Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer.

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying nonactionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%), and CDKN2A (12.2%) were the most frequently altered genes. SIGNIFICANCE: Although clear progress has been made in expanding the availability of precision oncology-based treatment paradigms, our results suggest a continued unmet need for innovative therapeutic strategies, particularly for cancers with currently undruggable oncogenic drivers. See related commentary by Horak and Fröhling, p. 18. This article is featured in Selected Articles from This Issue, p. 5.

The Role of B Lymphocyte Subsets in Adipose Tissue Development, Metabolism, and Aging.

Adipose tissue contains resident B lymphocytes (B cells) with varying immune functions and mechanisms, depending on the adipose depot type and location. The heterogeneity of B cells and their functions affect the immunometabolism of the adipose tissue in aging and age-associated metabolic disorders. B cells exist in categorizations of subsets that have developmental or phenotypic differences with varying functionalities. Subsets can be categorized as either protective or pathogenic depending on their secretion profile or involvement in metabolic maintenance. In this article, we summarized recent finding on the B cell heterogeneity and discuss how we can utilize our current knowledge of adipose resident B lymphocytes for potential treatment for age-associated metabolic disorders. © 2022 American Physiological Society. Compr Physiol 12: 1-13, 2022.

Identification of potential plasma protein biomarkers for feline pancreatic carcinoma by liquid chromatography tandem mass spectrometry.

In both humans and cats, pancreatic carcinoma is an aggressive cancer with a grave prognosis. Proteomics techniques have successfully identified several blood-based biomarkers of human pancreatic neoplasia. Thus, this study aims to investigate whether similar biomarkers can be identified in the plasma of cats with FePAC by using liquid chromatography tandem mass spectrometry (LC-MS/MS). To facilitate evaluation of the low abundance plasma proteome, a human-based immunodepletion device (MARS-2) was first validated for use with feline plasma. Marked reduction and/or complete removal of albumin and immunoglobulins was confirmed by analysis of electrophoretograms and mass spectral data. Subsequently, plasma collected from 9 cats with pancreatic carcinoma (FePAC), 10 cats with symptomatic pancreatitis, and 10 healthy control cats was immunodepleted and subjected to LC-MS/MS. Thirty-seven plasma proteins were found to be differentially expressed (p < .05 in one-way ANOVA, FC >2 in fold change analysis). Among these proteins, ETS variant transcription factor 4 (p < .05) was overexpressed, while gelsolin (p < .01), tryptophan 2,3-dioxygenase (p < .05), serpin family F member 1 (p < .01), apolipoprotein A-IV (p < .01) and phosphatidylinositol-glycan-specific phospholipase D (p < .05) were down-regulated in cats with FePAC. Further studies on these potential biomarkers are needed to investigate their diagnostic value.

Assessment of neutrophil function in canine cancer patients undergoing chemotherapy and correlation with neutrophil numbers.

Decreased neutrophil function following administration of chemotherapy has been reported in dogs with lymphoma. The first objective of our study was to determine if neutrophil oxidative burst and phagocytic activity are affected by chemotherapy 7 to 10 days following initiation of treatment in dogs with lymphoma and non-lymphoma malignancies. The second objective was to determine if there is a correlation between neutrophil numbers and neutrophil function before or after initiation of chemotherapy. Flow cytometric assessment of neutrophil oxidative burst and phagocytosis following stimulation with Escherichia coli was performed in 9 dogs diagnosed with lymphoma and 17 non-lymphoma tumor-bearing dogs pre- and post-chemotherapy, as well as 14 tumor-free control dogs. Spearman rank correlation was performed to determine if blood neutrophil numbers and neutrophil function were significantly correlated. Lymphoma patients showed significantly reduced percentage neutrophil oxidative burst post-chemotherapy compared to healthy controls as well as compared to pre-chemotherapy values (P = 0.0022 and P = 0.0020, respectively). Lymphoma patients also exhibited significantly reduced neutrophil phagocytosis activity post-chemotherapy compared to controls and pre-chemotherapy values (P = 0.0016 and P = 0.014, respectively). Dogs with non-lymphoma malignancies also showed a significant decrease in both percentage oxidative burst and phagocytosis post-chemotherapy compared to pre-chemotherapy values (P = 0.00040 and P = 0.029, respectively). Neutrophil numbers and function were not significantly correlated. The results of the study suggest that chemotherapeutic treatment decreases neutrophil oxidative burst and phagocytic activity 7 to 10 days post-treatment in dogs with various malignancies. Furthermore, neutrophil numbers cannot be used to predict neutrophil function.

