The rationale behind grafting haploidentical hematopoietic stem cells.

The ability to perform hematopoietic cell transplant across major histocompatibility complex barriers can dramatically increase the availability of donors and allow more patients across the world to pursue curative transplant procedures for underlying hematologic disorders. Early attempts at haploidentical transplantation using broadly reactive T-cell depletion approaches were compromised by graft rejection, graft-versus-host disease and prolonged immune deficiency. The evolution of haploidentical transplantation focused on expanding transplanted hematopoietic progenitors as well as using less broadly reactive T-cell depletion. Significant outcome improvements were identified with technology advances allowing selective depletion of donor allospecific T cells, initially ex-vivo with evolution to its current in-vivo approach with the infusion of the highly immunosuppressive chemotherapy agent, cyclophosphamide after transplantation procedure. Current approaches are facile and portable, allowing expansion of allogeneic hematopoietic cell transplantation for patients across the world, including previously underserved populations.

Racial/Ethnic Differences in Self-Reported Upper Limb Limitations among U.S. Older Adults.

BACKGROUND: The development of disability related to activities of daily living (ADL) is of great concern in the aging population, particularly for Hispanic and Non-Hispanic (NH) Black older adults, where disability prevalence is greater compared to NH Whites. ADL-disability is typically measured across many functional tasks without differentiating upper- versus lower-limb limitations, hindering our understanding of disability burden. Despite the importance of the upper limbs for completing ADL and known age-related declines in function, racial/ethnic differences in upper limb function remain largely unknown. METHODS: We identified 4,292 NH White, NH Black, and Mexican American older adults (≥65) from the 2011-2018 waves of the National Health and Nutrition Examination Survey (NHANES). We classified participants as having a limitation based on their ability to complete five upper limb tasks (preparing meals, eating, dressing, reaching overhead, grasping small objects) and compared limitation rates across racial/ethnic groups. RESULTS: Compared to NH Whites, NH Black older adults had significantly greater odds of reporting difficulties preparing meals (OR: 1.36, 95% CI: 1.01, 1.86) and dressing (OR: 1.55, 95% CI: 1.19, 2.02), while Mexican Americans had greater difficulty preparing meals (OR: 1.70, 95% CI: 1.12, 2.58), dressing (OR: 1.63, 95% CI: 1.12, 2.36), and grasping small objects (OR: 1.48, 95% CI: 1.06, 2.07). CONCLUSIONS: Our results demonstrate differences in self-reported upper limb ADL-disability across racial/ethnic groups, particularly for Mexican American older adults. Such findings underscore the need for routine monitoring of upper limb function throughout adulthood to identify limitations and target therapeutic interventions before independence is compromised.

The ectomycorrhizal fungus Paxillus ammoniavirescens influences the effects of salinity on loblolly pine in response to potassium availability.

Salinity is an increasing problem in coastal areas affected by saltwater intrusion, with deleterious effects on tree health and forest growth. Ectomycorrhizal (ECM) fungi may improve the salinity tolerance of host trees, but the impact of external potassium (K+ ) availability on these effects is still unclear. Here, we performed several experiments with the ECM fungus Paxillus ammoniavirescens and loblolly pine (Pinus taeda L.) in axenic and symbiotic conditions at limited or sufficient K+ and increasing sodium (Na+ ) concentrations. Growth rate, biomass, nutrient content, and K+ transporter expression levels were recorded for the fungus, and the colonization rate, root development parameters, biomass, and shoot nutrient accumulation were determined for mycorrhizal and non-mycorrhizal plants. P. ammoniavirescens was tolerant to high salinity, although growth and nutrient concentrations varied with K+ availability and increasing Na+ exposure. While loblolly pine root growth and development decreased with increasing salinity, ECM colonization was unaffected by pine response to salinity. The mycorrhizal influence on loblolly pine salinity response was strongly dependent on external K+ availability. This study reveals that P. ammoniavirescens can reduce Na+ accumulation of salt-exposed loblolly pine, but this effect depends on external K+ availability.

Central Nervous System Antimicrobial Exposure and Proposed Dosing for Anthrax Meningitis.

