bims-minfam 2022-01-16 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2022–01–16
nineteen papers selected by
Ayesh Seneviratne, University of Toronto

Toward More Complete Prognostication for Patients with Clonal Hematopoiesis.
Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases.
Dietary Phytochemicals that Can Extend Longevity by Regulation of Metabolism.
Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV.
The Mechanism of Stem Cell Aging.
Long-term consumption of a mediterranean diet or a low-fat diet on kidney function in coronary heart disease patients: The CORDIOPREV randomized controlled trial.
Interpretable machine learning for high-dimensional trajectories of aging health.
Age-Dependent Decline of NAD+-Universal Truth or Confounded Consensus?
The association of polypharmacy with functional status impairments, frailty, and health-related quality of life in older adults with gastrointestinal malignancy - Results from the Cancer and Aging Resilience Evaluation (CARE) registry.
Clonal evolution in patients developing therapy-related myeloid neoplasms following autologous stem cell transplantation.
NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.
The Influence of Pension Mode on the Mental Health of Older Adults-Evidence from Older Adults in China.
The metabolome as a biomarker of aging in Drosophila melanogaster.
Methionine Restriction Improves Gut Barrier Function by Reshaping Diurnal Rhythms of Inflammation-Related Microbes in Aged Mice.
Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.
Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation.
Multidisciplinary Approach to Older Adults with Hematologic Malignancies-a Paradigm Shift.
The Role of Sphingolipids Metabolism in Cancer Drug Resistance.
Age and Ageing journal 50th anniversary commentary seriesWhy illness is more important than disease in old age.

Blood Cancer Discov. 2021 May;2(3): 192-194

Toward More Complete Prognostication for Patients with Clonal Hematopoiesis.

Barbara Spitzer, Ross L Levine.

The study of clonal hematopoiesis is rapidly evolving, with the highest prevalence in aging populations and wide-ranging implications for health and disease, including an increased risk of subsequent myeloid malignancies and cardiovascular disease. In their article, Feusier and colleagues report on an expanded driver mutation list for capture of higher-risk clonal hematopoiesis mutations implicated in leukemia transformation. They also describe the prevalence of clonal hematopoiesis in several additional large studies, including, most importantly, in the pediatric context, which has not yet been extensively studied with respect to clonal hematopoiesis and clonal hematopoiesis-related sequelae.See related article by Feusier et al., p. 226.

DOI: https://doi.org/10.1158/2643-3230.BCD-21-0025
Clin Rev Allergy Immunol. 2022 Jan 15.

Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases.

Augusto Bleve, Francesca Motta, Barbara Durante, Chiara Pandolfo, Carlo Selmi, Antonio Sica.

  The immune system is the central regulator of tissue homeostasis, ensuring tissue regeneration and protection against both pathogens and the neoformation of cancer cells. Its proper functioning requires homeostatic properties, which are maintained by an adequate balance of myeloid and lymphoid responses. Aging progressively undermines this ability and compromises the correct activation of immune responses, as well as the resolution of the inflammatory response. A subclinical syndrome of "homeostatic frailty" appears as a distinctive trait of the elderly, which predisposes to immune debilitation and chronic low-grade inflammation (inflammaging), causing the uncontrolled development of chronic and degenerative diseases. The innate immune compartment, in particular, undergoes to a sequela of age-dependent functional alterations, encompassing steps of myeloid progenitor differentiation and altered responses to endogenous and exogenous threats. Here, we will review the age-dependent evolution of myeloid populations, as well as their impact on frailty and diseases of the elderly.

Keywords:  Age-related disease; Frailty; Immunosenescence; Inflammaging; Myeloid cells

DOI:  https://doi.org/10.1007/s12016-021-08909-7
Plant Foods Hum Nutr. 2022 Jan 13.

Dietary Phytochemicals that Can Extend Longevity by Regulation of Metabolism.

Jie Shen, Jianying Shan, Lichao Zhong, Boying Liang, Dake Zhang, Motao Li, Hao Tang.

  Diet provides energy and nutrition for human survival, and also provides various joy of taste. Extensive studies have shown that the major components of diet, such as protein, carbohydrate and fat, play important roles in regulating aging and longevity. Whether other dietary ingredients can help prevent aging and extend longevity is a very interesting question. Here based on recent findings, we discussed dietary plant ingredients that can extend longevity by regulation of metabolism, targeting TRP channels, mitophagy, senescence pathways and circadian rhythms. Better understanding of the detailed effects and mechanisms of dietary ingredients on longevity regulation, would be helpful for developing new intervention tools for preventing aging and aging related diseases.

