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Extended-spectrum β-lactamases (ESBLs)-producing E. coli have been proposed as an indicator bacterium for antimicrobial resistance (AMR) surveillance within a OneHealth framework. However, it is important to understand the effects and potential biases ESBL-selection has on E. coli populations. Utilising whole genome sequencing, this study compared 80 ESBL-selected E. coli isolates with 201 non-selected isolates from Australian wastewater. The findings revealed significant variations between these cohorts in genetic diversity, AMR profiles, and carriage of virulence-associated genes (VAGs), plasmids, and the transmissible Locus of Stress Tolerance (tLST), a genomic island that imparts resistance to extreme heat and chlorination. The study highlights the predominance of certain sequence types (STs), particularly ST131 (75 % clade A), in ESBL-selected isolates (40 % vs 2 %) and overall the ESBL-selected isolates were largely multidrug-resistant (MDR), predominantly carrying genes for resistance to aminoglycosides, extended-spectrum β-lactams, fluoroquinolone, macrolides, sulphonamides/trimethoprim, and tetracyclines. The ESBLs identified were almost exclusively bla CTX-M genes, most commonly bla CTX-M-15  > bla CTX-M-27  > bla CTX-M-14 . These were predominately carried on IncF plasmids or chromosomally (always ISEcp1 associated), in equal numbers. In contrast, 80 % of non-selected isolates carried no acquired ARGs, and none carried bla CTX-M genes. In both cohorts, extraintestinal pathogenic E. coli (ExPEC) was the dominate pathotype (35 % total) with few (4 % total) intestinal pathogenic E. coli pathotypes identified (aEPEC > ETEC > EAEC). Nevertheless, some clinically important genes were only identified in the non-selected group, namely tigecycline-resistance gene tet(X4) and AmpC ESBL bla CMY-2 . Additionally, the presence of tLST, associated with higher metal resistance gene carriage (Ag, As, Cu, Hg, Ni), in a substantial portion of non-selected isolates (20 % vs 0 %), underscores environmental pressures shaping bacterial populations in wastewater ecosystems. These insights are important for developing comprehensive, less biased genomic surveillance strategies to understand and manage public health threats posed by pathogenic E. coli and AMR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Antimicrobial resistance (AMR) is a major public health concern, and environmental bacteria have been recognized as important reservoirs of antimicrobial resistance genes (ARGs). Citrobacter, a common environmental bacterium and opportunistic pathogen in humans and other animals, has been largely understudied in terms of its diversity and AMR potential. Whole-genome (short-read) sequencing on a total of 77 Citrobacter isolates obtained from Australian silver gull (Chroicocephalus novaehollandiae) (n = 17) and influent wastewater samples (n = 60) was performed, revealing a diverse Citrobacter population, with seven different species and 33 sequence types, 17 of which were novel. From silver gull using non-selective media we isolated a broader range of species with little to no mobilised ARG carriage. Wastewater isolates (selected using Carbapenem- Resistant Enterobacterales (CRE) selective media) carried a heavy burden of ARGs (up to 21 ARGs, conferring resistance to nine classes of antibiotics), with several novel multidrug-resistant (MDR) lineages identified, including C. braakii ST1110, which carried ARGs conferring resistance to eight to nine classes of antibiotics, and C. freundii ST1105, which carried two carbapenemase genes, bla IMP-4 in class 1 integron structure, and bla KPC-2 . Additionally, we identified an MDR C. portucalensis isolate carrying bla NDM-1 , bla SHV-12 , and mcr-9. We identified IncC, IncM2, and IncP6 plasmids as the likely vectors for many of the critically important mobilised ARGs. Phylogenetic analyses were performed to assess any epidemiological linkages between isolation sources, demonstrating low relatedness across sources beyond the ST level. However, these analyses did reveal some closer relationships between strains from disparate wastewater sources despite their collection some 13,000 km apart. These findings support the need for future surveillance of Citrobacter populations in wastewater and wildlife populations to monitor for potential opportunistic human pathogens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

