Disparities in PI3K/mTOR inhibitor use, toxicities, and outcomes among patients with metastatic breast cancer.

PURPOSE: Novel agents such as PI3K and mTOR inhibitors (PI3K/mTORi) have expanded treatment options in metastatic breast cancer (MBC). Nevertheless, mortality rates remain disproportionately high for Black patients and patients with lower socioeconomic status. Furthermore, clinical trials for these novel agents lacked diversity, so their toxicity profile in minority populations is uncertain. METHODS: We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database for patients with HR+, HER2- MBC. Multivariable logistic regression was used to evaluate factors associated with PI3K/mTORi use and toxicity outcomes. RESULTS: A total of 9169 patients with MBC were included in our analysis, of which 1780 (19.4%) received a PI3K/mTORi. We estimated the conditional total effect of insurance through Medicaid, and found lower odds of use of PI3K/mTORi among patients on Medicaid compared to those with commercial insurance (OR 0.73, 95% CI 0.54-0.99, p = 0.049). Odds of PI3K/mTORi use were higher for patients treated at an academic center (OR 1.28, CI 1.06-1.55, p = 0.01). Modeled as a controlled direct effect, Black/African American (Black/AA) race had no impact on odds of PI3K/mTOR use. Black/AA patients had twice the odds of developing hyperglycemia on PI3K/mTORi compared to White patients (OR 2.02, CI 1.24-3.39, p < 0.01). CONCLUSION: This analysis of real-world data suggests that the use of PI3K/mTORi is influenced by socioeconomic factors. We also found racial disparities in toxicity outcomes, with Black/AA patients having twice the risk of hyperglycemia. Our findings call for greater efforts to ensure access to novel treatments and improve their tolerability in diverse populations.

Health Communication in an Era of Disinformation: Perceived Source Credibility Among Transgender and Gender Diverse Individuals.

This study examines perceived source credibility of health information in a moment of TGD health disinformation. Through thematic analysis of in-depth interviews with 30 transgender and gender diverse (TGD) individuals, findings suggest health information is marred by anti-TGD legislation, a sociopolitical force that bleeds into health information spaces. Disinformation and TGD health communication are intertwined in complex ways, whereby disinformation can undermine trust in healthcare institutions, lead to harmful behaviors, and contribute to the spread of diseases. Health communication practitioners need to center the safety and humanity of TGD people, addressing TGD health disinformation.

Social determinants of health and CDK4/6 inhibitor use and outcomes among patients with metastatic breast cancer.

BACKGROUND: Survival outcomes in metastatic breast cancer (MBC) have improved due to novel agents such as CDK4/6 inhibitors (CDK4/6i). Nevertheless, Black patients and patients with lower socioeconomic status (SES) continue to bear a disproportionate mortality burden. METHODS: We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database (FHD). A dataset was constructed to include Black/African-American (Black/AA) and White patients with hormone receptor (HR)-positive, HER2-negative MBC. Outcomes included CDK4/6i use (overall and first-line), and rates of leukopenia, dose reduction, and time on treatment for first-line CDK4/6i. Multivariable logistic regression was used to evaluate factors associated with use and outcomes. RESULTS: A total of 6802 patients with MBC were included, of which 5187 (76.3%) received CDK4/6i. Of those, 3186 (61.4%) received CDK4/6i first-line. Overall, 86.7% of patients were categorized as White and 13.3% as Black/AA; 22.4% were > 75 years old; 12.6% were treated at an academic site; 3.3% had Medicaid insurance. In addition to advanced age and poorer performance status, lower use of CDK4/6i was associated with Black/AA vs White race (72.9% vs 76.8%; OR 0.83, 95% CI 0.70-0.99, p = 0.04) and Medicaid vs commercial insurance (69.6% vs 77.4%; OR: 0.68, 95% CI 0.49-0.95, p = 0.02). Odds of CDK4/6i use were twofold higher for patients treated at an academic center (p < 0.001). Rates of CDK4/6i-induced leukopenia and dose reductions did not differ significantly by race, insurance type, or treatment site. Time on CDK4/6i was significantly lower among Medicaid patients (395 days) than patients with commercial insurance (558 days) or Medicare (643 days) (p = 0.03). CONCLUSION: This analysis of real-world data suggests that Black race and lower SES are associated with decreased CDK4/6i use. However, among patients treated with CDK4/6i, subsequent toxicity outcomes are similar. Efforts to ensure access to these life-prolonging medications are warranted.

