Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In ...phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo–expanded autologous central memory–enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 106 in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8+ TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval CI: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4+ and CD8+ TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4+/CD8+ TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749.
•TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT.•Addition of a CD28 costimulatory domain to the CAR, plus changes to T-cell product manufacturing, resulted in improved T-cell expansion.
Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas’ disease and African sleeping sickness, respectively. Both parasites rely on essential cysteine proteases for survival: ...cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against a panel of human cysteine and serine proteases to determine selectivity, and a cocrystal was obtained of our most potent analogue bound to cruzain.
Abstract Introduction To our knowledge, successful breastfeeding in the population with single ventricle congenital heart disease has not been reported in the literature, particularly during the ...interstage period. Method A retrospective case study including inpatient nutrition and a complete history of daily logs with the home surveillance monitoring program was performed. Results Successful full breastfeeding (exceeding prescribed weight growth goals) after Stage I surgery was achieved during the interstage period. The infant was discharged at 3.41 kg, not consistently breastfeeding, and progressed to 7.05 kg at 5 months of age, fully breastfeeding. Conclusion Supporting breastfeeding for infants who have undergone repairs for single ventricle anatomy can be challenging but can be accomplished. It requires a concerted team effort, clear communication, and collaboration among caregivers, the mother, and her supporters.
This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or ...relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1-14 along with 375 mg/m(2) of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. ...Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug–target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52), possess desirable attributes for further studying the effect of in vivo LDH inhibition.
Assessing the linkage between breeding and non-breeding areas has important implications for understanding the fundamental biology of and conserving animal species. This is a challenging task for ...marine species, and in sea turtles a combination of stable isotope analysis (SIA) and satellite telemetry has been increasingly used. The Northwest Atlantic (NWA) loggerhead (
Caretta caretta
) Regional Management Unit, one of the largest sea turtle populations in the world, provides an excellent opportunity to investigate key biological patterns as well as methodological aspects related to the use of stable isotopes to infer spatial distribution of turtles in foraging areas. We provide the first comprehensive assessment of the annual distribution of NWA adult female loggerheads among foraging areas and investigate the efficacy of various analytical approaches as well as the effect of sample size in these types of studies. A total of 5168 individual females were sampled from seven Management Units (MUs) between 2013-2018. We provide the first estimate of the proportion of females originating from each MU that uses each foraging area and show how this proportion varies over time. We also estimate the relative importance (in terms of number of turtles) of each foraging area to the overall loggerhead breeding aggregation nesting in Florida and in the NWA for each year of the study. The foraging area used by reproductively active females differs considerably across MUs. One of these, the Subtropical NWA, is by far the most important foraging area in terms of both number of individuals and genetic diversity, and therefore this region may be considered as a conservation priority. Through simulations, we show that limited sizes of sample groups (unknowns; training; priors) may result in false geographic differentiation and consequently mislead interpretations. We provide thresholds and methodological recommendations for future studies. This study establishes a fundamental baseline for monitoring the annual contribution of foraging area to a terrestrial-based breeding aggregation of a marine animal in a cost-effective way. This type of monitoring allows for early detection of changes in foraging distributions—a possible effect of climate change on marine ecosystems or of area-specific anthropogenic threats.
The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with ...sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo.
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•Specific LDH inhibition in vivo reduces growth rate of glycolytic tumors•Depth and duration of tumor LDH inhibition can be monitored in real time by HP-MRSI•LDH inhibition in vivo redirects pyruvate to support oxidative phosphorylation•Inhibiting mitochondrial complex 1 and LDH enhances durability of anti-tumor response
Oshima et al. use hyperpolarized magnetic resonance spectroscopy to dynamically monitor tumor glycolysis and oxidative phosphorylation. LDH inhibition slows tumor growth but rapidly redirects pyruvate to support mitochondrial metabolism. Inhibiting both mitochondrial complex 1 and LDH suppresses metabolic plasticity of glycolytic tumors in vivo, significantly prolonging tumor growth inhibition.
