Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies.

Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19 and CD123 hematological cancers.

Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches.

Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow elimination of CAR-T cells.

Clinical and Laboratory Profile of Persons Living with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome and Histoplasmosis from a Colombian Hospital.

Histoplasmosis is common among persons living with human immunodeficiency virus/acquired immune deficiency syndrome (PLWHA) in Latin America, but its diagnosis is difficult and often nonspecific. We conducted prospective screening for histoplasmosis among PLWHA with signs or symptoms suggesting progressive disseminated histoplasmosis (PDH) and hospitalized in Hospital La María in Medellín, Colombia. The study's aim was to obtain a clinical and laboratory profile of PLWHA with PDH.

Notes from the Field: Probable Mucormycosis Among Adult Solid Organ Transplant Recipients at an Acute Care Hospital - Pennsylvania, 2014-2015.

On September 17, 2015, the Pennsylvania Department of Health (PADOH) notified CDC of a cluster of three potentially health care-associated mucormycete infections that occurred among solid organ transplant recipients during a 12-month period at hospital A. On September 18, hospital B reported that it had identified an additional transplant recipient with mucormycosis. Hospitals A and B are part of the same health care system and are connected by a pedestrian bridge.

Agreement of Direct Antifungal Susceptibility Testing from Positive Blood Culture Bottles with the Conventional Method for Candida Species.

Early availability of antifungal susceptibilities can ensure timely institution of targeted therapy in candidemia, which can improve patient outcomes. This study prospectively determines the agreement between the results of direct testing of antifungal susceptibilities from blood culture bottles by disk diffusion and Etest and the results of standardized susceptibility testing methods; direct testing would allow susceptibility results to be available 1 to 2 days earlier. A total of 104 blood cultures with different Candida species (28% C.

Evaluation of the Specificity of Two Enzyme Immunoassays for Coccidioidomycosis by Using Sera from a Region of Endemicity and a Region of Nonendemicity.

Coccidioidomycosis (CM), a serious life-threatening fungal infection endemic to arid regions of the western United States and Mexico, can be challenging to diagnose in a timely manner. Commercially developed enzyme immunoassays (EIAs) (from Meridian Biosciences and Immuno-Mycologics [IMMY]) have provided faster, simpler means for serodiagnosis; however, independent evaluations have questioned EIA specificity, particularly IgM-positive/IgG-negative results. This study was conducted to evaluate EIA specificity among persons residing in Puerto Rico (n = 534), where CM is not endemic (who were not likely to have been exposed to Coccidioides spp.

Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET).

Transplant recipients are at a high risk for developing invasive fungal infections. The agents of phaeohyphomycosis are environmental molds found worldwide, and they cause a broad spectrum of disease including skin and subcutaneous lesions, pneumonia, central nervous system disease, fungemia, and disseminated disease. Using data from the Transplant Associated Infection Surveillance Network (TRANSNET), we evaluated patients with proven and probable phaeohyphomycosis.

Notes from the field: Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement--Connecticut, 2014.

In October 2014, a hospital in Connecticut notified CDC and the Connecticut Department of Public Health of a fatal case of gastrointestinal mucormycosis in a preterm infant. The infant, born at 29 weeks' gestation and weighing 1,400 grams (about 3 pounds), had developed signs and symptoms initially consistent with necrotizing enterocolitis approximately 1 week after birth. Exploratory laparotomy revealed complete ischemia of the gastrointestinal tract from the esophagus to the rectum; a portion of necrotic cecum was sent for microscopic examination.

Utility of real-time PCR for detection of Exserohilum rostratum in body and tissue fluids during the multistate outbreak of fungal meningitis and other infections.

Exserohilum rostratum was the major cause of the multistate outbreak of fungal meningitis linked to contaminated injections of methylprednisolone acetate produced by the New England Compounding Center. Previously, we developed a fungal DNA extraction procedure and broad-range and E. rostratum-specific PCR assays and confirmed the presence of fungal DNA in 28% of the case patients.

Valley fever: finding new places for an old disease: Coccidioides immitis found in Washington State soil associated with recent human infection.

We used real-time polymerase chain reaction and culture to demonstrate persistent colonization of soils by Coccidioides immitis, an agent of valley fever, in Washington State linked to recent human infections and located outside the endemic range. Whole-genome sequencing confirmed genetic identity between isolates from soil and one of the case-patients.

Validation of an enzyme-linked immunosorbent assay that detects Histoplasma capsulatum antigenuria in Colombian patients with AIDS for diagnosis and follow-up during therapy.

We validated an antigen capture enzyme-linked immunosorbent assay (ELISA) in Colombian persons with AIDS and proven histoplasmosis and evaluated the correlation between antigenuria and clinical improvement during follow-up. The sensitivity of the Histoplasma capsulatum ELISA was 86%, and the overall specificity was 94%. The antigen test successfully monitored the response to therapy.

Whole-genome analysis of Exserohilum rostratum from an outbreak of fungal meningitis and other infections.