Une diminution de la fonction des neutrophiles après l'administration d'une chimiothérapie a été rapportée chez des chiens atteints de lymphome. Le premier objectif de notre étude était de déterminer si la stimulation oxydative des neutrophiles et l'activité phagocytaire sont affectées par la chimiothérapie 7 à 10 jours après le début du traitement chez les chiens atteints de lymphomes et de tumeurs malignes non lymphomateuses. Le deuxième objectif était de déterminer s'il existe une corrélation entre les nombres de neutrophiles et la fonction des neutrophiles avant ou après le début de la chimiothérapie. L'évaluation par cytométrie en flux de la stimulation oxydative des neutrophiles et de la phagocytose après stimulation par Escherichia coli a été réalisée chez neuf chiens diagnostiqués avec un lymphome et 17 chiens avec des tumeurs non lymphomateuses avant et après la chimiothérapie, ainsi que 14 chiens témoins sans tumeur. Une corrélation des rangs de Spearman a été effectuée pour déterminer si les nombres de neutrophiles sanguins et la fonction des neutrophiles étaient significativement corrélés. Les patients atteints de lymphome ont montré un pourcentage significativement réduit de stimulation oxydative des neutrophiles après la chimiothérapie par rapport aux témoins sains ainsi que par rapport aux valeurs pré-chimiothérapie (P = 0,0022 et P = 0,0020, respectivement). Les patients atteints de lymphome ont également présenté une activité de phagocytose par les neutrophiles significativement réduite après la chimiothérapie par rapport aux témoins et aux valeurs pré-chimiothérapie (P = 0,0016 et P = 0,014, respectivement). Les chiens atteints de tumeurs malignes non lymphomateuses ont également montré une diminution significative du pourcentage de stimulation oxydative et de la phagocytose post-chimiothérapie par rapport aux valeurs pré-chimiothérapie (P = 0,00040 et P = 0,029, respectivement). Les nombres et la fonction des neutrophiles n'étaient pas significativement corrélés. Les résultats de l'étude suggèrent que le traitement chimiothérapeutique diminue la poussée oxydative des neutrophiles et l'activité phagocytaire 7 à 10 jours après le traitement chez les chiens atteints de diverses tumeurs malignes. De plus, les nombres de neutrophiles ne peuvent pas être utilisés pour prédire la fonction des neutrophiles.(Traduit par Docteur Serge Messier).

Variaciones en el estado nutricional, presión arterial y en los patrones dietéticos de jóvenes posterior al ingreso a la educación superior

RESUMEN El objetivo fue analizar los cambios en el estado nutricional, presión arterial y patrones dietéticos de jóvenes evaluados durante la primera semana de inducción y seis meses posterior al ingreso a la Facultad de Ciencias de la Salud de una universidad pública de Valparaíso, Chile. Estudio comparativo, con diseño longitudinal de cohorte, análisis por-protocolo. Los patrones dietéticos se determinaron mediante una Encuesta de Tendencia de Consumo Cuantificado, la evaluación antropométrica incluyó mediciones estandarizadas de peso, estatura y perímetro de cintura, la composición corporal se determinó mediante impedancia bioeléctrica, y la presión arterial con esfigmomanómetro digital. Las mediciones se realizaron al inicio y término del primer semestre de 2017 (n= 76). En ambos sexos se observó una ganancia significativa de peso corporal, IMC, masa grasa e incremento de la presión arterial sistólica, además en hombres aumentó el perímetro de cintura y la presión arterial diastólica (p<0,05). Los hombres disminuyeron significativamente el consumo de lácteos (-43,1%) y aumentaron el consumo de carnes procesadas y comida rápida (40,6%), en cambio las mujeres disminuyeron significativamente el consumo de bebidas y refrescos (-58,0%) y de alimentos con cafeína (-54,1%). No hubo cambios en el consumo de energía y macronutrientes, sin embargo, un alto porcentaje presentó un consumo deficiente de ácidos grasos poliinsaturados ω-3, fibra dietética, ciertas vitaminas y minerales, y principalmente excesivo en ácidos grasos saturados, fósforo y sodio. Se identificaron cambios negativos en el estado nutricional, presión arterial y en los patrones dietéticos posterior al ingreso a la educación superior.

