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Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Advancing age is a major risk factor for developing cardiovascular disease because of the lifelong exposure to cardiovascular risk factors and specific alterations affecting the heart and the vasculature during ageing. Indeed, the ageing heart is characterized by structural and functional changes that are caused by alterations in fundamental cardiomyocyte functions. In particular, the myocardium is heavily dependent on mitochondrial oxidative metabolism and is especially susceptible to mitochondrial dysfunction. Indeed, primary alterations in mitochondrial function, which are subsequently amplified by defective quality control mechanisms, are considered to be major contributing factors to cardiac senescence. In this Review, we discuss the mechanisms linking defective mitochondrial quality control mechanisms (that is, proteostasis, biogenesis, dynamics, and autophagy) to organelle dysfunction in the context of cardiac ageing. We also illustrate relevant molecular pathways that might be exploited for the prevention and treatment of age-related heart dysfunction.

Purpose To evaluate the impact of molecular subtype on incidence and prognosis of brain metastasis from breast cancer. Methods The Surveillance, Epidemiology, and End Results (SEER) 18 registry was used to select breast cancer patients from 2010 to 2014. Molecular subtypes were classified as luminal A (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), luminal B (HR+/HER2+), HER2 (HR-/HER2+), or triple negative breast cancer (TNBC) (HR-/HER2-). The incidence and prognosis of brain metastasis was evaluated according to molecular subtype. Results Among the 206913 breast cancer patients, the HER2 subtype showed the highest incidence of brain metastasis (1.0%). HER2 and TNBC with multiple extracranial metastases (bone, liver, and lung) showed a high incidence of brain metastasis (28.0 and 30.8%, respectively). Median survival of luminal A, luminal B, HER2, and TNBC in brain metastasis was 12, 23, 10, and 6 months ( p  < 0.001), and in brain metastasis without visceral metastasis was 14, 34, 17, and 8 months ( p  < 0.001). On multivariate analysis, the order of subtype by favorable prognosis was luminal B, luminal A, HER2, and TNBC in all brain metastasis, while for brain metastasis patients without visceral metastasis, the order was luminal B, HER2, luminal A, and TNBC. Conclusions Molecular subtype and visceral metastasis should be considered for prediction of prognosis for patients with brain metastasis. The patients with HER2 and TNBC cancer subtypes having visceral metastasis, close surveillance could contribute to early detection of brain metastasis and may putatively lead to improved quality of life and survival.

Compared with open resection, laparoscopic resection of rectal cancers is associated with improved short-term outcomes, but high-level evidence showing similar long-term outcomes is scarce. We aimed to compare survival outcomes of laparoscopic surgery with open surgery for patients with mid-rectal or low-rectal cancer. The Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was an open-label, non-inferiority, randomised controlled trial done between April 4, 2006, and Aug 26, 2009, at three centres in Korea. Patients (aged 18–80 years) with cT3N0–2M0 mid-rectal or low-rectal cancer who had received preoperative chemoradiotherapy were randomly assigned (1:1) to receive either open or laparoscopic surgery. Randomisation was stratified by sex and preoperative chemotherapy regimen. Investigators were masked to the randomisation sequence; patients and clinicians were not masked to the treatment assignments. The primary endpoint was 3 year disease-free survival, with a non-inferiority margin of 15%. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00470951. We randomly assigned 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170). 3 year disease-free survival was 72·5% (95% CI 65·0–78·6) for the open surgery group and 79·2% (72·3–84·6) for the laparoscopic surgery group, with a difference that was lower than the prespecified non-inferiority margin (–6·7%, 95% CI −15·8 to 2·4; p<0·0001). 25 (15%) patients died in the open group and 20 (12%) died in the laparoscopic group. No deaths were treatment related. Our results show that laparoscopic resection for locally advanced rectal cancer after preoperative chemoradiotherapy provides similar outcomes for disease-free survival as open resection, thus justifying its use. National Cancer Center, South Korea.

has complex and intricate interactions with host immune cells. can survive, persist, and grow within macrophages and thereby circumvent detection by the innate immune system. Recently, the field of immunometabolism, which focuses on the link between metabolism and immune function, has provided us with an improved understanding of the role of metabolism in modulating immune function. For example, host immune cells can switch from oxidative phosphorylation to glycolysis in response to infection, a phenomenon known as the Warburg effect. In this state, immune cells are capable of amplifying production of both antimicrobial pro-inflammatory mediators that are critical for the elimination of bacteria. Also, cells undergoing the Warburg effect upregulate production of nitric oxide augment the synthesis of bioactive lipids. In this review, we describe our current understanding of the Warburg effect and discuss its role in promoting host immune responses to . In most settings, immune cells utilize the Warburg effect to promote inflammation and thereby eliminate invading bacteria; interestingly, exploits this effect to promote its own survival. A better understanding of the dynamics of metabolism within immune cells together with the specific features that contribute to the pathogenesis of tuberculosis (TB) may suggest potential host-directed therapeutic targets for promoting clearance of and limiting its survival .

Ischemia/reperfusion (I/R) injury remains a major complication of liver resection, transplantation, and hemorrhagic shock. Although the mechanisms that contribute to hepatic I/R are complex and diverse involving the interaction of cell injury in hepatocytes, immune cells, and endothelium, mitochondrial dysfunction is a cardinal event culminating in hepatic reperfusion injury. Mitochondrial autophagy, so-called mitophagy, is a key cellular process that regulates mitochondrial homeostasis and eliminates damaged mitochondria in a timely manner. Growing evidence accumulates that I/R injury is attributed to defective mitophagy. This review aims to summarize the current understanding of autophagy and its role in hepatic I/R injury and highlight the various therapeutic approaches that have been studied to ameliorate injury.