Coupling-Condensation Strategy for the Convergent Synthesis of an Imidazole-Fused 2-Aminoquinoline NLRP3 Agonist.

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.

Serum Sickness like Reaction Postequine Rabies Immunoglobulins.

A 30-year-old, previously healthy adult male received equine rabies immunoglobulins (Ig) (ERIG) along with anti-rabies vaccinations as per protocol for postexposure prophylaxis after an unprovoked rabid dog bite of grade three wound over the shin of the left lower limb. On the 8th day, he developed urticarial rashes beginning from the site of the wound, which gradually became a widespread maculopapular rash. Development of the rash was followed by low-grade fever, nonspecific arthralgias and soreness in the throat. A diagnosis of serum sickness-like illness was made based on history, temporal correlation of administration of ERIG and development of symptoms. He responded well to antihistaminic and a short course of injectable steroids. The purpose of this article is to increase awareness regarding the clinical presentation and management of this rare yet potentially curable adverse event if identified timely.

Persistent opioid use in patients with multiple myeloma post-ASCT.

PURPOSE: Bone pain is a common presenting symptom of multiple myeloma (MM) and is frequently treated with opioids in addition to myeloma directed therapy. With improved response and survival with modern myeloma therapy, it is important to re-examine the role of opioids in managing symptomatic myeloma. PATIENTS AND METHODS: We performed a retrospective analysis of patients with myeloma at Rutgers Cancer Institute of New Jersey (RCINJ) who received an ASCT between January 1, 2012, and December 30, 2017, and who had subsequent follow-up (a total of 138 patients). We sought information specifically from the visits after induction therapy but prior to ASCT, at 100 days and 1-year post-ASCT follow-up visits. We compared opioid users and non-users in relation to treatment response, co-morbid conditions, and symptoms. We also examined amounts, duration, and odds of continued opioid use. RESULTS: At the time of the first analysis (before transplant), 34.8% of patients were using opioids and opioid use was more frequent in younger patients and, as expected, in patients with bone lesions. At 1 year, 31.9% of patients were still using opioids and continued opioid use was not correlated with disease response. Of the patients using opioids at the time of transplant, 58% either maintained their opioid dose or increased it at 1-year post-transplant. CONCLUSIONS: This retrospective analysis shows that despite a small decrease in opioid use over time, opioid use remains frequent in MM patients and is correlated with younger age and bone involvement but not with response to therapy. Over half the patients using opioids at the time of transplant continued or increased opioid use over the following year. With increasing survival in myeloma patients, further attention is required to distinguish cancer pain from chronic pain in cancer patients.

Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy.

AIMS: Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. METHODS: Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK-based predictions with observed PK profiles. RESULTS: Predicted exposure (AUC0-6h ) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0-6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. CONCLUSION: A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure-response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.

The Hindi Version of International Consensus Criteria: A Cross-cultural Adaptation and Validation Study for Myalgic Encephalomyelitis in Post-COVID Patients.