Exserohilum rostratum was the cause of most cases of fungal meningitis and other infections associated with the injection of contaminated methylprednisolone acetate produced by the New England Compounding Center (NECC). Until this outbreak, very few human cases of Exserohilum infection had been reported, and very little was known about this dematiaceous fungus, which usually infects plants. Here, we report using whole-genome sequencing (WGS) for the detection of single nucleotide polymorphisms (SNPs) and phylogenetic analysis to investigate the molecular origin of the outbreak using 22 isolates of E.

Real-time PCR assays for genotyping of Cryptococcus gattii in North America.

Background: Cryptococcus gattii has been the cause of an ongoing outbreak starting in 1999 on Vancouver Island, British Columbia and spreading to mainland Canada and the US Pacific Northwest. In the course of the outbreak, C. gattii has been identified outside of its previously documented climate, habitat, and host disease.

Coccidioides immitis identified in soil outside of its known range - Washington, 2013.

Coccidioidomycosis ("valley fever") is caused by inhaling spores of the soil-dwelling fungi Coccidioides immitis or Coccidioides posadasii. Most infections are subclinical. When clinical manifestations do occur (typically 1-4 weeks after exposure), they are similar to those associated with influenza or community-acquired pneumonia.

Utility of (1-3)-β-D-glucan testing for diagnostics and monitoring response to treatment during the multistate outbreak of fungal meningitis and other infections.

Background:  The 2012 outbreak of fungal meningitis associated with contaminated methylprednisolone produced by a compounding pharmacy has resulted in >750 infections. An important question facing patients and clinicians is the duration of antifungal therapy. We evaluated (1-3)-β-d-glucan (BDG) as a marker for monitoring response to treatment.

Clinical findings for fungal infections caused by methylprednisolone injections.

Background: Since September 18, 2012, public health officials have been investigating a large outbreak of fungal meningitis and other infections in patients who received epidural, paraspinal, or joint injections with contaminated lots of methylprednisolone acetate. Little is known about infections caused by Exserohilum rostratum, the predominant outbreak-associated pathogen. We describe the early clinical course of outbreak-associated infections.

Filamentous Basidiomycetes in the Clinical Laboratory.

Filamentous basidiomycetes are difficult to identify in the clinical laboratory, mostly due to lack of sporulation, and their role as agents of fungal infection can be difficult to assess. More cases of infection with these agents are being reported as more laboratories gain proficiency with the recognition of their subtle morphologic features and the use of DNA-based methods for identification. Most infections occur in the respiratory tract and sinuses, although brain infection has been reported.

Species identification of invasive yeasts including Candida in Pakistan: limitations of phenotypic methods.

Objective: To compare phenotypic and genotypic methods of yeast identification.

Methods: The in-vitro cross-sectional study was conducted from January 2006 to May 2009. Invasive yeasts isolated at the clinical microbiology laboratory at the Aga Khan University (AKU), Karachi, Pakistan, were identified.

Exserohilum infections associated with contaminated steroid injections: a clinicopathologic review of 40 cases.

September 2012 marked the beginning of the largest reported outbreak of infections associated with epidural and intra-articular injections. Contamination of methylprednisolone acetate with the black mold, Exserohilum rostratum, was the primary cause of the outbreak, with >13,000 persons exposed to the potentially contaminated drug, 741 confirmed drug-related infections, and 55 deaths. Fatal meningitis and localized epidural, paraspinal, and peripheral joint infections occurred.

Preliminary laboratory report of fungal infections associated with contaminated methylprednisolone injections.

In September 2012, the Centers for Disease Control and Prevention (CDC) initiated an outbreak investigation of fungal infections linked to injection of contaminated methylprednisolone acetate (MPA). Between 2 October 2012 and 14 February 2013, the CDC laboratory received 799 fungal isolates or human specimens, including cerebrospinal fluid (CSF), synovial fluid, and abscess tissue, from 469 case patients in 19 states. A novel broad-range PCR assay and DNA sequencing were used to evaluate these specimens.

PRP8 intein in cryptic species of Histoplasma capsulatum: evolution and phylogeny.

The PRP8 intein is the most widespread intein among the Kingdom Fungi. This genetic element occurs within the prp8 gene, and is transcribed and translated simultaneously with the gene. After translation, the intein excises itself from the Prp8 protein by an autocatalytic splicing reaction, subsequently joining the N and C terminals of the host protein, which retains its functional conformation.

Trichosporon asahii among intensive care unit patients at a medical center in Jamaica.

We investigated an increase in Trichosporon asahii isolates among inpatients. We identified 63 cases; 4 involved disseminated disease. Trichosporon species was recovered from equipment cleaning rooms, washbasins, and fomites, which suggests transmission through washbasins.

Detection of fungal DNA in human body fluids and tissues during a multistate outbreak of fungal meningitis and other infections.

Exserohilum rostratum was the major cause of an outbreak of fungal infections linked to injections of contaminated methylprednisolone acetate. Because almost 14,000 persons were exposed to product that was possibly contaminated with multiple fungal pathogens, there was unprecedented need for a rapid throughput diagnostic test that could detect both E. rostratum and other unusual agents of fungal infection.