dogs had low-grade/grade II neoplasms. No dogs had mutations in c-KIT exons 8 and 11. Treatment included antihistamines (8/8), corticosteroids (7/8), lokivetmab (3/8), and toceranib (1/8). Six dogs were alive with lesions at the end of the study with a median follow-up time of 898 days, while 2 dogs were euthanized. In dogs with high-grade/grade II neoplasms, one continued to develop lesions at 1922 days post-diagnosis, while the other dog was euthanized at 56 days post-diagnosis. One dog was euthanized 621 days post-diagnosis due to rupture of a neoplasm. CM occurs in young dogs and is histologically indistinguishable from cMCT. Current histologic grading systems did not apply uniformly to the dogs of the study and further studies are needed.
Abstract
The transcription factor BHLHE40 is an emerging regulator of the immune system. Recent studies suggest that BHLHE40 regulates type 2 immunity, but this has not been demonstrated in vivo. We ...found that BHLHE40 is required in T cells for a protective TH2 cell response in mice infected with the helminth Heligmosomoides polygyrus bakeri. H. polygyrus elicited changes in gene and cytokine expression by lamina propria CD4+ T cells, many of which were BHLHE40 dependent, including production of the common β (CSF2RB) chain family cytokines GM-CSF and IL-5. In contrast to deficiency in GM-CSF or IL-5 alone, loss of both GM-CSF and IL-5 signaling impaired protection against H. polygyrus. Overall, we show that BHLHE40 regulates the TH2 cell transcriptional program during helminth infection to support normal expression of Csf2, Il5, and other genes required for protection and reveal unexpected redundancy of common β chain–dependent cytokines previously thought to possess substantially divergent functions.
ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase ...inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis.
A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis.
We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors.
We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.
Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca2+ pump ATP2A2. Defective intracellular calcium signaling in ...the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine.
In this study of subjects who had no adenomas or cancers on baseline screening colonoscopy, advanced adenomas were detected in only 1.3% of those who returned for rescreening after 5 years. These ...findings support a rescreening interval of 5 years or longer for patients at average risk who have normal findings on colonoscopy.
In this study of subjects who had no adenomas or cancers on baseline screening colonoscopy, advanced adenomas were detected in only 1.3% of those who returned for rescreening after 5 years.
Colonoscopy has gained widespread acceptance and even some preference as the primary screening method for the detection of colorectal cancer and precancerous polyps.
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There is concern about whether adequate resources exist to satisfy the demand for colonoscopy,
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and some data suggest that colonoscopy may be performed too frequently and for inappropriate indications.
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Determination of the appropriate frequency of rescreening for persons with normal findings on initial screening colonoscopy could have a substantial effect on the cost of colonoscopy and the capacity to provide it.
Guidelines for colorectal cancer screening from the U.S. Multisociety Task Force on Colorectal . . .
Septic shock may be associated with myocardial damage; however, the prognostic value of cardiac enzymes in cancer patients with septic shock is unknown. In this study, we evaluated the prognostic ...significance of cardiac enzymes in combination with established prognostic factors in predicting the 7-day mortality rate of patients with septic shock, and we constructed a new scoring system, Septic Oncologic Patients in Emergency Department (SOPED), which includes cardiac enzymes, to predict 7-day mortality rates.
We performed a retrospective cohort study of 375 adult cancer patients with septic shock who visited the emergency department of a comprehensive cancer center between 01/01/2004 and 12/31/2013. The 7-day and 28-day mortality rates were 19.7% and 37.6%, respectively. The creatine kinase myocardial band fraction and troponin-I were significantly higher in patients who died in ≤7 days and ≤28 days than in those who did not. In Cox regression models, troponin-I >0.05 ng/mL plus Predisposition, Infection, Response, and Organ Failure (PIRO2011) or Mortality in Emergency Department Sepsis (MEDS) score was a significant predictor of survival for ≤7 days. With our new SOPED scoring system, the receiver operating characteristic area under the curve was 0.836, higher than those for PIRO2011 and MEDS.
Troponin-I >0.05 ng/mL was an important predictor of short-term mortality (≤7 days). The SOPED scoring system, which incorporated troponin-I, was more prognostically accurate than were other scores for 7-day mortality. Large multicenter studies are needed to verify our results and prospectively validate the prognostic performance of the SOPED score.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the ...inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts.
Methods
We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided.
Results
A novel risk locus in the USP7 gene (rs74010351, odds ratio OR = 1.44, 95% confidence interval CI = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias.
Conclusions
These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).
Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to ...examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1).
Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018.
With a median follow-up period of 6.4 years (range, 0.3-17.9 years), the 10-year overall survival (OS) was 54.7% (SE = 2.9), which is significantly higher than the 27.6% (SE = 2.9) observed in the historical cohort from 1985 to 2000. There was no significant impact of sex, age, white blood cell count, central nervous system disease status, T-cell maturity, or BM disease burden at EOI on OS. Postinduction complete remission (CR) was achieved in 93% of patients with 10-year OS of 59.6% (SE = 3.1%) and disease-free survival (DFS) of 56.3% (SE = 3.1%). Among the patients who achieved CR, 72% underwent HSCT and their 10-year DFS (with a 190-day landmark) was significantly better than nontransplanted patients (63.8% SE = 3.6
45.5% SE = 7.1;
= .005), with OS of 66.2% (SE = 3.6) versus 50.8% (SE = 6.8);
= .10, respectively.
Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.
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