There are limited data on clinical outcomes in patients re-admitted with decompensated heart failure (HF) with concomitant liver cirrhosis. We conducted a cross sectional analysis of the Nationwide Readmissions Database (NRD) years 2010 thru 2012. An Index admission was defined as a hospitalization for decompensated heart failure among persons aged ≥ 18 years with an alive discharge status. The main outcome was 30 - day all-cause rehospitalization. Survey logistic regression provided the unadjusted and adjusted odds of 30 - day rehospitalization among persons with and without cirrhosis, accounting for age, gender, kidney dysfunction and other comorbidities. There were 2,147,363 heart failure (HF) hospitalizations among which 26,156 (1.2%) had comorbid cirrhosis. Patients with cirrhosis were more likely to have a diagnosis of acute kidney injury (AKI) during their index hospitalization (18.4% vs 15.2%). There were 469,111 (21.9%) patients with readmission within 30 - days. The adjusted odds of a 30 - day readmission was significantly higher among patients with cirrhosis compared to without after adjusting for comorbid conditions (adjusted Odds Ratio [aOR], 1.3; 95% Confidence Interval [CI}: 1.2 to 1.4). The relative risk of 30 - day readmission among those with cirrhosis but without renal disease (aOR, 1.3; 95% CI: 1.3 to 1.3) was lower than those with both cirrhosis and renal disease (aOR, 1.8; 95% CI: 1.6 to 2.0) when compared to persons without either comorbidities. Risk of 30 - day rehospitalization was significantly higher among patients with heart failure and underlying cirrhosis. Concurrent renal dysfunction among patients with cirrhosis hospitalized for decompensated HF was associated with a greater odds of rehospitalization., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Genomic chimerism represents co-existing cells with different genotypes and has diagnostic significance in transplant engraftment monitoring, residual cancer detection, and other contexts. We previously described an approach to chimerism detection by interrogating variably present or absent genomic loci using single-molecule molecular inversion probes (smMIPs) and next-generation sequencing, which provided ultrasensitive limits of detection (<1 in 10,000 cells) but was not reliably quantitative. Herein, smMIP testing was modified to accurately quantitate chimeric cells by incorporating copy number neutral control loci for data normalization and computationally modeling cell mixtures from individual-specific genotypes. Data demonstrate precision and accuracy over three orders of magnitude (0.01% to 50% chimerism). Seventy hematopoietic stem cell transplant specimens from single (n = 42) or double (n = 28) donors were evaluated, benchmarking smMIP against conventional variable number tandem repeat (VNTR) analysis and an unrelated, ultrasensitive polymorphism-specific quantitative PCR (PS-qPCR) assay. Quantitative concordance of all three assays was high (P < 0.0005, Pearson correlation coefficient), although smMIP correlated better with VNTR testing than PS-qPCR. smMIP and PS-qPCR collectively identified low-level chimerism in all specimens testing negative by VNTR (n = 41 and n = 45 of 48 specimens, respectively). This work demonstrates the feasibility of smMIP-based chimerism testing for quantitative and ultrasensitive measurement of genomic chimerism at practical levels approaching one in one million cells, and cross-validates the approach., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Development of neural interface and brain-machine interface (BMI) systems enables the treatment of neurological disorders including cognitive, sensory, and motor dysfunctions. While neural interfaces have steadily decreased in form factor, recent developments target pervasive implantables. Along with advances in electrodes, neural recording, and neurostimulation circuits, integration of disease biomarkers and machine learning algorithms enables real-time and on-site processing of neural activity with no need for power-demanding telemetry. This recent trend on combining artificial intelligence and machine learning with modern neural interfaces will lead to a new generation of low-power, smart, and miniaturized therapeutic devices for a wide range of neurological and psychiatric disorders. This paper reviews the recent development of the 'on-chip' machine learning and neuromorphic architectures, which is one of the key puzzles in devising next-generation clinically viable neural interface systems., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Coronavirus disease-19 (COVID-19) infection is associated with an uncontrolled systemic inflammatory response. Statins, given their anti-inflammatory properties, may reduce the associated morbidity and mortality. This study aimed to determine the association between statin use prior to hospitalization and in-hospital mortality in COVID-19 patients., Methods: In this retrospective study, clinical data were collected from the electronic medical records of patients admitted to the hospital with confirmed COVID-19 infection from March 1, 2020 to April 24, 2020. A multivariate regression analysis was performed to study the association of pre-admission statin use with in-hospital mortality., Results: Of 255 patients, 116 (45.5%) patients were on statins prior to admission and 139 (54.5%) were not. The statin group had a higher proportion of end stage renal disease (ESRD) (13.8% vs. 2.9%, p = 0.001), diabetes mellitus (63.8% vs. 35.2%, p<0.001), hypertension (87.9% vs. 61.1%, p < 0.001) and coronary artery disease (CAD) (33.6% vs. 5%, p < 0.001). On multivariate analysis, we found a statistically significant decrease in the odds of in-hospital mortality in patients on statins before admission (OR 0.14, 95% CI 0.03- 0.61, p = 0.008). In the subgroup analysis, statins were associated with a decrease in mortality in those with CAD (OR 0.02, 95% CI 0.0003-0.92 p = 0.045) and those without CAD (OR 0.05, 95% CI 0.005-0.43, p = 0.007)., Conclusions: Our study suggests that statins are associated with reduced in-hospital mortality among patients with COVID-19, regardless of CAD status. More comprehensive epidemiological and molecular studies are needed to establish the role of statins in COVID-19., Competing Interests: Declaration of Competing Interest No conflict of interest for any of the authors., (Copyright © 2021. Published by Elsevier Inc.)

