Imaging Approaches in Cancer Biology.

A majority of cancer research is focused on defining the cellular and molecular basis of cancer cells and the signals that control oncogenic transformation; as a consequence, we know very little about the dynamic behavior of cancer cells in vivo. To begin to view and understand the mechanisms and interactions that control cancer initiation, growth, and metastatic progression and how these processes are influenced by the microenvironment and the signals derived from it, it is essential to develop strategies that allow imaging of the cancer cells in the context of the living microenvironment. Here, we discuss emerging work designed to visualize how cancer cells function within the microenvironment to discover how these interactions act coordinately to enable aberrant growth and to understand how they could be targeted to design new approaches to intercept the disease.

Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia.

Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML) the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, increased lethality and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase Polrmt and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic, and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.

Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer.

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.

The Role of the Microenvironment and Immune System in Regulating Stem Cell Fate in Cancer.

Despite gains in knowledge of the intrinsic signals governing cancer progression, effective clinical management of cancer remains a challenge. Drug resistance and relapse, pose the greatest barriers to cancer care, and are often driven by the co-option of stem cell programs by subpopulations of aggressive cancer cells. Here, we focus on the role of the microenvironment in the acquisition and/or maintenance of stem cell states in cancer in the context of resistance and metastasis. We further discuss the role of cancer stem cells in immune evasion through the course of metastasis, dormancy, and relapse. Understanding the niche in which cancer stem cells live and the signals that sustain them may lead to new strategies that target them by disrupting microenvironmental support.

Stem cells in cancer initiation and progression.

While standard therapies can lead to an initial remission of aggressive cancers, they are often only a transient solution. The resistance and relapse that follows is driven by tumor heterogeneity and therapy-resistant populations that can reinitiate growth and promote disease progression. There is thus a significant need to understand the cell types and signaling pathways that not only contribute to cancer initiation, but also those that confer resistance and drive recurrence. Here, we discuss work showing that stem cells and progenitors may preferentially serve as a cell of origin for cancers, and that cancer stem cells can be key in driving the continued growth and  functional heterogeneity of established cancers. We also describe emerging evidence for the role of developmental signals in cancer initiation, propagation, and therapy resistance and discuss how targeting these pathways may be of therapeutic value.

Effect of an Incentive Spirometer Patient Reminder After Coronary Artery Bypass Grafting: A Randomized Clinical Trial.

Importance: Incentive spirometers (ISs) were developed to reduce atelectasis and are in widespread clinical use. However, without IS use adherence data, the effectiveness of IS cannot be determined. Objective: To evaluate the effect of a use-tracking IS reminder on patient adherence and clinical outcomes following coronary artery bypass grafting (CABG) surgery. Design, Setting, and Participants: This randomized clinical trial was conducted from June 5, 2017, to December 29, 2017, at a tertiary referral teaching hospital and included 212 patients who underwent CABG, of whom 160 participants were randomized (intent to treat), with 145 completing the study per protocol. Participants were stratified by surgical urgency (elective vs nonelective) and sex (men vs women). Interventions: A use-tracking, IS add-on device (SpiroTimer) with an integrated use reminder bell recorded and timestamped participants' inspiratory breaths. Patients were randomized by hourly reminder "bell on" (experimental group) or "bell off" (control group). Main Outcomes and Measures: Incentive spirometer use was recorded for the entire postoperative stay and compared between groups. Radiographic atelectasis severity (score, 0-10) was the primary clinical outcome. Secondary respiratory and nonrespiratory outcomes were also evaluated. Results: A total of 145 per-protocol participants (112 men [77%]; mean age, 69 years [95% CI, 67-70]; 90 [62%] undergoing a nonelective procedure) were evaluated, with 74 (51.0%) in the bell off group and 71 (49.0%) in the bell on group. The baseline medical and motivation-to-recover characteristics of the 2 groups were similar. The mean number of daily inspiratory breaths was greater in bell on (35; 95% CI, 29-43 vs 17; 95% CI, 13-23; P < .001). The percentage of recorded hours with an inspiratory breath event was greater in bell on (58%; 95% CI, 51-65 vs 28%; 95% CI, 23-32; P < .001). Despite no differences in the first postoperative chest radiograph mean atelectasis severity scores (2.3; 95% CI, 2.0-2.6 vs 2.4; 95% CI, 2.2-2.7; P = .48), the mean atelectasis severity scores for the final chest radiographs conducted before discharge were significantly lower for bell on than bell off group (1.5; 95% CI, 1.3-1.8 vs 1.8; 95% CI, 1.6-2.1; P = .04). Of those with early postoperative fevers, fever duration was shorter for bell on (3.2 hours; 95% CI, 2.3-4.6 vs 5.2 hours; 95% CI, 3.9-7.0; P = .04). Having the bell turned on reduced noninvasive positive pressure ventilation use rates (37.2%; 95% CI, 24.1%-52.5% vs 19.2%; 95% CI, 10.2%-33.0%; P = .03) for participants undergoing nonelective procedures. Bell on reduced the median postoperative length of stay (7 days; 95% CI, 6-9 vs 6 days; 95% CI, 6-7; P = .048) and the intensive care unit length of stay for patients undergoing nonelective procedures (4 days; 95% CI, 3-5 vs 3 days; 95% CI, 3-4; P = .02). At 6 months, the bell off mortality rate was higher than bell on (9% vs 0%, P = .048) for participants undergoing nonelective procedures. Conclusions and Relevance: The incentive spirometer reminder improved patient adherence, atelectasis severity, early postoperative fever duration, noninvasive positive pressure ventilation use, ICU and length of stay, and 6-month mortality in certain patients. With the reminder, IS appears to be clinically effective when used appropriately. Trial Registration: ClinicalTrials.gov identifier: NCT02952027.