ABSTRACT The objective was to analyze the changes in nutritional status, blood pressure and dietary patterns, of young people evaluated during their induction week and six months after being admitted to the Faculty of Health Sciences of a public university in Valparaiso, Chile. This was a comparative study, with a longitudinal cohort, per-protocol analysis. Anthropometric evaluation included standardized measures of weight, height and waist circumference. Body composition was determined through bioelectrical impedance, and blood pressure was measured using a digital sphygmomanometer. Dietary patterns were determined through a survey of quantified consumption trends. Measurements were taken at the beginning (n= 139) and end of the first term in 2017 (n=76). In both sexes, significant increases in body weight, BMI, fat mass and systolic blood pressure were observed. Furthermore, in men, increases in waist circumference and diastolic blood pressure (p<0.05) were observed. Men significantly decreased their dairy consumption (-43.1%) and increased their consumption of processed meats and fast-food (40.6%). Conversely, women significantly decreased their soft drink consumption (-58.0%) and caffeinated products (-54.1%). No changes in energy and macronutrient consumption were observed. A high percentage of the participants presented a deficient consumption of polyunsaturated fatty acids ω-3, dietary fiber, and certain vitamins and minerals. They also presented excessive consumption of saturated fatty acids, phosphorus and sodium. Negative changes were identified in nutritional state, blood pressure and dietary patterns when admitted in tertiary education.

Psychometry and empathy levels and its dimensions in postgraduate students of dental specialties.

BACKGROUND: Empathy is an attribute that has an important role in the dentist-patient therapeutic relationship, clinical care and adherence to treatment, amongst other benefits. The aim of this research was to determine empathy in dentists in the process of specialisation. MATERIALS AND METHODS: Through an observational and cross-sectional study, all postgraduate students of Dentistry Faculty of Universidad Andrés Bello (Chile) were analysed (N = 195). The Jefferson Scale of Physician Empathy Scale was applied. RESULTS: The results show an adequate reliability of the empathy measure (α = 0.819, ω = 0.928). A three-factor structure is evidenced by confirmatory factor analysis (χ2 /df = 1.445, GFI = 0.952, RMSEA = 0.047) and adequate factor invariance between men and women. Women showed greater empathy on the global scale and in the perspective adoption dimension, with no gender differences found in the dimension Compassionate care and putting oneself in the other's shoes (POOS). The median empathy reaches 120 points. Below, are placed, the specialty of oral rehabilitation (Med = 114.5), surgery (Med = 117) and periodontics (Med. = 117.5). With superior scores, temporomandibular disorder (Med. = 121), endodontics (Med. = 121), Orthodontics and dentofacial orthopedics Med. = 122), Implantology (Med. = 125) and Pediatric dentistry (Med. = 127.5) are located. CONCLUSION: Women were more empathetic than men. In general, empathy levels are relatively high, but the common feature in which all students examined in different specialties have low levels in dimension POOS.

Reference intervals for radiographic, echocardiographic and N-terminal pro B-type natriuretic peptide values in healthy kittens.