BACKGROUND: The high mortality of systemic anthrax is likely a consequence of the severe central nervous system (CNS) inflammation that occurs in anthrax meningitis. Effective treatment of such infections requires, at a minimum, adequate cerebrospinal fluid (CSF) antimicrobial concentrations. METHODS: We reviewed English medical literature and regulatory documents to extract information on serum and CSF exposures for antimicrobials with in vitro activity against Bacillus anthracis. Using CSF pharmacokinetic exposures and in vitro B. anthracis susceptibility data, we employed population pharmacokinetic modeling and Monte Carlo simulations to predict whether a specific antimicrobial dosage would likely achieve effective CSF antimicrobial activity in patients with normal to inflamed meninges (i.e., an intact to markedly disrupted blood brain barrier). RESULTS: Probability of microbiologic success at achievable antimicrobial dosages was high (≥95%) for ciprofloxacin, levofloxacin (500 mg q12 h), meropenem, imipenem/cilastatin, penicillin G, ampicillin, ampicillin/sulbactam, doxycycline, and minocycline; acceptable (90-95%) for piperacillin/tazobactam and levofloxacin (750 mg q24 h); and low (<90%) for vancomycin, amikacin, clindamycin, and linezolid. CONCLUSION: Prompt empiric antimicrobial therapy of patients with suspected or confirmed anthrax meningitis may reduce the high morbidity and mortality. Our data support using several ß-lactam-, fluoroquinolone-, and tetracycline-class antimicrobials as first-line and alternative agents for treatment of patients with anthrax meningitis; all should achieve effective microbiologic exposures. Our data also suggest antimicrobials that should not be relied upon to treat suspected or documented anthrax meningitis. Furthermore, the protein synthesis inhibitors clindamycin and linezolid can decrease toxin production and may be useful components of combination therapy.

Modeling wood product carbon flows in southern us pine plantations: implications for carbon storage.

BACKGROUND: Wood products continue to store carbon sequestered in forests after harvest and therefore play an important role in the total carbon storage associated with the forest sector. Trade-offs between carbon sequestration/storage in wood product pools and managed forest systems exist, and in order for forest sector carbon modeling to be meaningful, it must link wood product carbon with the specific forest system from which the products originate and have the ability to incorporate in situ and ex situ carbon synchronously over time. RESULTS: This study uses elements of a life cycle assessment approach, tracing carbon from US southern pine timber harvests to emission, to create a decision support tool that practitioners can use to inform policy design around land- and bioproduct-based mitigation strategies. We estimate that wood products from annual loblolly and shortleaf pine timber harvests across the southern US store 29.7 MtC in the year they enter the market, and 11.4 MtC remain stored after 120 years. We estimate fossil fuel emissions from the procurement, transportation, and manufacturing of these wood products to be 43.3 MtCO2e year-1. We found that composite logs, used to manufacture oriented strand board (OSB), were the most efficient log type for storing carbon, storing around 1.8 times as much carbon as saw logs per tonne of log over 120 years. CONCLUSIONS: Results from our analysis suggest that adjusting rotation length based on individual site productivity, reducing methane emissions from landfills, and extending the storage of carbon in key products, such as corrugated boxes, through longer lifespans, higher recycling rates, and less landfill decomposition could result in significant carbon gains. Our results also highlight the benefits of high site productivity to store more carbon in both in situ and ex situ pools and suggest that shorter rotations could be used to optimize carbon storage on sites when productivity is high.

The Effects of Black Raspberry as a Whole Food-Based Approach on Biomarkers of Oxidative Stress in Buccal Cells and Urine of Smokers.

