Atrial fibrillation in cancer, anticancer therapies, and underlying mechanisms.

Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy induced AF.

Extracting, quantifying, and comparing dynamical and biomechanical properties of living matter through single particle tracking.

A panoply of new tools for tracking single particles and molecules has led to an explosion of experimental data, leading to novel insights into physical properties of living matter governing cellular development and function, health and disease. In this Perspective, we present tools to investigate the dynamics and mechanics of living systems from the molecular to cellular scale via single-particle techniques. In particular, we focus on methods to measure, interpret, and analyse complex data sets that are associated with forces, materials properties, transport, and emergent organisation phenomena within biological and soft-matter systems. Current approaches, challenges, and existing solutions in the associated fields are outlined in order to support the growing community of researchers at the interface of physics and the life sciences. Each section focuses not only on the general physical principles and the potential for understanding living matter, but also on details of practical data extraction and analysis, discussing limitations, interpretation, and comparison across different experimental realisations and theoretical frameworks. Particularly relevant results are introduced as examples. While this Perspective describes living matter from a physical perspective, highlighting experimental and theoretical physics techniques relevant for such systems, it is also meant to serve as a solid starting point for researchers in the life sciences interested in the implementation of biophysical methods.

Intracellular Signaling Pathways Mediating Tyrosine Kinase Inhibitor Cardiotoxicity.

Tyrosine kinase inhibitors (TKIs) are used to treat several cancers; however, a myriad of adverse cardiotoxic effects remain a primary concern. Although hypertension (HTN) is the most common adverse effect reported with TKI therapy, incidents of arrhythmias (eg, QT prolongation, atrial fibrillation) and heart failure are also prevalent. These complications warrant further research toward understanding the mechanisms of TKI-induced cardiotoxicity. Recent literature has given some insight into the intracellular signaling pathways that may mediate TKI-induced cardiac dysfunction. In this article, we discuss the cardiotoxic effects of TKIs on cardiomyocyte function, signaling, and possible treatments.

Non-equilibrium structural dynamics of supercoiled DNA plasmids exhibits asymmetrical relaxation.

Many cellular processes occur out of equilibrium. This includes site-specific unwinding in supercoiled DNA, which may play an important role in gene regulation. Here, we use the Convex Lens-induced Confinement (CLiC) single-molecule microscopy platform to study these processes with high-throughput and without artificial constraints on molecular structures or interactions. We use two model DNA plasmid systems, pFLIP-FUSE and pUC19, to study the dynamics of supercoiling-induced secondary structural transitions after perturbations away from equilibrium. We find that structural transitions can be slow, leading to long-lived structural states whose kinetics depend on the duration and direction of perturbation. Our findings highlight the importance of out-of-equilibrium studies when characterizing the complex structural dynamics of DNA and understanding the mechanisms of gene regulation.

Comprehensive evaluation of electrophysiological and 3D structural features of human atrial myocardium with insights on atrial fibrillation maintenance mechanisms.

Atrial fibrillation (AF) occurrence and maintenance is associated with progressive remodeling of electrophysiological (repolarization and conduction) and 3D structural (fibrosis, fiber orientations, and wall thickness) features of the human atria. Significant diversity in AF etiology leads to heterogeneous arrhythmogenic electrophysiological and structural substrates within the 3D structure of the human atria. Since current clinical methods have yet to fully resolve the patient-specific arrhythmogenic substrates, mechanism-based AF treatments remain underdeveloped. Here, we review current knowledge from in-vivo, ex-vivo, and in-vitro human heart studies, and discuss how these studies may provide new insights on the synergy of atrial electrophysiological and 3D structural features in AF maintenance. In-vitro studies on surgically acquired human atrial samples provide a great opportunity to study a wide spectrum of AF pathology, including functional changes in single-cell action potentials, ion channels, and gene/protein expression. However, limited size of the samples prevents evaluation of heterogeneous AF substrates and reentrant mechanisms. In contrast, coronary-perfused ex-vivo human hearts can be studied with state-of-the-art functional and structural technologies, such as high-resolution near-infrared optical mapping and contrast-enhanced MRI. These imaging modalities can resolve atrial arrhythmogenic substrates and their role in reentrant mechanisms maintaining AF and validate clinical approaches. Nonetheless, longitudinal studies are not feasible in explanted human hearts. As no approach is perfect, we suggest that combining the strengths of direct human atrial studies with high fidelity approaches available in the laboratory and in realistic patient-specific computer models would elucidate deeper knowledge of AF mechanisms. We propose that a comprehensive translational pipeline from ex-vivo human heart studies to longitudinal clinically relevant AF animal studies and finally to clinical trials is necessary to identify patient-specific arrhythmogenic substrates and develop novel AF treatments.