CONTEXT: Fatigue is the most prominent feature of long COVID. With the increasing burden of long COVID cases post-acute phase of illness after recurrent waves of the pandemic, understanding its pathophysiology is of paramount importance. Such fatigue and post-viral illness could be associated with features of neuroimmune exhaustion and thus be a part of a larger syndrome such as myalgic encephalomyelitis (ME). Identifying the proportion of patients having ME from those experiencing fatigue would bring us one step closer to understanding the pathophysiology. International consensus criteria (ICC) originally published in English (ICC-E) is a valid and reliable tool for identifying cases of ME. However, a validated Hindi version of ICC-E is not available. : To develop and validate an equivalent version of ICC-E in the native Hindi language (ICC-H) to suit Indian patients and health care workers even at peripheries and to make conducting large scales surveys more feasible. SUBJECTS AND METHODS: Once permission from the ethics board was granted, guidelines given by MAPI Research Trust were followed and ICC-H was developed from ICC-E, in the following steps: (a) translation to Hindi, (b) back translation, (c) comparison between the translated and back-translated version performed by experts, and (d) pre-pilot test in the intended population. The ICC-H was applied to 53 bilingual individuals knowing both Hindi and English. STATISTICAL ANALYSIS USED: The distribution of Hindi and English questionnaires was analyzed using the Chi-square test and Spearman's correlation coefficient was used for correlation between answers of each question. RESULTS: The score of individual items and its global score was highly correlated with each other (p<0.001). The scores of individual components and global scores of ICC-H at baseline and original ICC-E after 4 weeks did not differ significantly. CONCLUSION: This study shows that the ICC-H is a valid and reliable instrument for the assessment of ME. ICC-H can be used for Hindi speaking population for identifying cases of ME. Key Messages There is a significant overlap in symptoms of long COVID and ME, with fatigue being a major component in both. Understanding the prevalence of ME in the post-acute phase of COVID illness can bring us a step closer to understanding its pathophysiology. In a multilingual country like ours, regionally translated criteria are a must for conducting large-scale surveys.

SARS-CoV-2 nosocomial infection: Real-world results of environmental surface testing from a large tertiary cancer center.

BACKGROUND: Despite consensus guidelines, concern about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has dissuaded patients with cancer from seeking medical care. Studies have shown that contaminated surfaces may contain viable virus for up to 72 hours in laboratory settings. The purpose of this study was to investigate contamination of SARS-CoV-2 on commonly used environmental surfaces in a tertiary cancer care center. METHODS: This study evaluated the incidence of SARS-CoV-2 viral RNA in high-touch outpatient and inpatient cancer center spaces. Surfaces were tested over a 2-week period after patient or staff exposure but before scheduled disinfection services according to the World Health Organization protocols for coronavirus disease 2019 (COVID-19) surface sampling. Samples were analyzed via reverse transcriptase-polymerase chain reaction for the presence of SARS-CoV-2 RNA. RESULTS: Two hundred four environmental samples were obtained from inpatient and outpatient oncology clinics and infusion suites, and they were categorized as 1) public areas, 2) staff areas, or 3) medical equipment. One hundred thirty surfaces from 2 outpatient hematology and oncology clinics and 36 surfaces from an inpatient leukemia/lymphoma/chimeric antigen receptor T-cell unit were examined, and all 166 samples were negative for SARS-CoV-2. One of 38 samples (2.6%) from COVID-19+ inpatient units was positive. Altogether, the positive test rate for SARS-CoV-2 RNA across all surfaces was 0.5% (1 of 204). CONCLUSIONS: This prospective, systematic quality assurance investigation of real-world environmental surfaces, performed in inpatient and outpatient hematology/oncology units, revealed overall negligible detection of SARS-CoV-2 RNA when strict mitigation strategies against COVID-19 transmission were instituted. LAY SUMMARY: The potential risks of nosocomial infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have deterred patients with cancer from seeking timely care despite consensus guidelines. This study has found negligible rates of environmental contamination with SARS-CoV-2 across a multitude of commonly used surfaces in outpatient and inpatient hematology/oncology settings with adherence to strict infection control protocols.

Formulation effects on paclitaxel transfer and uptake in the human placenta.