Cigarette smoke is a rich source of free radicals that can promote oxidative stress and carcinogenesis, including head and neck squamous cell carcinoma (HNSCC) development; importantly, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-iso-prostaglandin F2α (8-isoprostane) are biomarkers of oxidative stress. Several mechanisms, including the antioxidant properties of black raspberry (BRB), account for their chemopreventive effects. In the present clinical trial, we tested the hypothesis that BRB administration reduces biomarkers levels of oxidative stress in buccal cells and urine of smokers. One week after enrolling 21 smokers, baseline buccal cells and urine samples were collected before the administration of BRB lozenges for 8 weeks (5/day, 1 gm BRB/lozenge). Buccal cells and urine samples were collected at the middle and the end of BRB administration. The last samples were collected after the BRB cessation (washout period). We analyzed levels of 8-oxodG and 8-isoprostane (LC/MS-MS), urinary cotinine (ELISA), and creatinine (spectrophotometry). BRB significantly reduced the levels of 8-oxodG by 17.08% (P = 0.00079) in buccal cells and 12.44% (P = 0.034) in urine at the middle of BRB administration as compared with baseline; the corresponding values at the end of BRB administration were 16.46% (P = 0.026) in buccal cells and 25.72% (P = 0.202) in urine. BRB had no significant effect on the levels of urinary 8-isoprostane. BRB's capacity to inhibit 8-oxodG formation of smokers' buccal cells and urine is clearly evident and the reduction in 8-oxodG suggests that antioxidant abilities are central to BRB's HNSCC chemopreventive properties. PREVENTION RELEVANCE: Cigarette smoke contains highly active components namely free radicals that can promote oxidative stress and oral cancer. We found that black raspberry (BRB) inhibited the formation of oxidative stress markers in the oral cavity and urine of smokers suggesting the antioxidant abilities of BRB in preventing oral cancer.

Dietary history of click beetles and wireworms in the genus Limonius (Coleoptera: Elateridae) revealed by molecular gut content analysis.

Wireworms, the larval stage of pest click beetle species (Coleoptera: Elateridae), are pests of many crops in North America including root vegetables and cereals. There is cause for concern amongst growers who are facing pressure from wireworms because there are a decreasing number of effective pesticides that can be used for wireworm management. Most research on pest elaterids has focused on the wireworm stage, which is the damage causing life stage. Recently, the focus in elaterid research has shifted to the adult click beetle stage, including identification of semiochemicals and development of effective traps. However, there is still a lot to be discovered about the basic biology of click beetles, including their feeding ecology. In an effort to understand the feeding ecology of click beetles, we investigated the presence of plant DNA in the digestive tracts of Limonius californicus (Mann.), L. canus (LeConte), and L. infuscatus (Mots.) beetles collected in 3 different locations within central Washington. To examine dietary histories of beetles and wireworms, specimens were collected from natural habitats and high-throughput sequencing of the plant genes trnF and ITS was used to identify their dietary history. Results revealed that click beetles do feed on a large variety of plants, which included a large quantity of brassicaceous plants commonly found in areas surrounding wireworm infested plots. The identification of the dietary history of the click beetles allowed us to infer their landscape-scale movements thus providing a means to better understand their behavior.

An intergenerational service-learning approach to improve hand function in older adults.

Homebound older adults are at greater risk for functional impairments, social isolation, and loss of independence. Adequate hand function is needed to perform many daily activities, yet is understudied, particularly in the homebound population. The purpose of this study was to pilot test an intergenerational program in which pre-health college students were trained to deliver hand exercises to homebound older adults receiving Meals on Wheels (MOW) services. Eight MOW clients (mean age: 80.1 ± 12.9y) and 17 students completed the program. Students visited clients 2×/week for 6 weeks and engaged in hand exercises and meaningful conversations. Measures of hand strength, dexterity, self-reported function, self-efficacy, depression, and social isolation were taken before and after the program. Clients and students also completed a post-program experience survey. Significant improvements in pinch strength were observed, and 75% of clients reported better upper limb mobility after training. Survey feedback was positive with clients saying they enjoyed interacting with college students, while students praised the hands-on nature of the program and engagement with older adults. Results from this pilot study demonstrate an intergenerational approach to deliver hand training is feasible and underscores the value of using such models to increase access to care for homebound older adults.

CDC Guidelines for the Prevention and Treatment of Anthrax, 2023.