Patients with acute myeloid leukemia (AML) who achieve morphologic remission in the bone marrow after initial treatment often continue to harbor residual leukemic cells that can give rise to disease relapse. Achievement of a deeper remission has been associated with a reduced risk of relapse and improved event-free and overall survival in several studies. However, standardization of diagnostic techniques, sample acquisition and test timing are needed before minimal, also known as measurable, residual disease (MRD) quantification can be used to guide treatment decision making. Furthermore, clinical trial evidence that preemptive intervention at MRD level can alter the natural history of AML is required. Herein, we outline the current landscape of MRD assessment in AML, summarize the available evidence and challenges, and highlight the potential for MRD status to serve as a surrogate endpoint for hard clinical outcomes and as an approvable endpoint in clinical trials for regulatory purposes., Competing Interests: Declaration of Competing Interest A.M.Z. received research funding (institutional) from Celgene, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Trovagene, Takeda, Ionis, and Epizyme. A.M.Z received travel support for meetings from Pfizer, Novartis, and Trovagene. None of these relationships were related to the development of this manuscript. The other authors have no relevant conflicts of interest to declare., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: As health-care institutions mobilize resources to address the coronavirus disease 2019 (COVID-19) pandemic, palliative care may potentially be underutilized. It is important to assess the use of palliative care in response to the COVID-19 pandemic., Methods: This is a retrospective single-center study of patients with COVID-19 diagnosed via reverse transcriptase-polymerase chain reaction assay admitted between March 1, 2020, and April 24, 2020. An analysis of the utilization of palliative care in accordance with patient comorbidities and other characteristics was performed while considering clinical outcomes. Chi-square test was used to determine associations between categorical variables while t-tests were used to compare continuous variables., Results: The overall mortality rate was 21.5% (n = 52), and in 48% (n = 25) of these patients, palliative care was not involved. Fifty-nine percent (n = 24) of those who had palliative consults eventually elected for comfort measures and transitioned to hospice care. Among those classified as having severe COVID-19, only 40% (n = 31) had palliative care involvement. Of these patients with severe COVID-19, 68% (n = 52) died. Patients who got palliative care consults were of older age, had higher rates of intubation, a need for vasopressors, and were dead., Conclusion: There was a low utilization rate of palliative care in patients with COVID-19. Conscious utilization of palliative care is needed at the time of COVID-19., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Chronic myeloid leukemia (CML) is the model cancer, demonstrating the clinical benefits of targeted therapy and the power of molecular diagnostics and monitoring. In CML, the BCR-ABL1 fusion gene and its companion messenger RNA offers a unique target differentiating cancer from the normal cell, affording the potential for very sensitive and specific assays. Because CML is such an ideal model, new methods are arising that should make testing in CML faster, more reliable, and reach a greater sensitivity. New ultrasensitive sequencing approaches, coupled with single-cell genomic approaches, further the study of measurable residual disease, clonal heterogeneity, and promise to make clinical trials more innovative and informative. These methods should be able to be transferred to other hematological and solid malignancies., (© 2019 by The American Society of Hematology.)