Artemisinins, endoperoxide-containing molecules, best known as antimalarials, have potent antineoplastic activity. The established antimalarial, artesunate (AS), and the novel artemisinin-derived ...trioxane diphenylphosphate dimer 838 (ART-838) inhibited growth of all 23 tested acute leukemia cell lines, reduced cell proliferation and clonogenicity, induced apoptosis, and increased intracellular levels of reactive oxygen species (ROS). ART-838 was 88-fold more potent that AS in vitro, inhibiting all leukemia cell lines at submicromolar concentrations. Both ART-838 and AS cooperated with several established antileukemic drugs and newer kinase inhibitors to inhibit leukemia cell growth. ART-838 had a longer plasma half-life than AS in immunodeficient NOD-SCID-IL2Rgnull (NSG) mice, remaining at effective antileukemic concentrations for >8h. Intermittent cycles of ART-838 inhibited growth of acute leukemia xenografts and primagrafts in NSG mice, at higher potency than AS. Based on these preclinical data, we propose that AS, with its established low toxicity and low cost, and ART-838, with its higher potency and longer persistence in vivo, should be further developed toward integration into antileukemic regimens.
Objectives
The purpose of this qualitative descriptive research study was to understand the current state, perceived content, and experiential needs of pediatric nurses preparing for global health ...(GH) fieldwork experience. This study aimed to inform stakeholders about the standard and unique preparation needs of pediatric GH nurses.
Study Design and Methods
One group and five individual interviews were held with nurses from a large pediatric quaternary care facility in the Northeast United States. Data from the interviews were transcribed verbatim, eliminating personal data. Only deidentified transcripts were used for data analysis. Members of the study team used content analysis to systematically code and analyze the data.
Results
Qualitative content analysis revealed five categories: (1) identifying clear objectives, (2) understanding the practice environment, (3) self‐assessment of clinical skills, cultural competencies, and adaptability, (4) safety and logistics planning, and (5) psychological self‐care and reentry anticipatory guidance.
Conclusions
Findings can provide a basis for program planning to prepare pediatric nurses for GH fieldwork. Program planning must account for the unique features of the site and situation. Organizational and personal preparation can influence the perceived success of the GH experience.
Angiotensin-converting enzyme inhibitor therapy is often initiated in pediatric patients who have had cardiac surgery. Acute kidney injury can occur in patients secondary to angiotensin-converting ...enzyme inhibitor initiation. Risk factors for acute kidney injury after angiotensin-converting enzyme inhibitor initiation have yet to be defined in postoperative pediatric cardiac patients.
To identify the frequency of acute kidney injury in patients receiving angiotensin-converting enzyme inhibitor therapy in postoperative pediatric cardiac surgical patients and to identify risk factors for acute kidney injury in this patient population.
None.
The pharmacy and surgery databases were used to identify all patients <18 yrs of age who received angiotensin-converting enzyme inhibitor therapy after cardiac surgery at our institution from January 2006 to December 2007. Patients who did not have a baseline serum creatinine and at least one serum creatinine obtained after angiotensin-converting enzyme inhibitor initiation were excluded. Data collection included demographic information and cardiac pathophysiology/surgery, diuretic and/or nephrotoxic medication use, and angiotensin-converting enzyme inhibitor characteristics and initiation date. Baseline, daily, and maximum serum creatinine values were collected. Acute kidney injury was defined as the maximum change in pediatric-modified RIFLE (Risk, Injury, Failure, Loss, End-stage) acute kidney injury criteria within 48 hrs of initiation or increase in dose of angiotensin-converting enzyme inhibitor. Descriptive statistics were used to characterize the patient population, and a multivariate logistic regression model was developed to identify independent predictors of angiotensin-converting enzyme inhibitor-associated acute kidney injury. The study included 415 patient admissions (386 patients), 57% (n = 239) being male and infants (31 days to 2 yrs) being the most common age group. A functional single ventricle was present in 46% of the patients. Enalapril was initiated in 60% (n = 250) and captopril in 40% (n = 165) of patient admissions. Acute kidney injury occurred in 21% (n = 88) of patients initiated on an angiotensin-converting enzyme inhibitor (pediatric-modified RIFLE categories: R = 15%, I = 3%, F = 4%). Logistic regression identified cyanosis, coadministration of furosemide, and baseline estimated creatinine clearance as independent risk factors for any degree of angiotensin-converting enzyme inhibitor-associated acute kidney injury (p < .05). The hospital lengths of stay of patients with angiotensin-converting enzyme inhibitor-associated acute kidney injury (median 12 days, range 4-298 days) were greater compared to those of patients without angiotensin-converting enzyme inhibitor-associated acute kidney injury (median 10 days, range 3-199 days, p < .05).
Initiation of angiotensin-converting enzyme inhibitor after cardiac surgery in pediatric patients may result in acute kidney injury. The presence of cyanosis and coadministration of furosemide are independent risk factors for acute kidney injury in patients receiving angiotensin-converting enzyme inhibitor.
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