This report updates previous CDC guidelines and recommendations on preferred prevention and treatment regimens regarding naturally occurring anthrax. Also provided are a wide range of alternative regimens to first-line antimicrobial drugs for use if patients have contraindications or intolerances or after a wide-area aerosol release of: Bacillus anthracis spores if resources become limited or a multidrug-resistant B. anthracis strain is used (Hendricks KA, Wright ME, Shadomy SV, et al.; Workgroup on Anthrax Clinical Guidelines. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014;20:e130687; Meaney-Delman D, Rasmussen SA, Beigi RH, et al. Prophylaxis and treatment of anthrax in pregnant women. Obstet Gynecol 2013;122:885-900; Bradley JS, Peacock G, Krug SE, et al. Pediatric anthrax clinical management. Pediatrics 2014;133:e1411-36). Specifically, this report updates antimicrobial drug and antitoxin use for both postexposure prophylaxis (PEP) and treatment from these previous guidelines best practices and is based on systematic reviews of the literature regarding 1) in vitro antimicrobial drug activity against B. anthracis; 2) in vivo antimicrobial drug efficacy for PEP and treatment; 3) in vivo and human antitoxin efficacy for PEP, treatment, or both; and 4) human survival after antimicrobial drug PEP and treatment of localized anthrax, systemic anthrax, and anthrax meningitis. Changes from previous CDC guidelines and recommendations include an expanded list of alternative antimicrobial drugs to use when first-line antimicrobial drugs are contraindicated or not tolerated or after a bioterrorism event when first-line antimicrobial drugs are depleted or ineffective against a genetically engineered resistant: B. anthracis strain. In addition, these updated guidelines include new recommendations regarding special considerations for the diagnosis and treatment of anthrax meningitis, including comorbid, social, and clinical predictors of anthrax meningitis. The previously published CDC guidelines and recommendations described potentially beneficial critical care measures and clinical assessment tools and procedures for persons with anthrax, which have not changed and are not addressed in this update. In addition, no changes were made to the Advisory Committee on Immunization Practices recommendations for use of anthrax vaccine (Bower WA, Schiffer J, Atmar RL, et al. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices, 2019. MMWR Recomm Rep 2019;68[No. RR-4]:1-14). The updated guidelines in this report can be used by health care providers to prevent and treat anthrax and guide emergency preparedness officials and planners as they develop and update plans for a wide-area aerosol release of B. anthracis.

Prophylaxis for the Unexpected: An Unusual Case of Herpes B Coverage for an Orangutan Bite in an Emergency Department Patient.

Patients presenting to the emergency department (ED) with an orangutan bite require a series of prophylactic treatments. We present a unique case of an orangutan bite in a 29-year-old male ED patient who was brought by Emergency Medical Services (EMS) for evaluation of an orangutan bite to the right upper extremity with a suspected fourth proximal phalanx fracture. He was referred to hand surgery for a washout and open reduction. Upon discharge, prophylactic medical treatments for unusual pathologies such as herpes B were considered. Appropriate evaluation and treatment of this unique ED condition is necessary to prevent additional patient morbidity.

Use of tamibarotene, a potent and selective RARα agonist, in combination with azacitidine in patients with relapsed and refractory AML with RARA gene overexpression.

Tamibarotene-based therapy is a novel targeted approach for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with retinoic acid receptor alpha (RARA) gene overexpression. Approximately, 50% of higher-risk myelodysplastic syndrome (MDS) patients and approximately 30% of AML patients are positive for RARA overexpression using a blood-based biomarker test that measures RARA expression in peripheral blasts. A phase 2 study investigating the activity of tamibarotene in patients with RARA overexpression was conducted in patients with AML and MDS (NCT02807558). In 28 patients with R/R AML and RARA overexpression treated with tamibarotene in combination with azacitidine, the median overall survival was 5.9 months. In 21 response-evaluable patients, the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 19%, and median time to initial CR/CRi was 1.2 months. The favorable safety profile and preliminary clinical activity support the development of combination therapies with tamibarotene in myeloid malignancies with RARA overexpression.

A case study assessing the impact of mating frequency on the reproductive performance of the Hawaiian bobtail squid Euprymna scolopes.