Diagnosis and treatment of breast cancer in pregnancy can result in morbidity and mortality for the mother and fetus. Many new paclitaxel nanoformulations commercially available worldwide for breast cancer treatment are being adopted due to favorable dosing regimens and side effect profiles, but their transplacental transport and resultant fetal exposure remain unknown. Here, we examine three formulations: Taxol (paclitaxel dissolved in Kolliphor EL and ethanol); Abraxane (albumin nanoparticle); and Genexol-PM (polymeric micelle). In the ex vivo dually perfused human placental cotyledon, placental accumulation of Genexol-PM is higher than Taxol, and both nanoformulations have lower maternal concentrations of paclitaxel over time. In vitro studies of these formulations and fluorescent nanoparticle analogs demonstrate that Genexol-PM allows paclitaxel to overcome P-glycoprotein efflux, but Abraxane behaves as a free drug formulation. We anticipate that these findings will impact future development of rational and safe treatment strategies for pregnancy-associated breast cancer and other diseases.

hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of hsa-mir183, the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication.

A high-content cytokine screen identifies myostatin propeptide as a positive regulator of primitive chronic myeloid leukemia cells.

Aberrantly expressed cytokines in the bone marrow (BM) niche are increasingly recognized as critical mediators of survival and expansion of leukemic stem cells. To identify regulators of primitive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34+ CD38low chronic phase CML cells. Out of the 313 unique human cytokines evaluated, 11 were found to expand cell numbers ≥2-fold in a 7-day culture. Focusing on novel positive regulators of primitive CML cells, the myostatin antagonist myostatin propeptide gave the largest increase in cell expansion and was chosen for further studies. Herein, we demonstrate that myostatin propeptide expands primitive CML and normal BM cells, as shown by increased colony-forming capacity. For primary CML samples, retention of CD34-expression was also seen after culture. Furthermore, we show expression of MSTN by CML mesenchymal stromal cells, and that myostatin propeptide has a direct and instant effect on CML cells, independent of myostatin, by demonstrating binding of myostatin propeptide to the cell surface and increased phosphorylation of STAT5 and SMAD2/3. In summary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells.

Lymphoma Occurring During Pregnancy: Current Diagnostic and Therapeutic Approaches.

PURPOSE OF REVIEW: Pregnancy-associated lymphoma (PAL) is an uncommon entity that lacks detailed prospective data. It poses significant management challenges that incorporate maternal and fetal risks associated with treatment or delayed intervention. Herein, we review the current literature for the diagnosis, management, and supportive care strategies for PAL. RECENT FINDINGS: Establishment of a multidisciplinary team, including hematology-oncology, maternal-fetal medicine, and neonatology, is critical in the management of PAL. For staging, ultrasound and MRI are preferred modalities with use of computerized tomography in select situations. Data for the safety and effectiveness of therapy for PAL is largely based on retrospective studies. The timing of lymphoma-directed antenatal systemic therapy depends on the trimester, gestational age, lymphoma subtype and aggressiveness, and patient wishes. Therapy in the first trimester is usually not advocated, while treatment in the second and third trimesters appears to result in similar outcomes for PAL compared with non-pregnant patients with lymphoma. An overarching goal in most PAL cases should be to plan for delivery at term (i.e., gestational age > 37 weeks). For supportive care, most antiemetics, including agents such as neurokinin-1 receptor antagonists, have been used safely during pregnancy. For prevention or treatment of infections, particular antibiotics (i.e., macrolides, cephalosporins, penicillins, metronidazole), antivirals (i.e., acyclovir, valacyclovir, famciclovir), and antifungals (amphotericin B) have demonstrated safety and with use of growth factors reserved for treatment of neutropenia (vs. primary prophylaxis). Therapy for PAL should be individualized with goals of care that balance maternal and fetal well-being, which should include a multidisciplinary care team and overall intent for term delivery in most cases.

Hydrogen Sulfide Capture: From Absorption in Polar Liquids to Oxide, Zeolite, and Metal-Organic Framework Adsorbents and Membranes.

