Background:Ischemic preconditioning (IPC) is an effective procedure to protect against ischemia/reperfusion (I/R) injury. Hypoxia-inducible factor-1α (Hif-1α) is a key molecule in IPC, and roxadustat ...(RXD), a first-in-class prolyl hydroxylase domain-containing protein inhibitor, has been recently developed to treat anemia in patients with chronic kidney disease. Thus, we investigated whether RXD pretreatment protects against I/R injury.Methods and Results:RXD pretreatment markedly reduced the infarct size and suppressed plasma creatinine kinase activity in a murine I/R model. Analysis of oxygen metabolism showed that RXD could produce ischemic tolerance by shifting metabolism from aerobic to anaerobic respiration.Conclusions:RXD pretreatment may be a novel strategy against I/R injury.
Mitochondrial DNA (mtDNA)-induced myocardial inflammation is intimately involved in cardiac remodeling. ZBP1 (Z-DNA binding protein 1) is a pattern recognition receptor positively regulating ...inflammation in response to mtDNA in inflammatory cells, fibroblasts, and endothelial cells. However, the role of ZBP1 in myocardial inflammation and cardiac remodeling remains unclear. The aim of this study was to elucidate the role of ZBP1 in mtDNA-induced inflammation in cardiomyocytes and failing hearts.
mtDNA was administrated into isolated cardiomyocytes. Myocardial infarctionwas conducted in wild type and ZBP1 knockout mice.
We here found that, unlike in macrophages, ZBP1 knockdown unexpectedly exacerbated mtDNA-induced inflammation such as increases in IL (interleukin)-1β and IL-6, accompanied by increases in RIPK3 (receptor interacting protein kinase 3), phosphorylated NF-κB (nuclear factor-κB), and NLRP3 (nucleotide-binding domain and leucine-rich-repeat family pyrin domain containing 3) in cardiomyocytes. RIPK3 knockdown canceled further increases in phosphorylated NF-κB, NLRP3, IL-1β, and IL-6 by ZBP1 knockdown in cardiomyocytes in response to mtDNA. Furthermore, NF-κB knockdown suppressed such increases in NLRP3, IL-1β, and IL-6 by ZBP1 knockdown in response to mtDNA. CpG-oligodeoxynucleotide, a Toll-like receptor 9 stimulator, increased RIPK3, IL-1β, and IL-6 and ZBP1 knockdown exacerbated them. Dloop, a component of mtDNA, but not
and
, components of nuclear DNA, was increased in cytosolic fraction from noninfarcted region of mouse hearts after myocardial infarction compared with control hearts. Consistent with this change, ZBP1, RIPK3, phosphorylated NF-κB, NLRP3, IL-1β, and IL-6 were increased in failing hearts. ZBP1 knockout mice exacerbated left ventricular dilatation and dysfunction after myocardial infarction, accompanied by further increases in RIPK3, phosphorylated NF-κB, NLRP3, IL-1β, and IL-6. In histological analysis, ZBP1 knockout increased interstitial fibrosis and myocardial apoptosis in failing hearts.
Our study reveals unexpected protective roles of ZBP1 against cardiac remodeling as an endogenous suppressor of mtDNA-induced myocardial inflammation.
Background
Malnutrition is an independent risk factor for postoperative mortality and morbidity in major gastrointestinal surgery. The aim of this study was to investigate the prevalence of ...malnutrition and identify the optimal preoperative nutritional support for preventing postoperative surgical site infections (SSIs) in malnourished gastric cancer patients undergoing gastrectomy.
Methods
We analyzed 800 patients with gastric cancer who underwent gastrectomy. Nutritional risk factors included weight loss >10 % within 6 months, body mass index <18.5 kg/m
2
, Subjective Global Assessment Grade C, and serum albumin <3.0 g/dl. Adequate energy intake was defined as receiving ≥25 kcal/kg ideal body weight per day. Optimal nutritional support was examined in terms of both duration and calorie intake.