BACKGROUND: The symbiosis between the Hawaiian bobtail squid Euprymna scolopes and bacterium Vibrio fischeri serves as a model for investigating the molecular mechanisms that promote the initial formation of animal-bacterial symbioses. Research with this system frequently depends on freshly hatched E. scolopes, but the husbandry factors that promote hatchling production in a mariculture facility remain underreported. Here we report on the reproductive performance of E. scolopes in response to decreased mating frequency. RESULTS: One animal cohort was maintained in a mariculture facility for 107 days, with females assigned to either a control group (mating once every 14 days) or an experimental group (mating once every 21 days). No differences between the groups were observed in survival, the number of egg clutches laid, or hatchling counts. Each group featured multiple females that were hyper-reproductive, i.e., they generated more than 8 egg clutches while in captivity. Examination of the distributions for daily hatchling counts of individual egg clutches revealed significant variation in the hatching patterns among clutches that was independent of mating frequency. Finally, an assessment of hatchling production showed that 93.5% of total hatchlings produced by the cohort were derived from egg clutches laid within the first 70 days. CONCLUSIONS: These results suggest a lower mating frequency does not impede hatchling production. Furthermore, the variation in hatchling production among egg clutches provides new insight into the reproductive performance of E. scolopes as a lab animal for microbiology research.

Quantification of the capacity of vibrio fischeri to establish symbiosis with Euprymna scolopes.

Most animals establish long-term symbiotic associations with bacteria that are critical for normal host physiology. The symbiosis that forms between the Hawaiian squid Euprymna scolopes and the bioluminescent bacterium Vibrio fischeri serves as an important model system for investigating the molecular mechanisms that promote animal-bacterial symbioses. E. scolopes hatch from their eggs uncolonized, which has led to the development of squid-colonization assays that are based on introducing culture-grown V. fischeri cells to freshly hatched juvenile squid. Recent studies have revealed that strains often exhibit large differences in how they establish symbiosis. Therefore, we sought to develop a simplified and reproducible protocol that permits researchers to determine appropriate inoculum levels and provides a platform to standardize the assay across different laboratories. In our protocol, we adapt a method commonly used for evaluating the infectivity of pathogens to quantify the symbiotic capacity of V. fischeri strains. The resulting metric, the symbiotic dose-50 (SD50), estimates the inoculum level that is necessary for a specific V. fischeri strain to establish a light-emitting symbiosis. Relative to other protocols, our method requires 2-5-fold fewer animals. Furthermore, the power analysis presented here suggests that the protocol can detect up to a 3-fold change in the SD50 between different strains.

Day 4 collection of granulocyte colony-stimulating factor-mobilized HLA-matched sibling donor peripheral blood allografts demonstrates no long-term increase in chronic graft-versus-host disease or relapse rates.

BACKGROUND AIMS: In a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD). METHODS: This was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT. RESULTS: At 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance. CONCLUSIONS: The authors' preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors.

Peers influence the tobacco and alcohol use of Chinese adolescents.

This two-wave longitudinal study examined peer selection and influence pertaining to tobacco and alcohol use by adolescents and their friends in a sample of 854 Chinese adolescents (384 girls: mean age = 13.33 years). Participants nominated friends and self-reported their tobacco and alcohol use at seventh and again at eighth grade. Longitudinal social network analyses revealed evidence of friend influence but not selection over smoking and drinking. Boys increased their levels of smoking at rates greater than that of girls, but no sex moderation of either selection or influence was found. In interpreting these results, it is important to understand the gender norms for Chinese boys and girls and the cultural context of tobacco and alcohol use.

Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia.

Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multicenter Beat AML cohort. Five hundred thirteen patients were included. Most patients had 1 or 2 ELN risk-defining abnormalities. In patients with ≥2 ELN risk-defining mutations, 44% (n = 132) had mutations spanning multiple ELN risk categories. Compared with ELN 2017 criteria, the updated ELN 2022 guidelines changed the assigned risk group in 15% of patients, including 10%, 26%, and 6% of patients categorized as being at ELN 2017 favorable-, intermediate-, and adverse-risk, respectively. The median overall survival across ELN 2022 favorable-, intermediate-, and adverse-risk groups was not reached, 16.8, and 9.7 months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 guidelines. The updated ELN 2022 guidelines better stratify survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.