Uso racional de medicamentos por agentes comunitarios en atención primaria de salud en los ambulatorios rurales del municipio Atures, estado Amazonas, Venezuela, año 2011 / Rational drug use by community workers in primary health care in the rural clinics of the municipality Atures, Amazonas State (Venezuela), year 2011

Venezuela cuenta con los auxiliares de medicina simplificada (AMS) y los agentes comunitarios para la atención primaria en salud (ACAPS), personal no profesional, capacitado para el diagnóstico y tratamiento de enfermedades frecuentes; brindando atención en áreas de difícil acceso y en zonas rurales dispersas. En este trabajo se describió el uso racional de medicamentos por el AMS/ACAPS en los ambulatorios rurales (AR) del municipio Atures, estado Amazonas, Venezuela, en el 2011. Para ello, se realizó un estudio no experimental, de campo, descriptivo, de corte transversal; utilizando los indicadores básicos del uso de medicamentos de la OMS. Se evaluaron 12 de los 16 AR tipo I y el AR tipo II del municipio; registrándose 830 consultas y 1.238 prescripciones de medicamentos durante el segundo trimestre del 2011. El AMS/ACAPS prescribió 1,51 medicamentos por consulta. Del total de las prescripciones, 86,92% se hicieron con su nombre genérico, 11,26% como un medicamento inyectable, 23,88% fueron un antibiótico y solo el 52,51% de las prescripciones estuvieron acordes al primer nivel de atención. De los 13 AR visitados, nueve tenían la lista de medicamentos, cuatro el formulario terapéutico nacional y ocho contaron con otra fuente de información (guías de formación del AMS o ACAPS). La disponibilidad de medicamentos clave tuvo un promedio crítico de 48,72%. La prescripción de medicamentos por el AMS/ACAPS resulta inadecuada debido a que se utiliza una lista de medicamentos que no es acorde para el primer nivel de atención.

Venezuela has simplified medical assistants (AMS) and non-professional community workers for primary health care (ACAPS), trained in the diagnosis and treatment of common diseases; providing care in inaccessible and remote rural areas. In this paper the rational use of drugs by the AMS/ACAPS in rural clinics (AR) of the municipality Atures, Amazonas state (Venezuela) in 2011, was described. For this, a descriptive, non-experimental, field and cross sectional study took place; using the WHO basic indicators of drug use. We evaluated 12 of the 16 type I ARs and the type II AR in the municipality; recording 830 consultations and 1,238 drug prescriptions during the second quarter of 2011. The AMS/ACAPS prescribed 1.51 drugs per consultation. Of all prescriptions, 86.92% were by generic names, 11.26% as an injectable drug, 23.88% were an antibiotic and only 52.51% were in accordance to the primary care level. Of the 13 ARs visited, 9 had the drug list, 4 the national therapeutic formulary and 8 had another source of information (AMS or ACAPS training guides). The availability of key drugs had a critical average of 48.72%. The prescription of drugs by the AMS/ACAPS is inadequate because a list of drugs, which is not according to the first level of care, is used.