Hydrogen sulfide removal is a long-standing economic and environmental challenge faced by the oil and gas industries. H2S separation processes using reactive and non-reactive absorption and adsorption, membranes, and cryogenic distillation are reviewed. A detailed discussion is presented on new developments in adsorbents, such as ionic liquids, metal oxides, metals, metal-organic frameworks, zeolites, carbon-based materials, and composite materials; and membrane technologies for H2S removal. This Review attempts to exhaustively compile the existing literature on sour gas sweetening and to identify promising areas for future developments in the field.

Autophagy in Dendritic Cells and B Cells Is Critical for the Inflammatory State of TLR7-Mediated Autoimmunity.

Individuals suffering from autoimmune disorders possess a hyperactive cellular phenotype where tolerance to self-antigens is lost. Autophagy has been implicated in both the induction and prevention of autoimmunity, and modulators of this cellular recycling process hold high potential for the treatment of autoimmune diseases. In this study, we determine the effects of a loss of autophagy in dendritic cells (DCs), as well as both B cells and DCs, in a TLR7-mediated model of autoimmunity, similar to systemic lupus erythematosus, where both cell types are critical for disease. Although a loss of DC autophagy slowed disease, the combined loss of autophagy in both cell types resulted in a lethal sepsis-like environment, which included tissue inflammation and hyperproduction of inflammasome-associated cytokines. Ablation of B cell signaling reversed this phenotype, indicating that activation of these cells is an essential step in disease induction. Thus, autophagy plays a dichotomous role in this model of disease.

Combined Medical and Surgical Management of Hepatic Mucormycosis in an Adult with Acute Myeloid Leukemia: Case Report and Review of the Literature.

Hepatic mucormycosis is a disease caused by a ubiquitous fungus which is especially important in patients with hematologic malignancies. We present a case of an adult patient with acute myeloid leukemia who developed the infection after undergoing chemotherapy. His successful management was an integrated approach of a minimally invasive surgical resection with anti-fungal therapy. We describe the management of this patient and a review of the literature.

CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells.

The regulation of hematopoietic stem cell (HSC) survival and self-renewal within the bone marrow (BM) niche is not well understood. We therefore investigated global transcriptomic profiling of normal human HSC/hematopoietic progenitor cells [HPCs], revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, and CXCL13) were upregulated in human quiescent CD34(+)Hoescht(-)Pyronin Y(-) and primitive CD34(+)38(-), as compared with proliferating CD34(+)Hoechst(+)Pyronin Y(+) and CD34(+)38(+) stem/progenitor cells. This suggested that chemokines might play an important role in the homeostasis of HSCs. In human CD34(+) hematopoietic cells, knockdown of CXCL4 or pharmacologic inhibition of the chemokine receptor CXCR2, significantly decreased cell viability and colony forming cell (CFC) potential. Studies on Cxcr2(-/-) mice demonstrated enhanced BM and spleen cellularity, with significantly increased numbers of HSCs, hematopoietic progenitor cell-1 (HPC-1), HPC-2, and Lin(-)Sca-1(+)c-Kit(+) subpopulations. Cxcr2(-/-) stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. Parallel studies on Cxcl4 demonstrated reduced numbers of CFC in primary and secondary assays following knockdown in murine c-Kit(+) cells, and Cxcl4(-/-) mice showed a decrease in HSC and reduced self-renewal capacity after secondary transplantation. These data demonstrate that the CXCR2 network and CXCL4 play a role in the maintenance of normal HSC/HPC cell fates, including survival and self-renewal.

Understanding the Reactive Adsorption of H2 S and CO2 in Sodium-Exchanged Zeolites.