Malaria is prevalent in tropical and subtropical regions of the globe. With over 200 million cases reported annually, particularly in sub-Saharan Africa, it is an unnecessary burden to already overworked and ailing healthcare structures. Traditional medicine (TM) remains vibrant in most of these regions wherein plants often serve as the first line of defense against malaria. Given this fact as well as the successes elsewhere of therapies such as Artemisia annua emanating from evidence-based TM, interest in plants as a source of new antimalarial drugs has been rejuvenated. The bulbous plant family Amaryllidaceae is recognized for its structurally-diverse alkaloid constituents which exhibit interesting biological properties. This review focuses on the in vitro activities demonstrated by its crinane alkaloids against various strains of the malaria-causing parasite Plasmodium falciparum. The survey embraces the twelve genera of the Amaryllidaceae whose nineteen representative species have been examined for antiplasmodial crinane alkaloid principles. A total of seventy-two compounds were screened against nine strains of P. falciparum, with the α-crinanes reflecting better overall activities than their corresponding β-crinane subgroup congeners. In terms of potency, an ED 50 of 0.14 μg/mL (for augustine in the D-6 strain) and IC 50 of 0.35 μg/mL (for haemanthidine in the K1 strain) were the lowest activity indices observed. Structure-activity relationship studies afforded useful insight on the antiplasmodial pharmacophore and the features supporting its efficacy. Overall, crinane alkaloids have provided a useful platform for the study of antiplasmodial effects, not only in terms of potency but also in terms of structural diversity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The birth, growth, proliferation and death of cells involve a rigorous and continuous process in place to ensure the survival of living organisms. The cell cycle prevails at the core of this process to facilitate the division of a parent cell as well as the duplication of its genetic matter. Although checkpoints exist to steer the course of a cell from one phase to the other, malfunctions at any point of the four active phases of the cell cycle can have detrimental effects. Cancer is thought to be a consequence of such a malfunction in the cell cycle which endows a cell with enhanced replicative potential, immunity to anti-growth signals and the ability to evade apoptosis. This characteristic has been exploited in cancer chemotherapy since a significant number of anticancer drugs manifest their action via cell cycle modulatory effects. The plant family Amaryllidaceae is distinguished for its alkaloid principles which exhibit potent (at the sub-nanomolar level in some cases) and cell line specific antiproliferative activities, with apoptosis induction a key feature of these properties. As a consequence there has been sustained interest in these chemical entities as a source of new anticancer drugs. This has been matched by the large body of work that has emerged over the past two decades addressing their cytotoxic potential, establishing a structure-activity relationship basis as well as probing their mode of action. This review focuses on studies which highlight how Amaryllidaceae alkaloids modulate the cell cycle of cancer cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials., Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18-50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5 × 10 10 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 10 8 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 μg) or low-dose (50 μg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703., Findings: Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys., Interpretation: The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629)., Funding: Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests.

The implementation of cytogenetic and molecular techniques into standard clinical practice has improved our ability to more accurately diagnose and monitor CML. Routine peripheral blood BCR-ABL transcript testing can help monitor response, predict outcome, and detect early resistance or poor adherence to TKI therapy. The widely-used Sokal, Hasford and EUTOS clinical risk stratification scores were developed in patients receiving chemotherapy, interferon and imatinib, respectively; their predictive ability in patients receiving next-generation tyrosine kinase inhibitors (TKIs) remains to be established. Newer more sensitive molecular techniques are being developed that may aid in the expanding emphasis on discontinuing therapy in patients with a deep and consistent molecular response., (Copyright © 2016. Published by Elsevier Ltd.)

Tyrosine kinase inhibitor (TKI) therapy has radically altered the treatment strategy for chronic myeloid leukemia. Allogeneic transplantation, which over a decade ago was considered the definitive therapy for CML, is now appropriately used in cases where all TKIs are not tolerated, in cases of resistance to TKI therapy, or when the disease progresses from chronic phase to accelerated or blast phase., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The JAK2 c.1849G>T (p.V617F) mutation leads to constitutive activation of Janus kinase (JAK)2 and contributes to dysregulated JAK signaling in myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). In the phase 3 Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I trial, patients with MF, post-PV MF, or post-ET MF achieved significant reductions in splenomegaly and improvements in symptoms with ruxolitinib vs placebo at week 24. This long-term follow-up analysis was performed to determine whether ruxolitinib therapy altered the JAK2p.V617F allele burden in JAK2p.V617F-positive patients. Assessments at baseline and weeks 24, 48, 120, 144, 168, and 216 demonstrated reductions in allele burden from baseline with ruxolitinib treatment that correlated with spleen volume reductions. Of 236 JAK2p.V617F-positive patients analyzed, 20 achieved partial and 6 achieved complete molecular responses, with median times to response of 22.2 and 27.5 months, respectively. Allele burden reductions were greater in patients with shorter disease duration, which suggests a potential benefit of earlier treatment. This trial was registered at www.clinicaltrials.gov as #NCT00952289., (© 2015 by The American Society of Hematology.)