Microbial source tracking and land use associations for antibiotic resistance genes in private wells influenced by human and livestock fecal sources.

Antimicrobial resistance is a growing public health problem that requires an integrated approach among human, agricultural, and environmental sectors. However, few studies address all three components simultaneously. We investigated the occurrence of five antibiotic resistance genes (ARGs) and the class 1 integron gene (intI1) in private wells drawing water from a vulnerable aquifer influenced by residential septic systems and land-applied dairy manure. Samples (n = 138) were collected across four seasons from a randomized sample of private wells in Kewaunee County, Wisconsin. Measurements of ARGs and intI1 were related to microbial source tracking (MST) markers specific to human and bovine feces; they were also related to 54 risk factors for contamination representing land use, rainfall, hydrogeology, and well construction. ARGs and intI1 occurred in 5%-40% of samples depending on target. Detection frequencies for ARGs and intI1 were lowest in the absence of human and bovine MST markers (1%-30%), highest when co-occurring with human and bovine markers together (11%-78%), and intermediate when co-occurring with just one type of MST marker (4%-46%). Gene targets were associated with septic system density more often than agricultural land, potentially because of the variable presence of manure on the landscape. Determining ARG prevalence in a rural setting with mixed land use allowed an assessment of the relative contribution of human and bovine fecal sources. Because fecal sources co-occurred with ARGs at similar rates, interventions intended to reduce ARG occurrence may be most effective if both sources are considered.

Targeting RARA overexpression with tamibarotene, a potent and selective RARα agonist, is a novel approach in AML.

A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a phase 2 clinical study in 51 newly diagnosed unfit patients with AML identified as RARA-positive (n = 22) or RARA-negative (n = 29) for RARA mRNA overexpression in peripheral blasts using a blood-based biomarker test. In 18 response-evaluable RARA-positive patients, complete remission (CR)/CR with incomplete hematologic recovery rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response-evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well tolerated. The majority of nonhematologic adverse events were low grade and hematologic adverse events were comparable to single-agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in patients with AML or MDS with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02807558.

Comprehensive molecular characterization of a rare case of Philadelphia chromosome-positive acute myeloid leukemia.

The Philadelphia chromosome (Ph) resulting from the t(9;22) translocation generates the oncogenic BCR::ABL1 fusion protein that is most commonly associated with chronic myeloid leukemia (CML) and Ph-positive (Ph+) acute lymphoblastic leukemia (ALL). There are also rare instances of patients (≤1%) with newly diagnosed acute myeloid leukemia (AML) that harbor this translocation (Paietta et al., Leukemia 12: 1881 [1998]; Keung et al., Leuk Res 28: 579 [2004]; Soupir et al., Am J Clin Pathol 127: 642 [2007]). AML with BCR::ABL has only recently been provisionally classified by the World Health Organization as a diagnostically distinct subtype of AML. Discernment from the extremely close differential diagnosis of myeloid blast crisis CML is challenging, largely relying on medical history rather than clinical characteristics (Arber et al., Blood 127: 2391 [2016]). To gain insight into the genomic features underlying the evolution of AML with BCR::ABL, we identified a patient presenting with a high-risk myelodysplastic syndrome that acquired a BCR::ABL alteration after a peripheral blood stem cell transplant. Serial samples were collected and analyzed using whole-exome sequencing, RNA-seq, and ex vivo functional drug screens. Persistent subclones were identified, both at diagnosis and at relapse, including an SF3B1p.Lys700Glu mutation that later cooccurred with an NRASp.Gly12Cys mutation. Functional ex vivo drug screening performed on primary patient cells suggested that combination therapies of ABL1 with RAS or PI3K pathway inhibitors could have augmented the patient's response throughout the course of disease. Together, our findings argue for the importance of genomic profiling and the potential value of ABL1 inhibitor-inclusive combination treatment strategies in patients with this rare disease.

Postexposure Prophylaxis and Treatment of Bacillus anthracis Infections: A Systematic Review and Meta-analyses of Animal Models, 1947-2019.

BACKGROUND: Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies. METHODS: We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans. RESULTS: We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, ß-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx. CONCLUSIONS: These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.