Purifying sour natural gas streams containing hydrogen sulfide and carbon dioxide has been a long-standing environmental and economic challenge. In the presence of cation-exchanged zeolites, these two acid gases can react to form carbonyl sulfide and water (H2 S+CO2 ⇌H2 O+COS), but this reaction is rarely accounted for. In this work, we carry out reactive first-principles Monte Carlo (RxFPMC) simulations for mixtures of H2 S and CO2 in all-silica and Na-exchanged forms of zeolite beta to understand the governing principles driving the enhanced conversion. The RxFPMC simulations show that the presence of Na+ cations can change the equilibrium constant by several orders of magnitude compared to the gas phase or in all-silica beta. The shift in the reaction equilibrium is caused by very strong interactions of H2 O with Na+ that reduce the reaction enthalpy by about 20 kJ mol-1 . The simulations also demonstrate that the siting of Al atoms in the framework plays an important role. The RxFPMC method presented here is applicable to any chemical conversion in any confined environment, where strong interactions of guest molecules with the host framework and high activation energies limit the use of other computational approaches to study reaction equilibria.

Echocardiography allows for analysis of pulmonary arterial flow in mice with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a structural birth defect associated with pulmonary hypoplasia and pulmonary arterial hypertension (PAH). We hypothesize that echocardiography provides a method to assess real-time right ventricle (RV) function, remodeling, and pulmonary artery (PA) flow. MATERIALS AND METHODS: Slit3 wild-type (WT) (n = 6) and knockout (KO) (n = 5) mice were analyzed at 2-3 months of age. Mice were anesthetized using isoflurane. Echocardiography was performed to analyze left and right ventricular wall thickness, internal diameter (ID), and function. Color Doppler was used to analyze flow in the PA and across the tricuspid valve. RESULTS: There was significant RV dilation in the KO mice versus WT, with an average RVID of 1.99 mm versus 1.26 mm, respectively (P = 0.007). Flow in the PA of KO mice was altered compared to WT, with elevated PA velocity time indices, 30.68 mm versus 22.13 mm (P = 0.012), elevated PA peak velocities, 952.61 mm/s versus 628.73 mm/s (P = 0.003), and decreased pulmonary acceleration times, 8.94 ms versus 16.18 ms (P = 0.002), respectively. Pulmonary vascular resistance, calculated by measuring tricuspid regurgitation peak velocity and right ventricular outflow tract velocity time index, was increased in KO versus WT mice, 17.61 mm2/s versus 8.91 mm2/s (P = 0.003), respectively. CONCLUSIONS: Slit3 KO mice with CDH show evidence of PAH and resultant RV dilation. Using direct cardiac puncture, elevated RV systolic pressures have been demonstrated in KO mice as evidence of PAH. Echocardiography allows direct analysis of the PA and real-time RV function without sacrifice of the mouse. This mode of evaluation allows longitudinal study in mice with PAH and CDH.

Preservation of Quiescent Chronic Myelogenous Leukemia Stem Cells by the Bone Marrow Microenvironment.

The majority of leukemia patients achieving remission ultimately relapse. Persistence of leukemia stem cells (LSC) capable of regenerating leukemia is a major cause of relapse. There is a pressing need to better understand mechanisms of LSC regulation and their resistance to therapy in order to improve outcomes for leukemia. Chronic myelogenous leukemia (CML) is a lethal myeloproliferative disorder that that is caused by hematopoietic stem cell (HSC) transformation by the BCR-ABL tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKI) has revolutionized CML treatment, but fails to eliminate LSC responsible for propagating and regenerating leukemia. Therefore, patients require continued treatment to prevent relapse. Leukemic and normal stem cells share properties of quiescence and self-renewal, that are supported by bone marrow niches. Persistence of LSC after TKI treatment is related to tyrosine kinase independent mechanisms which include intrinsic properties of LSCs determined by epigenetic alterations, altered transcriptional regulatory networks or mitochondrial/metabolic changes. In addition to cell intrinsic changes, signals from the bone marrow microenvironment (BMM) play a critical role in protecting LSC from TKI treatment. Each type of alteration may offer potential points of intervention for therapeutic targeting of LSC.