Tyrosine kinase inhibitors with activity against BCR-ABL form the cornerstone of CML therapy, and are particularly effective in those with chronic-phase disease. Because some patients exhibit primary resistance or secondary failure to TKI therapy, it is recommended that continued monitoring of disease burden be performed. In this article, we review methods of detecting the Philadelphia chromosome and BCR-ABL transcript, and discuss the correlation of response with patient outcomes. Expert guidelines that incorporate definitions and milestones of response are referenced to aid in clinical decision-making., (Copyright © 2015 Elsevier Inc. All rights reserved.)

NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Children's Oncology Group/Children's Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease., (© 2014 by The American Society of Hematology.)

An ongoing search for alkaloids in the Amaryllidaceae species using GC-MS resulted in the identification of two crinine-type alkaloids, aulicine (1) and 3-O-methyl-epimacowine, (2) from the indigenous Brazilian species Hippeastrum aulicum and Hippeastrum calyptratum, respectively. In addition, two alkaloids, 11-oxohaemanthamine (3) and 7-methoxy-O-methyllycorenine (4) were both isolated from H. aulicum. Furthermore, we provide here complete NMR spectroscopic data for the homolycorine analogues nerinine (5) and albomaculine (6). The absolute stereochemistry of the 5,10b-ethano bridge in the crinine variants was determined by circular dichroism and X-ray crystallographic analysis, thus presenting the first direct evidence for the presence of crinine-type alkaloids in the genus Hippeastrum., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Physical activity (PA) has been found to be an excellent predictor of mortality beyond traditional measures in COPD. We aimed to determine the association between depression and anxiety with accelerometry-based PA in patients with COPD., Methods: We performed a cross-sectional analysis of baseline data from 148 stable patients with COPD enrolled in an ongoing, longitudinal, observational study. We measured PA (total daily step count) with a Stepwatch Activity Monitor over 7 days, depression and anxiety with the Hospital Anxiety and Depression Scales (HADSs), dyspnea with the Shortness of Breath Questionnaire, and functional capacity with the 6-min walk test., Results: Increased anxiety was associated with higher levels of PA such that for every one-point increase in the HADS-Anxiety score there was a corresponding increase of 288 step counts per day (β=288 steps, P<.001), after adjusting for all other variables. Higher levels of depressive symptoms were associated with lower PA (β=-176 steps, P=.02) only when anxiety was in the model. The interaction term for anxiety and depression approached significance (β=26, P=.10), suggesting that higher levels of anxiety mitigate the negative effects of depression on PA., Conclusions: The increased PA associated with anxiety in COPD is, to our knowledge, a novel finding. However, it is unclear whether anxious patients with COPD are more restless, and use increased psychomotor activity as a coping mechanism, or whether those with COPD who push themselves to be more physically active experience more anxiety symptoms. Future studies should evaluate for anxiety and PA to better inform how to improve clinical outcomes., Trial Registry: Clinicaltrials.gov; No.: NCT01074515; URL: www.clinicaltrials.gov.

Treatment for chronic myeloid leukemia (CML) has improved substantially in the past 20 years, especially since the introduction of oral BCR-ABL inhibitors a decade ago. However, for patients to reap the benefits of BCR-ABL inhibitors, they must likely receive therapy for the remainder of their lives. In this situation, adherence to medication becomes a concern. Adherence to therapy for chronic health conditions, including CML, has been demonstrated to be poor. Studies have shown nonadherence in CML to be common in one-third or more of patients, and 100% adherence is rare. Furthermore, evidence suggests that reduced adherence to BCR-ABL inhibitors is associated with reduced efficacy and increased healthcare costs. Factors that can cause nonadherence, including dose, toxicity, time from diagnosis to prescription, and the number of concomitant medications, should be addressed and monitored by the physician. To maximize adherence, CML treatment should be individualized to the patient and simplified as appropriate., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Although many studies have reported on the morphology of maxillary first premolars, to our knowledge, there has never been an investigation reporting the anatomic position of the palatal (P) root tip relative to the B root tip in mesiodistal (MD), buccopalatal (BP), and apicocoronal (AC) dimensions. Such information could help clinicians more accurately locate root apices, reduce surgical morbidity, and improve the precision and prognosis of endodontic periradicular surgery for this tooth., Methods: Fifty extracted, bifurcated, human maxillary first premolars were individually mounted and photographed under 10x magnification and oriented to simulate a clinical view., Results: The P apex was superimposed by the B apex in 25 of 50 specimens, distal to the B apex in 24 of 50, and mesial to the B apex in only 1 instance. When not superimposed by or mesial to the B apex, the P apex was usually 1.4+/-0.7 mm distal to the B apex. In 98% of specimens, the P apex was positioned palatocoronal or palatocoronodistal to the B apex., Conclusions: This knowledge can be used to clinically minimize the size of osteotomies required to locate P root apices during endodontic surgery., (Copyright (c) 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

