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1.
Michala G. Rolver Lya K. K. Holland Muthulakshmi Ponniah Nanditha S. Prasad Jiayi Yao Julie Schnipper Signe Kramer Line Elingaard-Larsen Elena Pedraz-Cuesta Bin Liu Luis A. Pardo Kenji Maeda Albin Sandelin Stine Falsig Pedersen 《International journal of cancer. Journal international du cancer》2023,152(8):1668-1684
The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pHe) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pHe, but not at acidic pHe. Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches. 相似文献
2.
Shimon Kurasawa Takahiro Imaizumi Shoichi Maruyama Keitaro Tanaka Yoko Kubo Mako Nagayoshi Hiroaki Ikezaki Sadao Suzuki Teruhide Koyama Chihaya Koriyama Aya Kadota Sakurako Katsuura-Kamano Kiyonori Kuriki Kenji Wakai Keitaro Matsuo 《International journal of cancer. Journal international du cancer》2023,153(4):732-741
The association between kidney function and cancer incidence is inconsistent among previous reports, and data on the Japanese population are lacking. It is unknown whether kidney function modifies the cancer risk of other factors. We aimed to evaluate the association of estimated glomerular filtration rate (eGFR) with cancer incidence and mortality in 55 242 participants (median age, 57 years; 55% women) from the Japan Multi-Institutional Collaborative Cohort Study. We also investigated differences in cancer risk factors between individuals with and without kidney dysfunction. During a median 9.3-year follow-up period, 4278 (7.7%) subjects developed cancer. Moderately low and high eGFRs were associated with higher cancer incidence; compared with eGFR of 60-74 ml/min/1.73 m2, the adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) for eGFRs of ≥90, 75-89, 45-59, 30-44 and 10-29 ml/min/1.73 m2 were 1.18 (1.07-1.29), 1.09 (1.01-1.17), 0.93 (0.83-1.04), 1.36 (1.00-1.84) and 1.12 (0.55-2.26), respectively. High eGFR was associated with higher cancer mortality, while low eGFR was not; the adjusted subdistribution HRs (95% CIs) for eGFRs of ≥90 and 75-89 ml/min/1.73 m2 were 1.58 (1.29-1.94) and 1.27 (1.08-1.50), respectively. Subgroup analyses of participants with eGFRs ≥60 and <60 ml/min/1.73 m2 revealed elevated cancer risks of smoking and family history of cancer in those with eGFR <60 ml/min/1.73 m2, with significant interactions. Our findings suggest that the relationship between eGFR and cancer incidence was U-shaped. Only high eGFR was associated with cancer mortality. Kidney dysfunction enhanced cancer risk from smoking. 相似文献
3.
Shinichi Tsuruta Kenichi Kohashi Yuichi Yamada Minako Fujiwara Yutaka Koga Eikichi Ihara Yoshihiro Ogawa Eiji Oki Masafumi Nakamura Yoshinao Oda 《Cancer science》2020,111(3):1008-1019
ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid‐type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid‐type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid‐type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid‐type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid‐type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid‐type PDAs. In the MMR‐deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR‐proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid‐type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated‐type adenocarcinoma to solid‐type PDA. 相似文献
4.
Hirokazu Miki Shingen Nakamura Masahiro Oura Hirofumi Hamano Kenji Ikuta Naoto Okada Yasunobu Okamoto Kimiko Sogabe Mamiko Takahashi Masami Iwasa Kengo Udaka Takeshi Harada Kiyoe Kurahashi Shiro Fujii Sumiko Yoshida Kumiko Kagawa Itsuro Endo Ken-ichi Aihara Masahiro Abe 《British journal of haematology》2019,186(2):355-358
5.
6.
Tetsuo Yamaguchi Daisuke Ueshima Makoto Utsunomiya Akihiro Matsui Toru Miyazaki Masaaki Matsumoto Tsukasa Shimura Naotaka Murata Yasushi Komatsu Kazuki Tobita Yo Fujimoto Takahide Kodama Kenji Suzuki Hitoshi Anzai Kentaro Jujo Michiaki Higashitani 《Journal of cardiology》2021,77(2):109-115
BackgroundMalnutrition measured by the geriatric nutritional risk index (GNRI) was reported to be associated with poor prognosis for patients with peripheral artery disease (PAD). However, the optimal cut-off value of preprocedural GNRI for critical limb ischemia (CLI) and intermittent claudication (IC) is unknown. We aimed to determine its optimal cut-off value for CLI or IC patients requiring endovascular revascularization.MethodsWe explored data of 2246 patients (CLI: n = 1061, IC: n = 1185) registered in the Tokyo-taMA peripheral vascular intervention research COmraDE (TOMA-CODE) registry, which prospectively enrolled consecutive PAD patients who underwent endovascular revascularization in 34 hospitals in Japan from August 2014 to August 2016. The optimal cut-off values of GNRI were assessed by the survival classification and regression tree (CART) analyses, and the survival curve analyses for major adverse cardiovascular and limb events (MACLEs) were performed for these cut-off values.ResultsIn addition to the first cut-off value of 96.2 in CLI and 85.6 in IC, the survival CART provided an additional cut-off value of 78.2 in CLI and 106.0 in IC for further risk stratification. The survival curve was significantly stratified by the GNRI-based malnutrition status in both CLI [high risk: 47.7% (51/107), moderate: 30.1% (118/392), and low: 10.2% (53/520), log–rank p < 0.001] and IC [high risk: 14.3% (7/49), moderate: 4.5% (29/646), and low: 0.5% (2/407), log–rank p < 0.001]. The multivariate Cox-proportional hazard analysis showed that a higher GNRI was significantly associated with a better outcome in both CLI [hazard ratio (HR) per 1-point increase: 0.97, 95% CI: 0.96–0.98, p < 0.001] and IC (HR: 0.94, 95% CI: 0.91–0.97, p < 0.001).ConclusionsPreprocedural nutritional status significantly stratified future events in patients with PAD. Given that the optimal cut-off value of GNRI in CLI was almost 10-points lower than that of IC, using a disease-specific cut-off value is important for risk stratification. 相似文献
7.