Nursing, advocacy and public policy.

This article draws attention to the nature and importance of public policy. It argues that if nurses are to influence the quality of healthcare effectively, they must be engaged with policymakers to get nursing care issues on the policy agenda. There is an ethical imperative to do so, driven by the advocacy role of the nurse and rooted in the values base of nursing. In addition, it is argued that if one takes the role of patient advocacy seriously, as core to the nursing role, two things are required of nurses: We must (a) broaden the conceptualisation of patient advocacy beyond the individual patient to the system of healthcare resourcing and provision and (b) see systemic change as important as change at the bedside.

Single-molecule visualization of the effects of ionic strength and crowding on structure-mediated interactions in supercoiled DNA molecules.

DNA unwinding is an important cellular process involved in DNA replication, transcription and repair. In cells, molecular crowding caused by the presence of organelles, proteins, and other molecules affects numerous internal cellular structures. Here, we visualize plasmid DNA unwinding and binding dynamics to an oligonucleotide probe as functions of ionic strength, crowding agent concentration, and crowding agent species using single-molecule CLiC microscopy. We demonstrate increased probe-plasmid interaction over time with increasing concentration of 8 kDa polyethylene glycol (PEG), a crowding agent. We show decreased probe-plasmid interactions as ionic strength is increased without crowding. However, when crowding is introduced via 10% 8 kDa PEG, interactions between plasmids and oligos are enhanced. This is beyond what is expected for normal in vitro conditions, and may be a critically important, but as of yet unknown, factor in DNA's proper biological function in vivo. Our results show that crowding has a strong effect on the initial concentration of unwound plasmids. In the dilute conditions used in these experiments, crowding does not impact probe-plasmid interactions once the site is unwound.

Visualizing structure-mediated interactions in supercoiled DNA molecules.

We directly visualize the topology-mediated interactions between an unwinding site on a supercoiled DNA plasmid and a specific probe molecule designed to bind to this site, as a function of DNA supercoiling and temperature. The visualization relies on containing the DNA molecules within an enclosed array of glass nanopits using the Convex Lens-induced Confinement (CLiC) imaging method. This method traps molecules within the focal plane while excluding signal from out-of-focus probes. Simultaneously, the molecules can freely diffuse within the nanopits, allowing for accurate measurements of exchange rates, unlike other methods which could introduce an artifactual bias in measurements of binding kinetics. We demonstrate that the plasmid's structure influences the binding of the fluorescent probes to the unwinding site through the presence, or lack, of other secondary structures. With this method, we observe an increase in the binding rate of the fluorescent probe to the unwinding site with increasing temperature and negative supercoiling. This increase in binding is consistent with the results of our numerical simulations of the probability of site-unwinding. The temperature dependence of the binding rate has allowed us to distinguish the effects of competing higher order DNA structures, such as Z-DNA, in modulating local site-unwinding, and therefore binding.

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons.

Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3'UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal.

Open-frame system for single-molecule microscopy.

We present the design and construction of a versatile, open frame inverted microscope system for wide-field fluorescence and single molecule imaging. The microscope chassis and modular design allow for customization, expansion, and experimental flexibility. We present two components which are included with the microscope which extend its basic capabilities and together create a powerful microscopy system: A Convex Lens-induced Confinement device provides the system with single-molecule imaging capabilities, and a two-color imaging system provides the option of imaging multiple molecular species simultaneously. The flexibility of the open-framed chassis combined with accessible single-molecule, multi-species imaging technology supports a wide range of new measurements in the health, nanotechnology, and materials science research sectors.

Pathological factors affecting gastric adenocarcinoma survival in a Caribbean population from 2000-2010.