OBJECTIVES: Assessment of heart size in kittens is important, and there is a need for reference intervals (RIs) to prevent misinterpretation of cardiomegaly in this patient population. The purpose of this study was to generate RIs for echocardiographic and radiographic quantification of cardiac size in healthy kittens. METHODS: In total, 88 kittens aged 6-16 weeks were enrolled in this study. Physical examination, and radiographic and echocardiographic evaluations were performed without sedation. Thoracic radiographs and echocardiographic images were measured to establish RIs for vertebral heart score (VHS), cardiac thoracic ratio (CTR) and multiple echocardiographic variables. N-terminal pro B-type natriuretic peptide (NT-proBNP) was measured. Statistical correlations between echocardiographic parameters and age, body weight and sex were all evaluated and RIs were generated. RESULTS: Low-grade heart murmurs were appreciated in 26/88 kittens (29.5%). Kittens had a median VHS of 9.5 vertebrae (95% RI 8.0-10.9) and a median CTR of 67.2% (95% RI 54.4-79.8%). Measured NT-proBNP levels were comparable to healthy adult cats with a median of 31 pmol/l (upper reference limit 75 pmol/l). Multiple moderate-to-strong correlations between body weight and age with various echocardiographic parameters were observed and allometric scaling was performed for body weight. RIs for echocardiographic parameters were generated based on patient weight using allometric scaling formulas. Tricuspid valve regurgitation was a common finding and was present in 37.5% (n = 33) of the kittens. CONCLUSIONS AND RELEVANCE: This study establishes RIs for thoracic radiograph assessment, echocardiography and cardiac biomarkers in kittens, which fills a critical gap in the veterinary literature. The VHS reported in this study is higher than previously reported for adult cats.

An arrestin-1 surface opposite of its interface with photoactivated rhodopsin engages with enolase-1.

Arrestin-1 is the arrestin family member responsible for inactivation of the G protein-coupled receptor rhodopsin in photoreceptors. Arrestin-1 is also well-known to interact with additional protein partners and to affect other signaling cascades beyond phototransduction. In this study, we investigated one of these alternative arrestin-1 binding partners, the glycolysis enzyme enolase-1, to map the molecular contact sites between these two proteins and investigate how the binding of arrestin-1 affects the catalytic activity of enolase-1. Using fluorescence quench protection of strategically placed fluorophores on the arrestin-1 surface, we observed that arrestin-1 primarily engages enolase-1 along a surface that is opposite of the side of arrestin-1 that binds photoactivated rhodopsin. Using this information, we developed a molecular model of the arrestin-1-enolase-1 complex, which was validated by targeted substitutions of charge-pair interactions. Finally, we identified the likely source of arrestin's modulation of enolase-1 catalysis, showing that selective substitution of two amino acids in arrestin-1 can completely remove its effect on enolase-1 activity while still remaining bound to enolase-1. These findings open up opportunities for examining the functional effects of arrestin-1 on enolase-1 activity in photoreceptors and their surrounding cells.

Providers' Perspectives on Adherence to Hormonal Therapy in Breast Cancer Survivors. Is there a Role for the Digital Health Feedback System?

OBJECTIVE: Despite the benefits of hormonal therapy (HT) adherence remains suboptimal in ER positive breast cancer patients. Medication adherence is challenging to assess and tends to be overestimated. The Digital Health Feedback System (DHFS) consists of an ingestible sensor attached to a pill that sends intake date and time to a smart phone or computer. Patients can share this information with health care providers and other persons. The DHFS can also send reminders. This mixed methods study examined providers' perceptions of HT medication adherence. The potential role of the DHFS in enhancing medication tracking and adherence was also explored. METHODS: We conducted semi-structured interviews with key informants (N=10). Questions examined perceptions about adherence barriers and facilitators, challenges tracking adherence, and views on the DHFS. Findings informed the development of a survey that was administered online (N=19). RESULTS: Providers emphasized the importance of fostering open and trustful communication around adherence. The most mentioned challenges to assessing adherence were the patient not disclosing discontinuation immediately (78.9%) and over-reporting adherence (57.9%). The perceived potential benefits of DHFS were the ability to track adherence better (94.7%) and reminders to take the medication (68.4%). Safety to ingest a sensor was as a major perceived barrier (8 4.2%). CONCLUSION: Interventions that target providers and doctor-patient communication are warranted to enhance adherence and reduce communication delays around HT discontinuation. PRACTICE IMPLICATIONS: DHFS has the potential to enhance HT adherence by directly targeting barriers. Future studies should also examine the feasibility of adopting the DHFS with cancer patients.