Results
Overall, 152 patients (19.0 %) were classified as malnourished. The incidence of SSIs was significantly higher in malnourished patients than in well-nourished patients (35.5 vs. 14.0 %;
p
< 0.0001). The incidence of SSIs in malnourished patients was significantly lower in the well-supported group receiving adequate energy support for at least 10 days than in the poorly-supported group, which received inadequate or no energy support or adequate energy support for <10 days (17.0 vs. 45.4 %;
p
= 0.0006). In multivariate analysis, well-managed nutritional support was identified as an independent factor associated with fewer SSIs (odds ratio 0.14; 95 % confidence interval 0.05–0.37;
p
= 0.0002).
Conclusions
Malnutrition, a risk factor for SSI, was prevalent in gastric cancer patients preoperatively. Well-managed preoperative nutritional support decreased the incidence of postoperative SSIs in malnourished patients.
The Cancer-VTE Registry evaluates the occurrence and management of venous thromboembolism in Japanese participants with major solid tumors. Using Registry data, we evaluated the frequency of ...concurrent venous thromboembolism in cancer patients prior to treatment initiation by cancer type.
The Cancer-VTE Registry is an ongoing (March 2017-September 2020) prospective cohort study using a nationwide, multicentre clinical registry. Participants aged ≥20 years with colorectal, lung, stomach, pancreatic, breast or gynecologic cancer, confirmed staging, ≥6 months life expectancy post-registration and who had undergone venous thromboembolism screening were managed with routine clinical care. Venous thromboembolism frequency at registration was evaluated.
Of 9735 participants, 571 (5.9%) had venous thromboembolism at baseline, including asymptomatic 5.5% (n = 540) and symptomatic venous thromboembolism 0.3% (n = 31). Most participants with venous thromboembolism (n = 506, 5.2%) had deep vein thrombosis only; 65 (0.7%) had pulmonary embolism with/without deep vein thrombosis. The prevalence of distal and proximal deep vein thrombosis was 4.8% (n = 466) and 0.9% (n = 83), respectively. The highest prevalence of venous thromboembolism was for pancreatic cancer (8.5%) and the lowest for breast cancer (2.0%). Venous thromboembolism prevalence increased as cancer stage advanced.
Although there was a marked difference in venous thromboembolism by cancer type, the data suggest that cancer stage is an important risk factor for venous thromboembolism. Thus, metastasis seems a critical risk factor for venous thromboembolism. This is the first demonstration of venous thromboembolism prevalence and risk factors in Japanese cancer patients prior to treatment.
UMIN000024942.
We established a preoperative exercise and nutritional support program for elderly sarcopenic patients with gastric cancer. Twenty-two gastric cancer patients aged 65 years or older with a diagnosis ...of sarcopenia according to the algorithm proposed by the European Working Group on Sarcopenia in Older People received our preoperative program. The median duration of the program participation was 16 days. Total calorie and protein intakes were significantly higher after the program than before 29.4 ± 6.9 kcal/kg ideal body weight (IBW) vs 27.3 ± 5.6 kcal/kg IBW,
p
= 0.049, and 1.3 ± 0.4 g/kg IBW vs 1.1 ± 0.3 g/kg IBW,
p
= 0.0019, respectively. Handgrip strength significantly increased after the program (21.2 ± 5.2 kg vs 20.0 ± 5.3 kg,
p
= 0.022). Likewise, gait speed and skeletal muscle mass index increased, although the differences did not reach statistical significance. Four patients became nonsarcopenic after the program. Postoperative complications were observed in three patients (13.6%); however, none of these complications were severe (Clavien-Dindo grade III or lower). A preoperative exercise and nutritional support program has the potential to reduce sarcopenia and improve postoperative outcome in elderly sarcopenic patients with gastric cancer.