Keywords:  Aging; Capsaicin; Fisetin; Metabolism; Nobiletin; Phytochemical; Urolithin a

DOI:  https://doi.org/10.1007/s11130-021-00946-z
Sci Rep. 2022 Jan 12. 12(1): 577

Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV.

Swiss HIV Cohort Study

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.

DOI: https://doi.org/10.1038/s41598-021-04308-2
Stem Cell Rev Rep. 2022 Jan 09.

The Mechanism of Stem Cell Aging.

Liangyu Mi, Junping Hu, Na Li, Jinfang Gao, Rongxiu Huo, Xinyue Peng, Na Zhang, Ying Liu, Hanxi Zhao, Ruiling Liu, Liyun Zhang, Ke Xu.

  Stem cells have self-renewal ability and multi-directional differentiation potential. They have tissue repair capabilities and are essential for maintaining the tissue homeostasis. The depletion of stem cells is closely related to the occurrence of body aging and aging-related diseases. Therefore, revealing the molecular mechanisms of stem cell aging will set new directions for the therapeutic application of stem cells, the study of aging mechanisms, and the prevention and treatment of aging-related diseases. This review comprehensively describes the molecular mechanisms related to stem cell aging and provides the basis for further investigations aimed at developing new anti-stem cell aging strategies and promoting the clinical application of stem cells.

Keywords:  Aging; Epigenetics; Perception associated secret types; Senescence; Stem cell

DOI:  https://doi.org/10.1007/s12015-021-10317-5
Clin Nutr. 2022 Jan 06. pii: S0261-5614(22)00002-4. [Epub ahead of print]41(2): 552-559

Long-term consumption of a mediterranean diet or a low-fat diet on kidney function in coronary heart disease patients: The CORDIOPREV randomized controlled trial.

Alicia Podadera-Herreros, Juan F Alcala-Diaz, Francisco M Gutierrez-Mariscal, Jose Jimenez-Torres, Silvia de la Cruz-Ares, Antonio P Arenas-de Larriva, Magdalena P Cardelo, Jose D Torres-Peña, Raul M Luque, Jose M Ordovas, Javier Delgado-Lista, Jose Lopez-Miranda, Elena M Yubero-Serrano.

   BACKGROUND & AIMS: Lifestyle and dietary habits influence kidney function, playing an important role in the prevention and development of chronic kidney disease (CKD). The effectiveness of the Mediterranean diet in preserving kidney function has been seen in primary prevention. However, no scientific evidence is currently available to determine which dietary pattern is more effective in the management of CKD in secondary cardiovascular disease prevention. Thus, our aim was to evaluate the efficacy of the long-term consumption of two healthy dietary patterns (a Mediterranean diet rich in extra-virgin olive oil (EVOO) compared to a low-fat diet rich in complex carbohydrates) in preserving kidney function in coronary heart disease (CHD) patients.
METHODS: CHD patients (n = 1002) from the CORDIOPREV study were randomized to follow a Mediterranean diet (35% fat, 22% MUFA, <50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, >55% carbohydrates). Kidney function was assessed by the determination of serum creatinine-based estimated glomerular filtration rate (eGFR) at baseline and after 5-years of dietary intervention. Patients were classified according to their type 2 diabetes (T2DM) status, using baseline eGFR (normal eGFR: ≥ 90 mL/min/1.73 m2; mildly-impaired eGFR: 60 to <90 mL/min/1.73 m2, severely-impaired eGFR: <60 mL/min/1.73 m2) to evaluate its influence on the progression of kidney function. Multiple linear regression analysis were performed to determine the contribution of different clinical and anthropometric parameters to changes in eGFR.
RESULTS: Although eGFR declined after both dietary interventions compared to baseline (all p < 0.001), the Mediterranean diet produced a lower decline of eGFR compared to the low-fat diet in patients with T2DM (p = 0.040). This effect was also observed when the overall population was considered (p = 0.033). No significant differences were observed in eGFR between the two diets in non-T2DM patients. In addition, this differential effect of the Mediterranean diet was mainly observed in patients with mildly-impaired eGFR in which this diet slowed eGFR progression (p = 0.002).
CONCLUSIONS: The long-term consumption of a Mediterranean diet rich in EVOO, when compared to a low-fat diet, may preserve kidney function, as shown by a reduced decline in eGFR in CHD patients with T2DM. Patients with mildly-impaired eGFR may benefit more from the beneficial effect of the consumption of the Mediterranean diet in preserving kidney function. These findings reinforce the clinical benefits of the Mediterranean diet in the context of secondary cardiovascular disease prevention.
CLINICAL TRIAL REGISTRATION: URL, http://www.cordioprev.es/index.php/en. Clinicaltrials.gov number, NCT00924937.

Keywords:  Coronary heart disease; Dietary intervention; Kidney function; Lifestyle; Mediterranean diet; Secondary prevention

DOI:  https://doi.org/10.1016/j.clnu.2021.12.041
PLoS Comput Biol. 2022 Jan 10. 18(1): e1009746

Interpretable machine learning for high-dimensional trajectories of aging health.

Spencer Farrell, Arnold Mitnitski, Kenneth Rockwood, Andrew D Rutenberg.

We have built a computational model for individual aging trajectories of health and survival, which contains physical, functional, and biological variables, and is conditioned on demographic, lifestyle, and medical background information. We combine techniques of modern machine learning with an interpretable interaction network, where health variables are coupled by explicit pair-wise interactions within a stochastic dynamical system. Our dynamic joint interpretable network (DJIN) model is scalable to large longitudinal data sets, is predictive of individual high-dimensional health trajectories and survival from baseline health states, and infers an interpretable network of directed interactions between the health variables. The network identifies plausible physiological connections between health variables as well as clusters of strongly connected health variables. We use English Longitudinal Study of Aging (ELSA) data to train our model and show that it performs better than multiple dedicated linear models for health outcomes and survival. We compare our model with flexible lower-dimensional latent-space models to explore the dimensionality required to accurately model aging health outcomes. Our DJIN model can be used to generate synthetic individuals that age realistically, to impute missing data, and to simulate future aging outcomes given arbitrary initial health states.

DOI: https://doi.org/10.1371/journal.pcbi.1009746
Nutrients. 2021 Dec 27. pii: 101. [Epub ahead of print]14(1):

Age-Dependent Decline of NAD+-Universal Truth or Confounded Consensus?

Augusto Peluso, Mads V Damgaard, Marcelo A S Mori, Jonas T Treebak.

  Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

Keywords:  C. elegans; NAD+; aging; human; monkey; mouse; rat; yeast

DOI:  https://doi.org/10.3390/nu14010101
J Geriatr Oncol. 2022 Jan 05. pii: S1879-4068(21)00648-2. [Epub ahead of print]

The association of polypharmacy with functional status impairments, frailty, and health-related quality of life in older adults with gastrointestinal malignancy - Results from the Cancer and Aging Resilience Evaluation (CARE) registry.

Darryl Outlaw, Chen Dai, Mustafa Al-Obaidi, Christian Harmon, Smith Giri, Smita Bhatia, Grant R Williams.

   OBJECTIVES: Polypharmacy is a common problem among older adults that can complicate cancer care and outcomes. Our objective was to examine the prevalence of polypharmacy and its potential association with functional status impairments, frailty, and health-related quality of life (HRQoL) in older adults with gastrointestinal (GI) malignancy.
METHODS: The Cancer and Aging Resilience Evaluation (CARE) registry is an ongoing prospective cohort study that uses a patient-reported geriatric assessment (GA) in older adults with cancer. For this cross-sectional analysis, we focused on older adults with GI malignancy that completed the GA prior to starting systemic cancer therapy. Polypharmacy was defined as patients reporting the use of ≥9 daily medications at their first visit to the medical oncology clinic. Using multivariable analyses, we examined the association of polypharmacy with functional status limitations, frailty, and HRQoL.
RESULTS: 357 patients were included in our analysis, with a mean age of 70.1 years. 24.1% of patients reported taking ≥9 medications. In multivariable analyses adjusted for age, sex, race, cancer type, cancer stage, and medical comorbid conditions, patients taking ≥9 medications were more likely to report limitations in activities of daily living (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI] 1.72-6.29) and instrumental activities of daily living (aOR 2.86, 95% CI 1.59-5.14), have a higher prevalence of frailty (aOR 3.06, 95% CI 1.73-5.41), and report lower physical HRQoL (aOR 2.82, 95% CI 1.70-4.69) and mental HRQoL (aOR 1.73, 95% CI 1.03-2.91).
CONCLUSIONS: Older adults with GI malignancy taking ≥9 medications prior to cancer therapy were more likely to report functional status limitations, frailty, and reduced HRQoL, independent of the presence of medical comorbid conditions.

Keywords:  Aging; Cancer; Geriatric assessment; Geriatric oncology; Polypharmacy

DOI:  https://doi.org/10.1016/j.jgo.2021.12.010
Bone Marrow Transplant. 2022 Jan 13.

Clonal evolution in patients developing therapy-related myeloid neoplasms following autologous stem cell transplantation.

Johannes Frasez Soerensen, Anni Aggerholm, Carina Agerbo Rosenberg, Marie Bill, Gitte Birk Kerndrup, Lene Hyldahl Ebbesen, Marcus Høy Hansen, Anne Stidsholt Roug, Maja Ludvigsen.

Clonal hematopoiesis (CH) denotes somatic mutations in genes related to myeloid neoplasms present at any variant allele frequency (VAF). Clonal hematopoiesis is associated with increasing age and with a factor 6 increase in the risk of developing therapy-related myeloid neoplasms (tMNs) following autologous stem cell transplantation (ASCT). However, the impact of specific mutations on progression from CH to tMN has yet to be unraveled, and it remains unclear whether mutations directly impact or even drive the development of tMN. We performed deep sequencing in longitudinal samples from a cohort of 12 patients with either multiple myeloma or lymphoma who developed tMN following ASCT. Nine patients had one or more mutations that could be tracked longitudinally. Seven patients had clonal expansion from time of ASCT to diagnosis of tMN. Of these, six patients had CH at VAF < 2% at baseline. The median VAF of non-DNMT3A clones increased from 1% (IQR 0.7%-10.0%) at time of ASCT to 37% (IQR 17%-47%) at tMN diagnosis (P = 0.002), while DNMT3A clones showed quiescent trajectories (P = 0.625). Our data provide evidence to support the hypothesis that the development of tMN following ASCT is likely instigated by CH present at VAFs as low as 0.5%, detectable years before tMN onset.

DOI: https://doi.org/10.1038/s41409-022-01567-z
Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01710-1. [Epub ahead of print]38(2): 110206

NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.

Rendan Yang, Yamei Li, Yanli Wang, Jingjing Zhang, Qijing Fan, Jianlin Tan, Weizhen Li, Xiaoju Zou, Bin Liang.

  Mitochondria are known as the powerhouse of the cell. Dysfunction of mitochondria homeostasis induces the mitochondrial unfolded protein response (UPRmt), altering cellular metabolism. How cells sense the UPRmt to rewire metabolism is largely unknown. Here, we show that inactivation of either the citric/tricarboxylic acid (TCA) cycle enzymes aco-2 or idha-1, which encode aconitase and isocitrate dehydrogenase respectively, leads to citrate accumulation. In Caenorhabditis elegans, both in vitro and in vivo, citrate accumulation consequently triggers the UPRmt and also promotes lipid accumulation. The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression. NHR-80 then upregulates lipogenesis and lipid accumulation, shifting excess citrate for use in lipogenesis and for storage as triacylglycerol in lipid droplets. Inactivation of DVE-1 or NHR-80 fully abolishes the citrate-induced lipid accumulation. Therefore, our work uncovers a DVE-1-NHR-80-lipogenesis axis linking the transmission of the mitochondrial stress signal to lipid metabolism.

Keywords:  citrate; citric/tricarboxylic acid (TCA) cycle; lipid accumulation; mitochondrial unfolded protein response (UPR(mt)); nuclear hormone receptor NHR-80

DOI:  https://doi.org/10.1016/j.celrep.2021.110206
Int J Environ Res Public Health. 2021 Dec 23. pii: 119. [Epub ahead of print]19(1):

The Influence of Pension Mode on the Mental Health of Older Adults-Evidence from Older Adults in China.

Liqing Li, Luyao Yu.

  Successful aging is achieved throughout the life course, and successful aging groups tend to have good psychosocial and physical conditions and are active in social activities. With increasing age, the mental health problems of older adults have become increasingly prominent, and the choice of pension mode is closely related to the mental health of older adults. Starting from the psychological level of the older adult, this paper used data from the 2018 Chinese Longitudinal Healthy Longevity Survey to study the impact of three pension methods on the mental health of older adults. The study found that, at present, there are three types of pension modes in China: living alone, family pension, and institutional care, and family pensions are still the mainstream pension mode. Older adults with deeper negative feelings are more inclined to family pensions than to live alone, but the spiritual comfort provided by family members does not improve the negative feelings of older adults. Institutional care deepens the negative feeling and reduces the positive feeling of older adults. In addition, retirement or pension and medical insurance, as life security in old age, can effectively reduce the negative feelings of old age and promote positive feelings. In view of the present situation of China's pension mode and the psychological characteristics of the older adults, we should further build a perfect family pension security system, promote the personalized service construction of older adult care institutions, promote applicable aging renovation of existing residential areas, and encourage older adults to engage in healthy exercise.

Keywords:  mental health; old-age care methods; older adult; successful aging

DOI:  https://doi.org/10.3390/ijerph19010119
Aging Cell. 2022 Jan 12. e13548

The metabolome as a biomarker of aging in Drosophila melanogaster.

Xiaqing Zhao, Forrest T Golic, Benjamin R Harrison, Meghna Manoj, Elise V Hoffman, Neta Simon, Richard Johnson, Michael J MacCoss, Lauren M McIntyre, Daniel E L Promislow.

  Many biomarkers have been shown to be associated not only with chronological age but also with functional measures of biological age. In human populations, it is difficult to show whether variation in biological age is truly predictive of life expectancy, as such research would require longitudinal studies over many years, or even decades. We followed adult cohorts of 20 Drosophila Genetic Reference Panel (DGRP) strains chosen to represent the breadth of lifespan variation, obtain estimates of lifespan, baseline mortality, and rate of aging, and associate these parameters with age-specific functional traits including fecundity and climbing activity and with age-specific targeted metabolomic profiles. We show that activity levels and metabolome-wide profiles are strongly associated with age, that numerous individual metabolites show a strong association with lifespan, and that the metabolome provides a biological clock that predicts not only sample age but also future mortality rates and lifespan. This study with 20 genotypes and 87 metabolites, while relatively small in scope, establishes strong proof of principle for the fly as a powerful experimental model to test hypotheses about biomarkers and aging and provides further evidence for the potential value of metabolomic profiles as biomarkers of aging.

Keywords:  aging; biomarker; drosophila; metabolomics; mortality

DOI:  https://doi.org/10.1111/acel.13548
Front Nutr. 2021 ;8 746592

Methionine Restriction Improves Gut Barrier Function by Reshaping Diurnal Rhythms of Inflammation-Related Microbes in Aged Mice.

Bo Ren, Luanfeng Wang, Aiziguli Mulati, Yan Liu, Zhigang Liu, Xuebo Liu.

  Age-related gut barrier dysfunction and dysbiosis of the gut microbiome play crucial roles in human aging. Dietary methionine restriction (MR) has been reported to extend lifespan and reduce the inflammatory response; however, its protective effects on age-related gut barrier dysfunction remain unclear. Accordingly, we focus on the effects of MR on inflammation and gut function. We found a 3-month methionine-restriction reduced inflammatory factors in the serum of aged mice. Moreover, MR reduced gut permeability in aged mice and increased the levels of the tight junction proteins mRNAs, including those of occludin, claudin-1, and zona occludens-1. MR significantly reduced bacterial endotoxin lipopolysaccharide concentration in aged mice serum. By using 16s rRNA sequencing to analyze microbiome diurnal rhythmicity during 24 h, we found MR moderately recovered the cyclical fluctuations of the gut microbiome which was disrupted in aged mice, leading to time-specific enhancement of the abundance of short-chain fatty acid-producing and lifespan-promoting microbes. Moreover, MR dampened the oscillation of inflammation-related TM7-3 and Staphylococcaceae. In conclusion, the effects of MR on the gut barrier were likely related to alleviation of the oscillations of inflammation-related microbes. MR can enable nutritional intervention against age-related gut barrier dysfunction.

Keywords:  aging; gut barrier; inflammation; methionine restriction; microbiome diurnal rhythmicity

DOI:  https://doi.org/10.3389/fnut.2021.746592
JAMA. 2022 Jan 10.

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Avishay Spitzer, Yoel Angel, Or Marudi, David Zeltser, Esther Saiag, Hanoch Goldshmidt, Ilana Goldiner, Moshe Stark, Ora Halutz, Ronni Gamzu, Marina Slobodkin, Nadav Amrami, Eugene Feigin, Meital Elbaz, Moran Furman, Yotam Bronstein, Amanda Chikly, Anna Eshkol, Victoria Furer, Talia Mayer, Suzy Meijer, Ariel Melloul, Michal Mizrahi, Michal Yakubovsky, Dana Rosenberg, Ari Safir, Liron Spitzer, Eyal Taleb, Ori Elkayam, Adi Silberman, Tali Eviatar, Ofir Elalouf, Tal Levinson, Katia Pozyuchenko, Ayelet Itzhaki-Alfia, Eli Sprecher, Ronen Ben-Ami, Oryan Henig.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers.
Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2.
Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status.
Exposures: Vaccination with a booster dose of BNT162b2 vaccine.
Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction.
Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20).
Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

DOI: https://doi.org/10.1001/jama.2021.23641
Cells. 2021 Dec 22. pii: 18. [Epub ahead of print]11(1):

Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation.

Sreepadaarchana Munjuluri, Dru A Wilkerson, Gagandeep Sooch, Xingjuan Chen, Fletcher A White, Alexander G Obukhov.

  Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000-9000 years. The fruits of Capsicum plants, such as chili pepper, have been long recognized for their high nutritional value. Additionally, capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties. However, a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessary high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions. This review focuses on vascular TRPV1 channels that are endogenously expressed in both vascular smooth muscle and endothelial cells and emphasizes the role of inflammation in sensitizing the TRPV1 channel to capsaicin activation. Tilting the balance between the beneficial vasodilatory action of capsaicin and its unwanted vasoconstrictive effects may precipitate adverse outcomes such as vasospasm and myocardial infarction, especially in the presence of proinflammatory mediators.

Keywords:  TRPV1; capsaicin; cardiovascular disease

DOI:  https://doi.org/10.3390/cells11010018
Curr Hematol Malig Rep. 2022 Jan 13.

Multidisciplinary Approach to Older Adults with Hematologic Malignancies-a Paradigm Shift.

Sarah A Wall, Erin Stevens, Jennifer Vaughn, Naresh Bumma, Ashley E Rosko, Uma Borate.

  Hematologic malignancies are most likely to present in the seventh and eighth decades of life. Continued population growth will lead to increasing numbers of older adults with hematologic malignancies. Oncology care for older adults is complex and must account for the effect of aging on disease biology and treatment tolerance. Multidisciplinary oncology care has been utilized in solid tumor oncology for decades, initially driven by the need for multi-modality treatment. In this review, we make the case for multidisciplinary oncogeriatric care for older adults with hematologic malignancies in order to best navigate the intersection of aging and blood cancer.

Keywords:  Geriatric Oncolog; Hematology; Multidisciplinary

DOI:  https://doi.org/10.1007/s11899-021-00646-0
Front Oncol. 2021 ;11 807636

The Role of Sphingolipids Metabolism in Cancer Drug Resistance.

Marina Bataller, Almudena Sánchez-García, Yoelsis Garcia-Mayea, Cristina Mir, Isabel Rodriguez, Matilde Esther LLeonart.

  Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer therapy, this review focuses on the main enzymes implicated in sphingolipids metabolism and their intermediate metabolites involved in cancer drug resistance.

Keywords:  acid ceramidase (AC); cancer; glucosylceramide synthase (GCS); shingolipids; sphingomyelinase (SMase); sphingosine kinase 1 (SPHK1)

DOI:  https://doi.org/10.3389/fonc.2021.807636
Age Ageing. 2022 Jan 10. pii: afab267. [Epub ahead of print]

Age and Ageing journal 50th anniversary commentary seriesWhy illness is more important than disease in old age.

Marcel G M Olde Rikkert, René J F Melis, Alan A Cohen, G M E E Geeske Peeters.

  Clinical reasoning and research in modern geriatrics often prioritises the disease concept. This is understandable as it has brought impressive advances in medicine (e.g. antibiotics, vaccines, successful cancer treatment and many effective surgeries). However, so far the disease framework has not succeeded in getting us to root causes of many age-related chronic diseases (e.g. Alzheimer's disease, diabetes, osteoarthritis). Moreover, in aging and disease constructs alone fail to explain the variability in illness presentations. Therefore, we propose to apply the underused illness concept in a new way by reconsidering the importance of common symptoms in the form of a dynamic network of symptoms as a complementary framework. We show that concepts and methods of complex system thinking now enable to fruitfully monitor and analyse the multiple interactions between symptoms in such in networks, offering new routes for prognosis and treatment. Moreover, close attention to the symptoms that bother older persons may also improve weighing the therapeutic objectives of well-being and survival and aligning treatment targets with the patients' priorities.

Keywords:  complexity; illness; networks; older people; well-being

DOI:  https://doi.org/10.1093/ageing/afab267