AIM: To investigate pathological factors related to long term patient survival post surgical management of gastric adenocarcinoma in a Caribbean population. METHODS: This is a retrospective, observational study of all patients treated surgically for gastric adenocarcinoma from January 1(st) 2000 to December 31(st) 2010 at The University Hospital of the West Indies, an urban Jamaican hospital. Pathological reports of all gastrectomy specimens post gastric cancer resection during the specified interval were accessed. Patients with a final diagnosis other than adenocarcinoma, as well as patients having undergone surgery at an external institution were excluded. The clinical records of the selected cohort were reviewed. The following variables were analysed; patient gender, patient age, the number of gastrectomies previous performed by the lead surgeon, the gross anatomical location and appearance of the tumour, the histological appearance of the tumour, infiltration of the tumour into stomach wall and surrounding structures, presence of Helicobacter pylori and the presence of gastritis. Patient status as dead vs alive was documented for the end of the interval. The effect of the aforementioned factors on patient survival were analysed using Logrank tests, Cox regression models, Ranksum tests, Kruskal-Wallis tests and Kaplan-Meier curves. RESULTS: A total of 79 patients, 36 males and 43 females, were included. Their median age was 67 years (range 36-86 years). Median survival time from surgery was 70 mo with 40.5% of patients dying before the termination date of the study. Tumours ranged from 0.8 cm in size to encompassing the entire stomach specimen, with a median tumour size of 6 cm. The median number of nodes removed at surgery was 8 with a maximum of 28. The median number of positive lymph nodes found was 2, with a range of 0 to 22. Patients' median survival time was approximately 70 mo, with 40.5% of the patients in this cohort dying before the terminal date. An increase in the incidence of cardiac tumours was noted compared to the previous 10 year interval (7.9% to 9.1%). Patients who had serosal involvement of the tumour did have a significantly shorter survival than those who did not (P = 0.017). A significant increase in the hazard ratio (HR), 2.424, for patients with circumferential tumours was found (P = 0.044). Via Kaplan-Meier estimates, the presence of venous infiltration as well as involvement of the circumferential resection margin were found to be poor prognostic markers, decreasing survival at 50 mo by 46.2% and 36.3% respectively. The increased HR for venous infiltration, 2.424, trended toward significant (P = 0.055) Age, size of tumour, number of positive nodes found and total number of lymph nodes removed were not useful predictors of survival. It is noted that the results were mostly negative, that is many tumour characteristics did not indicate any evidence of affecting patient survival. The current sample, with 30 observed events (deaths), would have about 30% power to detect a HR of 2.5. CONCLUSION: This study mirrors pathological factors used for gastric cancer prognostication in other populations. As evaluation continues, a larger cohort will strengthen the significance of observed trends.

Drug-induced QT-interval prolongation: considerations for clinicians.

Drug-induced proarrhythmia is a frequently encountered clinical problem and a leading cause for withdrawal or relabeling of prescription drugs. Suppression of the rapid component of the delayed rectifier potassium current, I(Kr), represents the principal pharmacodynamic mechanism leading to heterogeneous prolongation of the ventricular action potential and prolongation of the QT interval clinically. However, the risk of proarrhythmia by QT-interval-prolonging drugs is variable and critically dependent on several factors leading to multiple reductions in the cardiac repolarization reserve. As antiarrhythmic drugs that prolong the QT interval are usually aggressively managed with continuous electrocardiogram monitoring and screening for drug interactions when administered to patients who have a high risk of sudden cardiac death, their risk of mortality is not increased. However, noncardiovascular QT-interval-prolonging drugs, which often produce less QT-interval prolongation compared with antiarrhythmic drugs, are found to be associated with increased rates of death in patients who have a markedly lower de novo risk of sudden cardiac death. Thus, it is important for clinicians, particularly pharmacists, to be cognizant of the levels of risk associated with varying degrees of QT-interval prolongation caused by drugs so that they can develop strategies to either prevent or reduce the risk of proarrhythmias.

Delay control in attosecond pump-probe experiments.

The time delay between the pump and probe pulses in attosecond time-resolved experiments, such as attosecond streaking, is commonly introduced by splitting and recombining the two pulses in an interferometer. This technique suffers from instability in the optical path lengths of the two arms due to mechanical vibration of the optical elements and fluctuating environmental conditions. We present a technique with which the instability of the unconventional interferometer is suppressed while at the same time the time delay is controlled to within 20 as RMS using a feedback loop. Using this scheme, the streaked spectrogram of an attosecond pulse was measured.

Population-based assessment of hospitalizations for neutropenia from chemotherapy in older adults with non-Hodgkin's lymphoma (United States).

OBJECTIVE: To study neutropenia hospitalization (NH) incidence and risk factors in a population-based sample of older adults with non-Hodgkin's lymphoma (NHL) and evaluate the validity of inferences from Surveillance, Epidemiology and End Results (SEER)-Medicare linked databases. METHODS: NHL cases receiving first-course chemotherapy were identified from Iowa SEER-Medicare. Survival methods evaluated NH risk factors. Medical record and Medicare claims data on chemotherapy and NH were compared. RESULTS: Of 761 subjects, 165 (21.7%, 95% CI: 18.8, 24.6) were hospitalized for neutropenia. Of those hospitalized, 41% were hospitalized in cycle 1 and 22% in cycle 2. Significant multivariable risk factors for NH were diffuse large cell histology, renal disease, Charlson comorbidity index, and anthracycline chemotherapy but not patient age. Medicare and medical records agreed on month of chemotherapy initiation 95% of the time and chemotherapy type 95% of the time. ICD-9 code 288.0 sensitivity for NH was 80%. CONCLUSIONS: Neutropenia hospitalizations were common in the first 2 chemotherapy cycles, especially among older adults with comorbidity. Findings conflict with a prior medical records study in which age was a risk factor for NH and dose intensity a negative confounder. Valid inferences about age effects on chemotherapy toxicity require more clinical detail than is available in administrative data.

Effect of clinical characteristics on neutropenia-related inpatient costs among newly diagnosed non-Hodgkin's lymphoma cases during first-course chemotherapy.

STUDY OBJECTIVE: To estimate the costs of hospitalization for neutropenia among chemotherapy-treated patients with newly diagnosed non-Hodgkin's lymphoma and to assess baseline patient factors associated with these costs. DESIGN: Retrospective cohort study. DATA SOURCE: Linked Surveillance, Epidemiology, and End Results Program-Healthcare Cost and Utilization Project databases for Iowa from 1993-1998. PATIENTS: Patients with newly diagnosed non-Hodgkin's lymphoma who received all inpatient care at Iowa hospitals during their first course of chemotherapy. MEASUREMENTS AND MAIN RESULTS: Neutropenia-related hospitalization costs were estimated from discharge abstracts found within the earliest of the following: 6 months after the diagnosis month, the date of bone marrow transplantation, or date of death. We performed univariate tests of differences in neutropenia-related hospitalization costs in all patients in the sample, as well as tests for neutropenia-related hospitalization costs, length-of-stay, and cost/inpatient day for patients with at least one hospitalization for neutropenia. We modeled total inpatient charges over the period for patients with at least one neutropenia-related hospitalization (multiple regression). A total of 1636 patients with non-Hodgkin's lymphoma had chemotherapy in Iowa and met inclusion criteria; of these, 316 had at least one hospitalization for neutropenia. The 316 patients had 418 stays. Patients with advanced stage (vs limited stage), previous anemia (vs no anemia), positive Charlson comorbidity score (vs score of 0), and diffuse large cell histology (vs follicular) had higher mean neutropenia-related hospitalization cost/patient with non-Hodgkin's lymphoma (p<0.05). Among those with neutropenia-related hospitalizations, a longer length of stay was associated with nonfollicular histologies, previous anemia, and positive Charlson score (p<0.05). CONCLUSION: When estimating expected payments for neutropenia-related hospitalization in patients with non-Hodgkin's lymphoma, payers need to be aware of the distribution of clinical characteristics in these patients.

Days of prophylactic filgrastim use to reduce febrile neutropenia in patients with non-Hodgkin's lymphoma treated with chemotherapy.

BACKGROUND: Filgrastim prophylaxis lessens the occurrence of febrile neutropenia in patients with non-Hodgkin.s lymphoma (NHL) treated with chemotherapy, but differences in days of therapy and mode (primary or secondary) of prophylaxis may affect clinical outcomes. OBJECTIVE: To describe the patterns of use of filgrastim prophylaxis, especially days of therapy and mode, and the possible associated incidence of febrile neutropenia in patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. METHODS: Using medical records from the Oncology Practice Pattern Study in patients treated between 1991 and 1999 at 12 sites in the United States, we studied patients with intermediate-grade NHL treated with first-line CHOP chemotherapy and prophylactic filgrastim. The number of days of prophylactic filgrastim use, mode of prophylaxis, and incidence of febrile neutropenia were evaluated. The cycles were stratified into 2 groups based on days of filgrastim prophylaxis (<7 days [Group 1] and > or = 7 days [Group 2]). RESULTS: One hundred seventy patients were treated with 652 cycles of CHOP chemotherapy with filgrastim prophylaxis. The mean days of filgrastim prophylaxis was 9.5 days (95% confidence interval [CI], 9.3-9.7 days) across all cycles, 4.7 days (95% CI, 4.5-5.0 days) across Group 1 cycles (n=73), and 10.1 days (95% CI, 9.9-10.3 days) across Group 2 cycles (n=579). Thirty-seven percent of patients were treated with primary prophylaxis; 94% of these patients. cycles were Group 2 cycles. The incidence of febrile neutropenia was 3.6% and 7.7% across cycles in patients receiving primary versus secondary prophylaxis, respectively. In patients treated with secondary prophylaxis, the incidence was 16.7% and 6.1% in Group 1 and Group 2 cycles, respectively. Multiple logistic regression modeling indicated that a lower risk of febrile neutropenia was associated with primary prophylaxis (mainly Group 2) (odds ratio [OR] 0.3; 95% CI, 0.1-0.6) and secondary prophylaxis in Group 2 (OR 0.4; 95% CI, 0.2-0.8), and lower body surface area was associated with a greater risk of febrile neutropenia (OR 1.8; 95% CI, 1.1-3.0). CONCLUSION: Primary prophylaxis with filgrastim (mainly Group 2) and secondary prophylaxis in Group 2 (mean 10.1 days) may be associated with a lower incidence of febrile neutropenia than secondary prophylaxis in Group 1.