8.
Rika Yoshimatsu Takuji Yamagami Miki Nishimori Kenta Ogi Yoriko Murata Hitomi Iwasa Kenji Kajiwara Tomoaki Yamanishi Hiroki Minamiguchi Takashi Karashima Keiji Inoue 《Journal of vascular and interventional radiology : JVIR》2019,30(3):460-465
Purpose
To evaluate the influence of percutaneous cryoablation for renal cell carcinoma on function of the affected kidney.Materials and Methods
Between June 2016 and September 2017 at our institution, 12 inoperable patients underwent 15 cryoablation sessions for 17 small renal tumors. Of these, 9 patients who underwent 11 sessions of cryoablation were the focus of this study. For those patients, time-dependent changes in postoperative renal function were investigated by a retrospective review of clinical records. Evaluated were the estimated glomerular filtration rate (eGFR) and scintigraphy using 99m technetium-mercaptoacetyltriglycine (99mTc-MAG3) before and 1 week, 1–2 months, and more than 6 months after cryoablation.Results
Mean baseline eGFR was 76.88 ± 29.82 mL/min/1.73 m2 (mean ± standard deviation; range, 23.4–112.5). Mean eGFR 1 week, 1–2 months, and more than 6 months after cryoablation were 74.56 ± 26.68 mL/min/1.73 m2 (21.0–101.1), 69.5 ± 25.28 mL/min/1.73 m2 (24.1–105.6), and 75.08 ± 26.25 mL/min/1.73 m2 (29.0–107.3), respectively. Changes were statistically insignificant (P = .6044, P = .6699, and P = .9038, respectively). Regarding split renal function, the mean baseline contribution of the affected kidney determined by 99mTc-MAG3 was 47.27% ± 6.14 (38.8%–57.0%). Mean contributions of the affected kidney 1 week after, 1–2 months after, and more than 6 months after cryoablation were 44.40% ± 5.37 (38.3%–53.6%), 44.57% ± 6.52 (34.35%–55.0%), and 45.41% ± 7.77 (34.4%–56.5%), respectively. Differences from baseline were significant for the earliest 2 periods (P = .0473 and P = .0334, respectively) but not the later period (P = .2532).Conclusions
Results suggested that total renal function does not worsen after cryoablation; however, function of the affected kidney worsened after cryoablation but later partially recovered. 相似文献9.
Morihito Okada Yoshihiro Miyata Kazuya Takamochi Yasuhiro Tsutani Shiaki Oh Kenji Suzuki 《The Journal of thoracic and cardiovascular surgery》2019,157(1):388-395
Objective
Vascular sealing with an energy vessel sealing system during lung resection may allow surgeons to treat small vessels with minimal dissection, possibly decreasing likelihood of injury. Few large prospective trials have examined the proximal sides of vessels not ligated in addition to sealing during surgery. We therefore assessed feasibility of an energy device to seal pulmonary artery and vein branches without further ligation.Methods
This prospective, preoperative registration study at 2 institutions evaluated safety of energy sealing with the LigaSure (Medtronic, Minneapolis, Minn), with no additional reinforcing material such as suture ligation, for pulmonary vessels as large as 7 mm during anatomic lung resection (cohort 1 study). A postoperative hemorrhage occurred in the 128th case, so a cohort 2 study proceeded after we changed inclusion criterion for pulmonary arteries from a maximum of 7 mm to a maximum of 5 mm.Results
In cohort 1 (n = 128) and cohort 2 (n = 200), 216 and 250 pulmonary arteries and 189 and 213 pulmonary veins, respectively, were treated with energy sealing. Overall postoperative hemorrhage rate was 0.3% (1/328 patients); however, no serious postoperative complications were associated with energy sealing among the 200 patients in cohort 2. Subsequent inspection of the torn artery stump confirmed that the bleeding in the 128th case was in an area adjacent to the sealing zone.Conclusions
Energy sealing without reinforcement allows secure treatment during lung resection of pulmonary arteries as large as 5 mm in diameter and pulmonary veins as large as 7 mm. 相似文献10.
Eitaro Ito Akihiro Takai Yoshinori Imai Hiromi Otani Yoshihiro Onishi Yosuke Yamamoto Kohei Ogawa Taiji Tohyama Shunichi Fukuhara Yasutsugu Takada 《Surgery》2019,165(2):353-359