Bacillus Cereus Catheter Related Bloodstream Infection in a Patient with Acute Lymphoblastic Leukemia

Bacillus cereus infection is rarely associated with actual infection and for this reason single positive blood culture is usually regarded as contamination . However it may cause a number of infections, such catheter-related bloodstream infections. Significant catheter-related bloodstream infections (CRBSI) caused by Bacillus spp. are mainly due to B. cereus and have been predominantly reported in immunocompromised hosts. Catheter removal is generally advised for management of infection. In this report, catheter-related bacteremia caused by B. cereus in a patient with acute lymphoblast c leukemia (ALL) in Istanbul Medical Faculty was presented

Cockayne syndrome group B protein has novel strand annealing and exchange activities

Cockayne syndrome (CS) is a rare inherited human genetic disorder characterized by UV sensitivity, severe neurological abnormalities and prageroid symptoms. The CS complementation group B (CSB) protein is involved in UV-induced transcription coupled repair (TCR), base excision repair and general transcription. CSB also has a DNA-dependent ATPase activity that may play a role in remodeling chromatin in vivo. This study reports the novel finding that CSB catalyzes the annealing of complementary single-stranded DNA (ssDNA) molecules with high efficiency, and has strand exchange activity. The rate of CSB-catalyzed annealing of complementary ssDNA is 25-fold faster than the rate of spontaneous ssDNA annealing under identical in vitro conditions and the reaction occurs with a high specificity in the presence of excess non-homologous ssDNA. The specificity and intrinsic nature of the reaction is also confirmed by the observation that it is stimulated by dephosphorylation of CSB, which occurs after UV-induced DNA damage, and is inhibited in the presence of ATPγS. Potential roles of CSB in cooperation with strand annealing and exchange activities for TCR and homologous recombination are discussed

Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates

The Cockayne syndrome B (CSB) protein—defective in a majority of patients suffering from the rare autosomal disorder CS—is a member of the SWI2/SNF2 family with roles in DNA repair and transcription. We demonstrate herein that purified recombinant CSB and the major human apurinic/apyrimidinic (AP) endonuclease, APE1, physically and functionally interact. CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP–DNA substrates, with the latter being more pronounced (up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein, as no CSB-dependent stimulation was observed with Escherichia coli endonuclease IV or an N-terminal truncated APE1 fragment. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity. Moreover, human fibroblasts defective in CSB were found to be hypersensitive to both methyl methanesulfonate (MMS) and 5-hydroxymethyl-2′-deoxyuridine, agents that introduce base excision repair (BER) DNA substrates/intermediates

Evidence for B cell exhaustion in chronic graft-versus-host disease

Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). A number of studies support a role for B cells in the pathogenesis of cGvHD. In this study, we report the presence of an expanded population of CD19+CD21− B cells with features of exhaustion in the peripheral blood of patients with cGvHD. CD21− B cells were significantly increased in patients with active cGvHD compared to patients without cGvHD and healthy controls (median 12.2 versus 2.12 versus 3%, respectively; p < 0.01). Compared with naïve (CD27−CD21+) and classical memory (CD27+CD21+) B cells, CD19+CD21− B cells in cGvHD were CD10 negative, CD27 negative and CD20hi, and exhibited features of exhaustion, including increased expression of multiple inhibitory receptors such as FCRL4, CD22, CD85J, and altered expression of chemokine and adhesion molecules such as CD11c, CXCR3, CCR7, and CD62L. Moreover, CD21− B cells in cGvHD patients were functionally exhausted and displayed poor proliferative response and calcium mobilization in response to B-cell receptor triggering and CD40 ligation. Finally, the frequencies of circulating CD21− B cells correlated with cGvHD severity in patients after HSCT. Our study further characterizes B cells in chronic cGVHD and supports the use of CD21−CD27−CD10− B cell frequencies as a biomarker of disease severity

Asymptomatic giant coronary aneurysm in an adolescent with Behcet's syndrome

<p>Abstract</p> <p>Objective</p> <p>Behcet's is an idiopathic multi-organ syndrome, which may have onset during childhood. Vascular involvement is uncommon, with rarely reported coronary aneurysm formation. We present a case report of a teenager girl who developed recalcitrant life-threatening Behcet's vasculitis, involving both small and large venous and arterial systems including a giant coronary aneurysm.</p> <p>Case report</p> <p>De-identified data were collected retrospectively in case report format. Although our sixteen year old female with Behcet's vasculitis had resolution of many arterial aneurysms, she had persistent venous thrombosis of large vessels, as well as persistent, giant arterial aneurysms requiring intra-arterial coiling of a lumbar artery and coronary bypass grafting despite intensive immunosuppression including glucocorticoids, cyclophosphamide, infliximab, methotrexate, azathioprine and intravenous immunoglobulin.</p> <p>Conclusions</p> <p>Vascular manifestations may be seen in Behcet's syndrome, including asymptomatic coronary aneurysm, which may be refractory to immunosuppression and ultimately require surgical intervention. Increased awareness is essential for prompt diagnosis and management.</p

Federal Institutions and Strategic Policy Responses to COVID-19 Pandemic

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData Availability Statement: The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author.This essay examines the policy response of the federal and regional governments in federations to the COVID-19 crisis. We theorize that the COVID-19 policy response in federations is an outcome of strategic interaction among the federal and regional incumbents in the shadow of their varying accountability for health and the repercussions from the disruptive consequences of public health measures. Using the data from the COVID-19 Public Health Protective Policy Index Project, we study how the variables suggested by our theory correlate with the overall stringency of public health measures in federations as well as the contribution of the federal government to the making of these policies. Our results suggest that the public health measures taken in federations are at least as stringent as those in non-federations, and there is a cluster of federations on which a bulk of crisis policy making is carried by subnational governments. We find that the contribution of the federal government is, on average, higher in parliamentary systems; it appears to decline with the proximity of the next election in presidential republics, and to increase with the fragmentation of the legislative party system in parliamentary systems. Our analysis also suggests that when the federal government carries a significant share of responsibility for healthcare provision, it also tends to play a higher role in taking non-medical steps in response to the pandemic

A Phase I Study of Milademetan (DS3032B) in Combination With Low Dose Cytarabine With or Without Venetoclax in Acute Myeloid Leukemia: Clinical Safety, Efficacy, and Correlative Analysis

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response

A Phase I Study of Milademetan (DS3032b) in Combination With Low Dose Cytarabine With or Without Venetoclax in Acute Myeloid Leukemia: Clinical Safety, Efficacy, and Correlative Analysis

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response