Although tumour-treating fields (TTFields) is a promising physical treatment modality based on disruption of dipole alignments and generation of dielectrophoretic forces during cytokinesis, not much is known about TTFields-responsive sensitisers. Here, we report a novel TTFields-responsive sensitiser, barium titanate nanoparticles (BTNPs), which exhibit cytocompatibility, with non-cytotoxic effects on breast cancer cells. BTNPs are characterised by high dielectric constant values and ferroelectric properties. Notably, we found that BTNPs sensitised TTFields-resistant breast cancer cells in response to TTFields. In addition, BTNPs accumulated in the cytoplasm of cancer cells in response to TTFields. Further, we showed that TTFields combined with BTNPs exhibited antitumor activity by modulating several cancer-related pathways in general, and the cell cycle-related apoptosis pathway in particular. Therefore, our data suggest that BTNPs increase the antitumor action of TTFields by an electric field-responsive cytosolic accumulation, establishing BTNP as a TTFields-responsive sensitiser.

Background To develop and compare delta-radiomics signatures from 2- (2D) and 3-dimensional (3D) features that predict treatment outcomes following preoperative chemoradiotherapy (CCRT) and surgery for locally advanced rectal cancer. Methods In total, 101 patients (training cohort, n  = 67; validation cohort, n  = 34) with locally advanced rectal adenocarcinoma between 2008 and 2015 were included. We extracted 55 features from T2-weighted magnetic resonance imaging (MRI) scans. Delta-radiomics feature was defined as the difference in radiomics feature before and after CCRT. Signatures were developed to predict local recurrence (LR), distant metastasis (DM), and disease-free survival (DFS) from 2D and 3D features. The least absolute shrinkage and selection operator regression was used to select features and build signatures. The delta-radiomics signatures and clinical factors were integrated into Cox regression analysis to determine if the signatures were independent prognostic factors. Results The radiomics signatures for LR, DM, and DFS were developed and validated using both 2D and 3D features. Outcomes were significantly different in the low- and high-risk patients dichotomized by optimal cutoff in both the training and validation cohorts. In multivariate analysis, the signatures were independent prognostic factors even when considering the clinical parameters. There were no significant differences in C-index from 2D vs. 3D signatures. Conclusions This is the first study to develop delta-radiomics signatures for rectal cancer. The signatures successfully predicted the outcomes and were independent prognostic factors. External validation is warranted to ensure their performance.

Emerging evidence suggests that the mammalian target of rapamcyin (mTOR) pathway is associated with radio-resistance in cancer treatment. We hypothesised that phosphorylated ribosomal S6 kinase 1 (p-S6K1), a major downstream regulator of the mTOR pathway, may play a role in predicting radio-resistance. Therefore, we evaluated the association of p-S6K1 expression with radio-resistance in breast cancer cell lines and patients. During median follow-up of 33 (range, 0.1–111) months for 1770 primary breast cancer patients who underwent surgery, patients expressing p-S6K1 showed worse 10-year loco-regional recurrence-free survival (LRFS) compared to that of p-S6K1-negative patients after radiotherapy (93.4% vs. 97.7%, p  = 0.015). Multivariate analysis revealed p-S6K1 expression as a predictor of radio-resistance (hazard ratio 7.9, 95% confidence interval 1.1–58.5, p  = 0.04). In vitro , CD44 high /CD24 low MCF7 cells with a radioresistant phenotype expressed higher levels of p-S6K1 than control MCF7 cells. Furthermore, the combination of radiation with treatment of everolimus, an mTOR-S6K1 pathway inhibitor, sensitised CD44 high /CD24 low MCF7 cells to a greater extent than MCF7 cells. This study provides in vivo and in vitro evidence for p-S6K1 expression status as an important marker for predicting the resistance to radiotherapy and as a possible target for radio-sensitization in breast cancer patients.

Yes‐associated protein (YAP) is a key oncogenic effector and a well‐established driver of resistance to anticancer therapies, especially in tumors harboring KRAS mutations. Although YAP is clinically relevant, drug‐development efforts that directly inhibit its activity have been limited. Here, we show that basroparib—a selective tankyrase (TNKS) inhibitor that suppresses Wnt signaling—attenuates YAP‐driven oncogenic programs by stabilizing angiomotin (AMOT), an endogenous negative regulator of YAP. In colorectal cancer (CRC) cells, basroparib increased AMOT protein abundance, promoted AMOT–YAP complex formation, and enforced cytoplasmic sequestration of YAP, thereby dampening YAP‐dependent transcription. Basroparib preferentially sensitized YAP‐overexpressing, KRAS‐mutant CRC cell lines to MEK inhibition by inhibiting YAP signaling. In MEK inhibitor‐resistant CRC models, in which elevated YAP activity mediates escape, basroparib restored drug sensitivity both in vitro and in vivo. The compound also enhanced MEK inhibitor efficacy in other YAP‐active tumor types, while exerting minimal effects in YAP‐inactive models. Taken together, these results identify basroparib—now progressing through clinical development (Phase I, NCT04505839)—as a promising agent for dual Wnt–YAP pathway blockade and for overcoming therapeutic resistance in YAP‐driven cancers. Basroparib, a selective tankyrase inhibitor, suppresses Wnt signaling and attenuates YAP‐driven oncogenic programs by stabilizing angiomotin. It promotes AMOT–YAP complex formation, enforces cytoplasmic YAP sequestration, inhibits YAP/TEAD transcription, and sensitizes YAP‐active cancers, including KRAS‐mutant colorectal cancer, to MEK inhibition.

Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest in the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials to evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are currently undergoing. In this review, we summarize the current status of knowledge regarding the changes in CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biological mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.