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.

Aging is characterized by a progressive loss of physiological integrity, while cancer represents one of the primary pathological factors that severely threaten human lifespan and healthspan. In clinical oncology, drug resistance limits the efficacy of most anticancer treatments, and identification of major mechanisms remains a key to solve this challenging issue. Here, we highlight the multifaceted senescence‐associated secretory phenotype (SASP), which comprises numerous soluble factors including amphiregulin (AREG). Production of AREG is triggered by DNA damage to stromal cells, which passively enter senescence in the tumor microenvironment (TME), a process that remarkably enhances cancer malignancy including acquired resistance mediated by EGFR. Furthermore, paracrine AREG induces programmed cell death 1 ligand (PD‐L1) expression in recipient cancer cells and creates an immunosuppressive TME via immune checkpoint activation against cytotoxic lymphocytes. Targeting AREG not only minimized chemoresistance of cancer cells, but also restored immunocompetency when combined with classical chemotherapy in humanized animals. Our study underscores the potential of in vivo SASP in driving the TME‐mediated drug resistance and shaping an immunosuppressive niche, and provides the proof of principle of targeting major SASP factors to improve therapeutic outcome in cancer medicine, the success of which can substantially reduce aging‐related morbidity and mortality.

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.

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.

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Noninvasive positive pressure ventilation is safe for selected patients with acute lung injury. However, a larger randomized trial with need for intubation and mortality as the outcomes of interest is required.

Plant terpene synthases (TPSs) are key enzymes responsible for terpene biosynthesis, and can play important roles in defense against herbivore attack. In rice, the protein sequence of TPS46 was most closely related to maize TPS10. However, unlike maize tps10, tps46 was also constitutively expressed in rice even in the absence of herbivore attack. Potential roles or constitutive emissions of specific volatiles may due to the constitutive expressions of tps46 in rice. Therefore, in the present study, RNA interference (Ri) and overexpression (Oe) rice lines were generated to investigate the potential function of TPS46 in Oryza sativa sp. japonica. Interestingly, the rice plants become more susceptible to Rhopalosiphum padi when expression of tps46 was silenced compared with Wt in greenhouse conditions. Artificial infestation bioassays further confirmed that Ri rice lines were susceptible to R. padi, whereas Oe rice lines were repellent to R. padi. Based on GC-MS and ToF-MS analysis, a total of eight volatile products catalyzed by TPS46 in rice were identified. Among them, only limonene and Eβf could be detected in all the Ri, Oe, and Wt lines, whereas other six volatiles were only found in the blend of volatiles from Oe lines. Moreover, the amount of constitutive limonene and Eβf in the Ri lines was significantly lower than in Wt lines, while the amounts of these two volatiles in the Oe line were obviously higher than in control rice. Our data suggested that the constitutive emissions of Eβf and limonene regulated by the constitutive expression of tps46 may play a crucial role in rice defense against R. padi. Consequently, tps46 could be a potential target gene to be employed for improving the resistance of plants to aphids.

Improving the effectiveness of public health interventions relies as much on the attention paid to their design and feasibility as to their evaluation. Yet, compared to the vast literature on how to evaluate interventions, there is little to guide researchers or practitioners on how best to develop such interventions in practical, logical, evidence based ways to maximise likely effectiveness. Existing models for the development of public health interventions tend to have a strong social-psychological, individual behaviour change orientation and some take years to implement. This paper presents a pragmatic guide to six essential Steps for Quality Intervention Development (6SQuID). The focus is on public health interventions but the model should have wider applicability. Once a problem has been identified as needing intervention, the process of designing an intervention can be broken down into six crucial steps: (1) defining and understanding the problem and its causes; (2) identifying which causal or contextual factors are modifiable: which have the greatest scope for change and who would benefit most; (3) deciding on the mechanisms of change; (4) clarifying how these will be delivered; (5) testing and adapting the intervention; and (6) collecting sufficient evidence of effectiveness to proceed to a rigorous evaluation. If each of these steps is carefully addressed, better use will be made of scarce public resources by avoiding the costly evaluation, or implementation, of unpromising interventions.