Factors associated with early termination of CHOP therapy and the impact on survival among patients with chemosensitive intermediate-grade non-Hodgkin's lymphoma.

BACKGROUND: Six to eight cycles of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) is standard for intermediate-grade non-Hodgkin's lymphoma (NHL) but is associated with toxicity that may cause premature termination of therapy. METHODS: We studied factors associated with premature termination of CHOP therapy (receiving fewer than 6 cycles) and the relationship of premature termination with survival. Subjects consisted of a population-based sample of Iowa residents with intermediate-grade NHL who were planned to receive > or = 6 or more cycles of CHOP and who were chemosensitive (ie, achieved a documented partial or complete response to CHOP). RESULTS: In a comparison with patients 18-59 years of age, the odds of premature termination of CHOP therapy was 2.6 (95% CI, 0.7-9.2) for those aged 60-74 and 6.2 (95% CI, 1.7-23.3) for those aged > or = 75. Patients with cycle 1 febrile neutropenia hospitalization (FNH) were 4.4 times (95% CI, 1.4-13.8) more likely to terminate CHOP prematurely than those without cycle 1 FNH. Among patients aged 60-74, but not those aged > or = 75, premature termination appeared to be associated with decreased 5-year survival (hazard ratio [HR] = 6.0; 95% CI, 2.4-15.2) compared with those completing CHOP therapy (HR = 2.1; 95% CI, 1.0-4.2). Findings for overall survival were similar. CONCLUSIONS: First-cycle FNH and age > or = 60 years were associated with premature termination of CHOP therapy. The association of premature termination with survival among chemosensitive patients differed by age.

Anticholinergic agents for the treatment of "death rattle" in patients with myasthenia gravis.

Difficulty clearing upper airway secretions (death rattle) is a frequent problem at the end of life. Treatment often includes the use of anticholinergic drugs. Myasthenia gravis is a disease characterized by muscle weakness and fatigue caused by an immune-mediated deficiency of acetylcholine receptors at the neuromuscular junction, and it is treated with anticholinesterase agents. We report the case of a patient dying of myasthenia gravis who had problems with the "death rattle" and who presented a dilemma as to whether the use of anticholinergics would be helpful or would cause deterioration of her myasthenia. This is accompanied by a review of the relevant literature.

Was breast conserving surgery underutilized for early stage breast cancer? Instrumental variables evidence for stage II patients from Iowa.

OBJECTIVE: To estimate the average survival effects of breast conserving surgery plus irradiation relative to mastectomy for marginal stage II breast cancer patients in Iowa from 1989-1994. DATA SOURCES/DATA SETTING: Secondary linked Iowa SEER Cancer Registry--Iowa Hospital Association discharge abstract data for women in Iowa with stage II breast cancer from 1989-1994. STUDY DESIGN: Observational instrumental variables (IV) analysis. DATA COLLECTION/EXTRACTION METHODS: Women with stage II breast cancer from the Iowa SEER Cancer Registry 1989-1994 who received all of their inpatient care in Iowa were linked with their respective hospital discharge abstracts. PRINCIPAL FINDINGS: Breast conserving surgery plus irradiation decreased survival relative to mastectomy for marginal stage II breast cancer patients in Iowa during the early 1990s. In this study marginal patients were those whose surgery choices were affected by differences in area treatment rates and access to radiation facilities. CONCLUSIONS: If marginal patients are representative of patients whose treatment choices would be affected by changes in treatment rates, an increase in the breast conserving surgery plus irradiation rate for stage II early stage breast cancer patients would have decreased survival in Iowa during the early 1990s. Further research with newer data and broader samples is needed to make more current and specific assessments.