Propuesta de manual terapéutico dirigido a los agentes comunitarios de atención primaria en salud (ACAPS) del Municipio Atures del Estado Amazonas. Año 2011 / Proposal for a therapeutic manual aimed at community agents of primary health care (ACAPS) of the Atures Municipality of Amazonas State. Year 2011

El MPPS cuenta con los Agentes Comunitarios para la Atención Primaria en Salud (ACAPS) para la atención de la población en áreas de difícil acceso y zonas rurales dispersas. Para promover el Uso Racional de Medicamentos (URM), está publicada la Lista Básica Nacional de Medicamento Esenciales (LBNME) de uso en el Sistema Público Nacional de Salud a pesar de ello, se refleja una deficiencia en la selección de medicamentos de acuerdo a los niveles de atención, uso inadecuado de antimicrobianos, polimedicación y recetado no acorde con las directrices clínicas. Objetivo General: proponer un Manual Terapéutico dirigido a los ACAPS del Municipio Atures del Estado Amazonas, utilizando como metodología los Indicadores Básicos del Uso de Medicamentos de la OMS. Metodología: se evaluaron 13 ARI ubicados en el Municipio Atures donde labora un ACAPS/AMS, se registraron 830 consultas y 1.238 prescripciones de medicamentos durante el trimestre AbrilJunio del año 2011. Resultados: el ACAPS/AMS utiliza una media de 1,51 medicamentos por consulta, en promedio 86,92% prescribieron un genérico y 11,26% un inyectable, del total de prescripciones 23,88% correspondía a un antibiótico y solo 52,51% de las prescripciones estaban acordes para el Primer Nivel de Atención. Una evaluación complementaria determinó que de 295 prescripciones de antibióticos, 263 (89,15%) no estaban seleccionados para el Primer Nivel de Atención, de la revisión comparativa del Listado de Medicamentos local con la LBNME solo hay coincidencia de un 40%. El 69,23% de los ambulatorios cuentan con una Lista de medicamentos esenciales, el 30,77% disponen de un FTN en comparación a un 61,54% que cuenta con otras fuentes de información. La disponibilidad de medicamentos claves tiene un promedio crítico de 48,72 %. La accesibilidad de información actualizada e imparcial sobre las pautas de tratamientos establecidas para los ACAPS dentro de la APS como la propuesta del Manual Terapéutico, puede favorecer en proporcionar a cada paciente el mejor tratamiento y permitir el uso racional de los recursos disponibles.

MPPS has with Community Agents for Primary Health Care (ACAPS) to the attention of the population in areas of difficult access and remote rural areas. To promote Rational Use of Drugs (RUD), it is published la Lista Básica Nacional de Medicamentos Esenciales (LBNME) for use in the National Public Health System however a deficiency is reflected in the selection of drugs according to levels care, inappropriate use of antimicrobials, polypharmacy and prescribed not in accordance with clinical guidelines. General Objective: To propose a Therapeutic Manual aimed at ACAPS Atures Municipality State of Amazonas, using as a methodology the Core Drug Use Indicators WHO. Methodology: ARI 13 located in the municipality where they work one Atures ACAPS / AMS were evaluated 830 consultations and 1,238 drug prescriptions were recorded during the quarter April-June 2011 year Results: ACAPS / AMS uses an average of 1.51 drugs per encounter on average 86.92% prescribed a generic injectable and 11.26% of the total prescriptions 23.88% corresponded to an antibiotic and only 52.51% of prescriptions were in line for the primary care level. A complementary evaluation found that of 295 antibiotic prescriptions, 263 (89.15%) were not selected for the first level of care, comparative review of the local Drug List with no coincidental LBNME 40%. 69.23% of outpatients have a list of essential drugs, 30.77% have a FTN compared to 61.54% who have other sources of information. The availability of key drugs is a critical average of 48.72%. The accessibility of current and impartial treatment guidelines established for ACAPS within the APS as the proposal of Manual Therapy information can favor in providing each patient the best treatment and allow the rational use of available resources