Tumour-Node-Metastasis (TNM) staging of colorectal cancer (CRC) needs further classification for better treatment because of disease heterogeneity. Although molecular classifications which are ...expensive and laborious are under study, cost and labour efficient subtyping is desirable. We assessed the combinations of preoperative tumour marker (TM) elevation and tumour lymphovascular invasion (LVI) as a solution. We used the pooled data of 7151 colon cancer (CC) patients and 4620 rectal cancer (RC) patients who received curative surgery between 2004 and 2008 in Japan. The best-matched subtyping for predicting relapse-free survival (RFS) was statistically selected using the c-index and Akaike's information criterion. This subtyping (TM-LVI), which consisted of three categories by TM elevation status and severity of LVI status, was an independent prognostic factor for RFS of CC (stage IIa, IIIb, and IIIc) and RC (stage I, IIa, IIb, IIIa, and IIIb) and also for disease specific survival of CC (stage IIa, IIb, IIIb, and IIIc) and RC (all stage except for IIc). Although TM-LVI classified CRC patients into low and high recurrence risk groups, the application of adjuvant therapy was not accordance with the TM-LVI status. TM-LVI may be a cost and labour efficient subtyping of colorectal cancer for better treatment strategy.
Induced pluripotent stem cells (iPSCs) can be generated from differentiated human and mouse somatic cells using transcription factors such as Oct4, Sox2, Klf4, and c-Myc. It is possible to augment ...the reprogramming process with chemical compounds, but issues related to low reprogramming efficiencies and, with a number of protocols, residual vector sequences, remain to be resolved. We show here that it is possible to reprogram mouse and human cells to pluripotency by direct transfection of mature double-stranded microRNAs (miRNAs). Our approaches use a combination of mir-200c plus mir-302 s and mir-369 s family miRNAs. Because this reprogramming method does not require vector-based gene transfer, it holds significant potential for biomedical research and regenerative medicine.
► Transfected mature miRNAs can reprogram mouse somatic cells to pluripotency ► A combination of mir-200c plus mir-302 s and mir-369 s family miRNAs is required ► miRNA-generated mi-iPSCs show all characteristics of pluripotency ► The same combination of miRNAs can also reprogram human somatic cells
Background
Malignancy is a secondary cause of sarcopenia, which is associated with impaired cancer treatment outcomes. The aim of this study was to investigate the prevalence of preoperative ...sarcopenia among elderly gastric cancer patients undergoing gastrectomy and the differences in preoperative dietary intake and postoperative complications between sarcopenic and non-sarcopenic patients.
Methods
Ninety-nine patients over 65 years of age who underwent gastrectomy for gastric cancer were analyzed. All patients underwent gait and handgrip strength testing, and whole-body skeletal muscle mass was measured using a bioimpedance analysis technique based on the European Working Group on Sarcopenia in Older People (EWGSOP) algorithm for the evaluation of sarcopenia before surgery. Preoperative dietary intake was assessed using a food frequency questionnaire.
Results
Of these patients, 21 (21.2 %) were diagnosed with sarcopenia. Sarcopenic patients consumed fewer calories and less protein preoperatively (23.9 vs. 27.8 kcal/kg ideal weight/day and 0.86 vs. 1.04 g/kg ideal weight/day;
P
= 0.001 and 0.0005, respectively). Although the overall incidence of postoperative complications was similar in the two groups (57.1 % vs. 35.9 %;
P
= 0.08), the incidence of severe (Clavien–Dindo grade ≥ IIIa) complications was significantly higher in the sarcopenic group than in the non-sarcopenic group (28.6 % vs. 9.0 %;
P
= 0.029). In the multivariate analysis, sarcopenia alone was identified as a risk factor for severe postoperative complications (odds ratio, 4.76; 95 % confidence interval, 1.03–24.30;
P
= 0.046).
Conclusions
Preoperative sarcopenia as defined by the EWGSOP algorithm is a risk factor for severe postoperative complications in elderly gastric cancer patients undergoing gastrectomy.
Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of ...increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF.
Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix-metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared to WT mice.
The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF.
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