An investigation of the constituents in heartwood and resin of Prunus avium is reported. A mini-library of structurally diverse flavanones and flavones was screened for human cytochrome P450 1A1, 3A4 and 19 (aromatase) inhibition, and for antifungal activity against a panel of pathogenic fungi. The defensive role of these natural plant flavonoids as antifungal phytoalexins and phytoanticipins is discussed.

The direct chemoselective differential functionalization of the ring-C hydroxyl groups present in the Amaryllidaceae alkaloid lycorine is described allowing for selective manipulation of the 1,2-hydroxyl groups. A mini-library comprised of synthetic and natural lycorane alkaloids was prepared and their apoptosis-inducing activity investigated in human leukemia (Jurkat) cells. Further insights into the nature of this interesting apoptosis-inducing pharmacophore are described, including the requirement of both free hydroxyl groups in ring-C.

Rhesus macaque rhadinovirus (RRV) is closely related to Kaposi sarcoma-associated herpesvirus (KSHV) and is associated with the development of B-cell hyperplasia and persistent lymphadenopathy resembling multicentric Castleman disease in rhesus macaques (RMs) coinfected with simian immunodeficiency virus (SIV). Here we investigated whether RMs experimentally infected with SIV and RRV can develop other disease manifestations observed in HIV- and KSHV-infected patients. As reported earlier, inoculation of SIV-infected RMs with RRV results in persistent RRV infection, whereas immunocompetent animals infected with RRV exhibit viremia 2 weeks after infection, followed by a period of no virus detection until they are subsequently made immunodeficient by SIV infection. A subset of animals developed abnormal cellular proliferations characterized as extranodal lymphoma and a proliferative mesenchymal lesion. In situ hybridization and immunohistochemistry analysis indicate RRV is present in both malignancies, and DNA microarray analysis detected viral interleukin-6 (vIL-6) and viral FLICE-like inhibitory protein (vFLIP) transcripts. Reverse-transcriptase polymerase chain reaction analysis confirmed vIL-6 and vFLIP expression, and that of RRV open reading frames 72 and 73, homologs of KSHV open reading frames shown to be expressed in primary effusion lymphoma. These data support the utility of the RRV-/SIV-infected RM as an excellent animal model to investigate KSHV-like pathogenesis.

Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.

Therapeutic options for chronic myelogenous leukemia (CML) resistant to 400 to 600 mg imatinib are limited. Escalating imatinib doses may overcome resistance. Dasatinib, a significantly more potent inhibitor of BCR-ABL, is safe and effective in this population. Patients with imatinib-resistant chronic-phase (CP) CML were randomized 2:1 to 140 mg dasatinib (n=101) or 800 mg imatinib (n=49). With a median follow up of 15 months, complete hematologic responses were observed in 93% and 82% of patients receiving dasatinib and high-dose imatinib (P=.034), respectively. Dasatinib resulted in higher major cytogenetic response rates (52%) than high-dose imatinib (33%) (P=.023); this included complete cytogenetic response in 40% and 16% (P=.004). Major molecular responses were also more frequent with dasatinib (16% versus 4%; P=0.038). Treatment failure (hazard ratio [HR], 0.16; P<.001) and progression-free survival (HR, 0.14; P<.001) both favored dasatinib. Superficial edema (42% versus 15%) and fluid retention (45% versus 30%) were more prevalent with imatinib; pleural effusion was more common with dasatinib (17% versus 0%). Grade 3 to 4 nonhematologic toxicity was minimal. Cytopenias were more frequent and severe with dasatinib. Dasatinib represents a safe and effective therapy for CP-CML resistant to conventional imatinib doses with improved cytogenetic and molecular response rates and progression-free survival relative to high-dose imatinib.

The selective apoptosis-inducing activity of Amaryllidaceae alkaloids belonging to the crinane-type is reported. A mini-library of natural and synthetic crinane alkaloids was assembled. Biological screening indicated crinamine 4 and haemanthamine 9 to be potent inducers of apoptosis in tumour cells at micromolar concentrations. Structure-activity relationships demonstrated the requirement for both an alpha-C2 bridge and a free hydroxyl at the C-11 position as pharmacophoric requirements for this activity.