The Role of Autophagy and Senescence in the Responses of Non-Small Cell Lung Cancer Cells to Chemotherapy and Radiation

Cancer-associated deaths account for the second-highest mortality rates in the United States. Primary modalities of treatment often include surgery, radiation, and chemotherapy, and may also incorporate targeted therapy and immunotherapy. However, resistance to these treatments remains high, resulting in disease reoccurrence and poor survival rates. While apoptosis or cell death of tumor cells is the ideal outcome for anti-cancer therapy, this is often not the case, and in fact cancer cells may upregulate several pathways, such as autophagy and senescence, as a means to undergo alternative cell fate and evade apoptotic cell death. An essential tumor suppressor gene, TP53, regulates all three of these processes, apoptosis, autophagy, and senescence, and loss of function or mutated TP53 is often implicated in early tumorigenesis and reduced sensitivity to antineoplastic therapy. To assess the effects of p53 status on the functionality of autophagy and cellular responses to radiation and chemotherapy, we utilized a pair of isogenic non-small cell lung cancer cells (NSCLC) expressing wild type p53 (H460wt) or lacking p53 expression generated using CRISPR/Cas9 editing (H460crp53). Exposure to the DNA-damaging agents, cisplatin and radiotherapy, revealed differential sensitivity between H460wt and H460crp53 cells, in which H460crp53 cells were significantly less sensitive to cisplatin and radiation exposure compared to their wild-type counterpart. In response to radiotherapy, apoptosis was induced to similar extents in both cell lines, while autophagy interference identified a nonprotective function of autophagy in response in both cell lines, regardless of p53 status. Rather, the differential radiosensitivity exhibited between H460wt and H460crp53 cells was attributed to differences in senescence induction, where H460wt cells demonstrated a significantly greater extent of senescence induction. Of particular interest was the finding that when the same set of isogenic cell lines was exposed to cisplatin, the cells exhibited a similar extent of senescence induction over time; however, autophagy inhibition revealed two different functional forms of autophagy: nonprotective autophagy in H460wt cells and cytoprotective autophagy in H460crp53 cells. Blockade of cytoprotective autophagy in H460crp53 exposed to cisplatin was sufficient to restore sensitivity and apoptosis induction to a similar extent as in the H460wt cells, further confirming the existence of an autophagic switch and the role of cytoprotective autophagy in the initial resistance to cytotoxic therapy. Finally, given concomitant activation of both autophagy and senescence in response to chemotherapy and radiation, we also examined the relationship between these two processes. At least in the case of nonprotective autophagy, autophagy inhibition did not interfere with senescence induction or proliferative recovery from growth arrest, indicating these two processes may be dissociated when autophagy is nonprotective in function. Taken together, cancer chemotherapy and radiotherapy activate a number of cellular mechanisms, such as autophagy and senescence, and not solely apoptotic cell death; consequently, further analysis and screening are warranted prior to therapeutic administration of autophagy inhibitors to patients. While autophagy seems to be an attractive therapeutic target under its cytoprotective function, autophagy can in fact play multiple functions and switch functional responses. These studies demonstrate that autophagy is contextual in nature and may, in part, depend on the therapeutic modality utilized and the p53 status of the tumor cells

When Money Can’t Be Avoided: Helping Money Avoidant Widows Using the Changes and Grief Model (FTA Best Paper Award)

Widows represent one of the fastest-growing demographics due to the global COVID-19 pandemic. Many widows also lost their family’s financial manager because more men hold the role of household financial manager. When their spouse dies, the widow can experience unhealthy attitudes towards finances and financial anxiety. The Changes and Grief Model for Financial Guidance pairs financial therapy techniques and inquiry methods, such as The Work of Byron Katie®, with the grief process and the change cycle. Using this model enables financial practitioners, mental health practitioners, and financial therapists to recognize the stage of grief the widow is experiencing and use the proper financial therapy modalities to support the money-avoidant widow. The model presented will provide the process to deepen client relationships through meaningful communication while compassionately supporting money-avoidant widows through financial decisions during the difficult initial stages of grief

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Grading and Evaluation Procedures

This project investigates the perceived fairness of grading procedures by students and faculty at the U of I. On the basis of surveys, interviews, and literature research, the study finds that 61% of students felt that they had received an ???unfair??? grade during academic career here at the University and that 51% of students believe that their grades are an accurate representation of their abilities. There is a larger than expected fraction of satisfied students, which serves as a testament to the efforts of the University to use effective and fair procedures. Furthermore, many students accept that the system is not perfect and problems are bound to occur. Nevertheless, there remains a significant portion of students who remain unsatisfied. In a majority of instances dissatisfaction is directly related to some form of miscommunication on either the student or instructor???s behalf. The authors argue that it is the responsibility of the instructors and department heads to thoroughly communicate the goals of each course and also consistent means of judging coursework. Conversely, the diligent student has the responsibility to question the instructor until the goals and grading methods are clearly understood.unpublishe

Socioeconomic determinants of regional differences in nutritional status of children in India

While India has experienced rapid economic development during the last few decades, the prevalence of undernutrition remains high and the prevalence of overnutrition is increasing, creating a “double burden”. This trend is observed not only among the adult population of India, but also among the children of India. The National Family Health Surveys (NFHS), starting in 1992 and conducted every five years, collects nutritional data on participants and was used to address the question of which socioeconomic factors influence childhood nutritional status and whether or not these factors differ by state and wealth of different regions in India. To achieve this objective, the NFHS II data from 1998-1999 were studied using multiple linear regression analysis to predict child nutritional status for those under two years of age. Weight-for-height z-score (WHZ) was positively associated with Body Mass Index (BMI) and household standard of living, and an inverse relationship with respondent’s age. Height-for-age z-score (HAZ) was positively associated with years lived in place of residence, education level, BMI, and household standard of living and an inverse relationship with respondent’s age and type of employment. Analyses by region (West, South, North, Northeast, East, and Central) showed that the association between the socioeconomic factors with WHZ and HAZ among stunted, wasted, and overweight children varied among the six regions. In the wealthier regions, respondent’s age, place of residence, and years lived in residence are significant predictors. In the less wealthy regions, respondent’s ethnicity and employment are significant predictors. In conclusion, when assessing the nutritional status of children within the country of India, the association between socioeconomic factors with child WHZ and HAZ varies by region.M.S.Includes bibliographical referencesby Nipa Pate

Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy

Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit