Mammalian cells synthesize and release heterogeneous extracellular vesicles (EVs) which can be generally recognized as subclasses including exosomes, microvesicles (MVs), and apoptotic bodies (ABs), ...each differing in their biogenesis, composition and biological functions from others. EVs can originate from normal or cancer cells, transfer bioactive cargoes to both adjacent and distant sites, and orchestrate multiple key pathophysiological events such as carcinogenesis and malignant progression. Emerging as key messengers that mediate intercellular communications, EVs are being paid substantial attention in various disciplines including but not limited to cancer biology and immunology. Increasing lines of research advances have revealed the critical role of EVs in the establishment and maintenance of the tumor microenvironment (TME), including sustaining cell proliferation, evading growth suppression, resisting cell death, acquiring genomic instability and reprogramming stromal cell lineages, together contributing to the generation of a functionally remodeled TME. In this article, we present updates on major topics that document how EVs are implicated in proliferative expansion of cancer cells, promotion of drug resistance, reprogramming of metabolic activity, enhancement of metastatic potential, induction of angiogenesis, and escape from immune surveillance. Appropriate and insightful understanding of EVs and their contribution to cancer progression can lead to new avenues in the prevention, diagnosis and treatment of human malignancies in future medicine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aging is a major risk factor for numerous human pathologies, including cardiovascular, metabolic, musculoskeletal, and neurodegenerative conditions and various malignancies. While our understanding ...of aging is far from complete, recent advances suggest that targeting fundamental aging processes can delay, prevent, or alleviate age-related disorders. Cellular senescence is physiologically beneficial in several contexts, but it has causal roles in multiple chronic diseases. New studies have illustrated the promising feasibility and safety to selectively ablate senescent cells from tissues, a therapeutic modality that holds potential for treating multiple chronic pathologies and extending human healthspan. Here, we review molecular links between cellular senescence and age-associated complications and highlight novel therapeutic avenues that may be exploited to target senescent cells in future geriatric medicine.
Aging is the largest risk factor for most pathologies, ranging from cancer to neurodegenerative disorders.Senescent cells accumulate in organs during aging, promote tissue dysfunction, and cause pathological manifestations, with senescence as a defining feature of myriad aging-related diseases.Senescent cells display hallmark features, including the senescence-associated secretory phenotype (SASP), a major driver of pathologies, and alterations to the structure and function of organelles.Targeted elimination of senescent cells has emerged as a promising therapeutic solution to ameliorate tissue damage and promote repair and regeneration.In the scope of clinical medicine, advances that identify key biochemical pathways, specifically those differentiating senescent cells from their proliferating counterparts, would positively affect pathological and aging processes.
Cellular Senescence: The Sought or the Unwanted? Sun, Yu; Coppé, Jean-Philippe; Lam, Eric W.-F.
Trends in molecular medicine,
October 2018, 2018-10-00, Letnik:
24, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Cellular senescence is a process that results in irreversible cell-cycle arrest, and is thought to be an autonomous tumor-suppressor mechanism. During senescence, cells develop distinctive metabolic ...and signaling features, together referred to as the senescence-associated secretory phenotype (SASP). The SASP is implicated in several aging-related pathologies, including various malignancies. Accumulating evidence argues that cellular senescence acts as a double-edged sword in human cancer, and new agents and innovative strategies to tackle senescent cells are in development pipelines to counter the adverse effects of cellular senescence in the clinic. We focus on recent discoveries in senescence research and SASP biology, and highlight the potential of SASP suppression and senescent cell clearance in advancing precision medicine.
Cellular senescence is a highly conserved stress response that restrains the proliferation of cells at risk of oncogenic transformation.
Senescent cells spatially occupy tissue environmental niches and elaborate numerous extracellular factors encoded by the SASP, contributing to aging-related disorders, notably cancer.
In the tumor microenvironment, senescent cells can drive events that support malignant progression, including but not limited to therapeutic resistance, disease relapse, and distant metastasis.
In cancer clinics, the abundance of senescent cells can serve as a ‘molecular’ marker that predicts adverse outcomes, while senescent cell clearance significantly mitigates pathological exacerbation.
A new class of agents, termed senolytics, has been shown to be effective in extending healthspan, reducing frailty and improving stem cell function in animal models of aging.
The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular ...signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine.
Head and neck cancer is one of the most prevalent cancers around the world. Head and neck squamous cell carcinoma (HNSCC) accounts for nearly 90% of head and neck cancer. In recent years, significant ...advances have been made in immunotherapy for HNSCC. Although some clinical trials targeting immune checkpoints have shown success, the molecular mechanism for regulation of programmed death 1 (PD-1) and its ligand (PD-L1) is partially understood. In an effort to explore the effect of activation of signal transducers and activators of transcriptions (STAT3) on PD-1/PD-L1, the expression and correlation between phosphorylation of STAT3 and PD-1/PD-L1 were determined with immunostaining of human and mouse HNSCC tissue sections. PD-1/PD-L1 overexpression was found to be significantly associated with p-STAT3 in human and mouse HNSCC. Targeting STAT3 by a small molecule effectively inhibited the expression of PD-L1 in the CAL27 cell line. Furthermore, we found that blockade of STAT3 signaling downregulated PD-1/PD-L1 in a Tgfbr1/Pten 2cKO HNSCC mouse model. These findings suggest that STAT3 signaling plays an important role in PD-1/PD-L1 regulation and the antitumor immune response of HNSCC.
Lasing is observed from carbon nanodots (C‐dots) dispersed into a layer of poly(ethylene glycol) coated on the surface of optical fibers under 266 nm optical excitation. This is due to the ...enhancement of photoluminescence intensity via the esterification of carboxylic groups of the C‐dots, and the formation of high‐Q cylindrical microcavities to support second‐type whispering gallery modes.
•A new ventilated Trombe wall with PCM and active cooling/heating system is proposed.•ESRE is proposed, defined, and calculated for evaluating effectiveness of PCMs-VTW.•Both PCM transition ...temperature and thickness are discussed based on ESRE.•Overheating and supercooling of exterior PCM are mitigated by implementing coatings.
This study evaluated the thermal performance of a new ventilated Trombe wall integrated with phase change materials (PCMs-VTW) in a building in hot summer and cold winter region of China. The Trombe wall was constituted of double PCM wallboards, consisting: an exterior PCM wallboard with a high absorptivity/reflective coating and an interior PCM wallboard fitted with active hot/chilled water pipes. A numerical model using a heat-source transitioning method was developed to characterize the heat transfer mechanism of both PCM wallboards. The concept of energy storage and release efficiency (ESRE) has been defined and calculated to illustrate the potential of the new system for energy saving during both cooling and heating periods. Our findings show that the overheating and super-cooling problems could be mitigated by the use of either a high-reflective or high-absorptive coating on the exterior PCM wallboard depending on local climate, such as solar air temperature and radiation, achieving a 10% enhancement in ESRE in summer and 13% in winter. The optimum melting temperatures of exterior and interior PCM were 26 K and 22 K respectively in terms of ESRE enhancement, under which maximum values of ESRE: 16.8%/18.9% for exterior/interior PCM in summer and 23%/18.2% for exterior/interior PCM in winter, were achieved. Optimum thicknesses for exterior and interior PCM were 8 mm and 28 mm, resulting in 20.2% average ESRE for exterior PCM and 20.25% for interior PCM.
Summary
In a cohort of 393 Chinese women, by using high-resolution peripheral quantitative computed tomography (HR-pQCT), we found that significant cortical bone loss occurred after midlife. ...Prominent increase in cortical porosity began at the fifth decade but reached a plateau before the sixth decade. Trabecular bone loss was already evident in young adulthood and continued throughout life.
Introduction
This study aimed to investigate age-related differences in volumetric bone mineral density (vBMD), microarchitecture, and estimated bone strength at peripheral skeleton in Chinese female population.
Methods
In a cross-sectional cohort of 393 Chinese women aged 20–90 years, we obtained vBMD, microarchtecture, and micro-finite element-derived bone strength at distal radius and tibia using HR-pQCT.
Results
The largest predictive age-related difference was found for cortical porosity (Ct.Po) which showed over four-fold and two-fold differences at distal radius and tibia, respectively, over the adulthood. At both sites, cortical bone area, vBMD, and thickness showed significant quadratic association with age with significant decrease beginning after midlife. Change of Ct.Po became more prominent between age of 50 and 57 (0.26 %/year at distal radius, 0.54 %/year at distal tibia, both
p
≤ 0.001) but thereafter, reached a plateau (0.015 and 0.028 %/year, both
p
> 0.05). In contrast, trabecular vBMD and microarchitecture showed linear association with age with significant deterioration observed throughout adulthood. Estimated age of peak was around age of 20 for trabecular vBMD and microarchitecture and Ct.Po and age of 40 for cortical vBMD and microarchitecture. Estimated stiffness and failure load peaked at mid-30s at the distal radius and at age 20 at distal tibia.
Conclusions
Age-related differences in vBMD and microarchitecture in Chinese women differed by bone compartments. Significant cortical bone loss occurred after midlife. Prominent increase in Ct.Po began at the fifth decade but appeared to be arrested before the sixth decade. Loss of trabecular bone was already evident in young adulthood and continued throughout life.
Chemotherapy and radiation not only trigger cancer cell apoptosis but also damage stromal cells in the tumour microenvironment (TME), inducing a senescence-associated secretory phenotype (SASP) ...characterized by chronic secretion of diverse soluble factors. Here we report serine protease inhibitor Kazal type I (SPINK1), a SASP factor produced in human stromal cells after genotoxic treatment. DNA damage causes SPINK1 expression by engaging NF-κB and C/EBP, while paracrine SPINK1 promotes cancer cell aggressiveness particularly chemoresistance. Strikingly, SPINK1 reprograms the expression profile of cancer cells, causing prominent epithelial-endothelial transition (EET), a phenotypic switch mediated by EGFR signaling but hitherto rarely reported for a SASP factor. In vivo, SPINK1 is expressed in the stroma of solid tumours and is routinely detectable in peripheral blood of cancer patients after chemotherapy. Our study substantiates SPINK1 as both a targetable SASP factor and a novel noninvasive biomarker of therapeutically damaged TME for disease control and clinical surveillance.
The B.1.1.529/Omicron variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally
. It is expected to become ...dominant in the coming weeks
, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations
that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies
. This concern is amplified by the findings of our study. Here we found that B.1.1.529 is markedly resistant to neutralization by serum not only from patients who recovered from COVID-19, but also from individuals who were vaccinated with one of the four widely used COVID-19 vaccines. Even serum from individuals who were vaccinated and received a booster dose of mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies against all known epitope clusters on the spike protein, we noted that the activity of 17 out of the 19 antibodies tested were either abolished or impaired, including ones that are currently authorized or approved for use in patients. Moreover, we also identified four new spike mutations (S371L, N440K, G446S and Q493R) that confer greater antibody resistance on B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.
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