Assessing the Risk of Postoperative Delirium Through Comprehensive Geriatric Assessment and Eastern Cooperative Oncology Group Performance Status of Elderly Patients With Gastric Cancer.

BACKGROUND: Postoperative delirium is especially common and often problematic among elderly patients undergoing surgery. This study aimed to explore factors that can predict postoperative delirium in elderly patients undergoing gastric cancer surgery. METHODS: This cohort study included 255 patients age 75 years or older who underwent gastric cancer surgery between July 2010 and December 2020. All the patients underwent preoperative comprehensive geriatric assessment (CGA) evaluation by a geriatrician. In addition to the CGA items, this study investigated the association between postoperative delirium and clinicopathologic factors, including Eastern Cooperative Oncology Group performance status (ECOG-PS). RESULTS: The most common postoperative complication was delirium, present in 31 patients (12.2%). The group with delirium was significantly more likely to have ECOG-PS ≥ 2, diabetes mellitus, cardiovascular disease, or cerebral infarction. The CGA showed frailty in the Instrumental Activities of Daily Living scale (IADL), the Mini-Mental State Examination (MMSE), the Vitality Index (VI), and the Geriatric Depression Scale 15 (GDS-15). In the multivariate analysis, the independent risk factors for delirium were ECOG-PS ≥ 2 (P = 0.002) and MMSE-frailty (P < 0.001). Using an MMSE score of ≤ 23 and an ECOG-PS score of ≥ 2 as cutoffs, postoperative delirium was predicted with a sensitivity of 80.7% and a specificity of 74.1%. CONCLUSION: Postoperative delirium might be more easily predicted based on the combination of MMSE and ECOG-PS for elderly patients with gastric cancer undergoing gastrectomy.

Effects of interleukin-15 on autophagy regulation in the skeletal muscle of mice.

This study aimed to evaluate the role of skeletal muscle-derived interleukin (IL)-15 in the regulation of skeletal muscle autophagy using IL-15 knockout (KO) and transgenic (TG) mice. Male C57BL/6 wild-type (WT), IL-15 KO, and IL-15 TG mice were used in this study. Changes in muscle mass, forelimb grip strength, succinate dehydrogenase (SDH) activity, gene and protein expression levels of major regulators and indicators of autophagy, comprehensive gene expression, and DNA methylation in the gastrocnemius muscle were analyzed. Enrichment pathway analyses revealed that the pathology of IL-15 gene deficiency was related to the autophagosome pathway. Moreover, although IL-15 KO mice maintained gastrocnemius muscle mass, they exhibited a decrease in autophagy induction. IL-15 TG mice exhibited a decrease in gastrocnemius muscle mass and an increase in forelimb grip strength and SDH activity in skeletal muscle. In the gastrocnemius muscle, the ratio of phosphorylated adenosine monophosphate-activated protein kinase α (AMPKα) to total AMPKα and unc-51-like autophagy activating kinase 1 and Beclin1 protein expression were higher in the IL-15 TG group than in the WT group. IL-15 gene deficiency induces a decrease in autophagy induction. In contrast, IL-15 overexpression could improve muscle quality by activating autophagy induction while decreasing muscle mass. The regulation of IL-15 in autophagy in skeletal muscles may lead to the development of therapies for the autophagy-induced regulation of skeletal muscle mass and cellular quality control.NEW & NOTEWORTHY IL-15 gene deficiency can decrease autophagy induction. However, although IL-15 overexpression induced a decrease in muscle mass, it led to an improvement in muscle quality. Based on these results, understanding the role of IL-15 in regulating autophagy pathways within skeletal muscle may lead to the development of therapies for the autophagy-induced regulation of skeletal muscle mass and cellular quality control.

Knee Extensor Weakness Potently Predicts Postoperative Outcomes in Older Gastrointestinal Cancer Patients.

OBJECTIVES: Muscle weakness, assessed by grip strength, has been shown to predict postoperative mortality in older patients with cancer. Because lower extremity muscle strength well reflects physical performance, we examined whether lower knee extension muscle strength predicts postoperative mortality better than grip strength in older patients with gastrointestinal cancer. DESIGN: Prospective, observational study in a single institution. SETTING AND PARTICIPANTS: A total of 813 patients (79.0 ± 4.2 years, 66.5% male) aged 65 years or older with gastrointestinal cancer who underwent preoperative evaluation of grip strength and isometric knee extension muscle strength between April 2012 and April 2019 were included. METHODS: The study participants were prospectively followed up for postoperative mortality. Muscle weakness was defined as the lowest quartile of grip strength or knee extension strength (GS-muscle weakness and KS-muscle weakness, respectively). RESULTS: Among the study participants, 176 patients died during a median follow-up of 716 days. In the Kaplan-Meier analysis, we found that patients with both GS-muscle weakness and KS-muscle weakness had a lower survival rate than those without muscle weakness. As expected, higher clinical stages and abdominal and thoracic surgeries compared with endoscopic surgery were associated with increased all-cause mortality. In addition, we found that KS-muscle weakness, but not GS-muscle weakness, was an independent prognostic factor after adjusting for sex, body mass index, cancer stage, surgical technique, and surgical site in the Cox proportional hazard model. CONCLUSIONS AND IMPLICATIONS: In older patients with gastrointestinal cancer, muscle weakness based on knee extension muscle strength can be a better predictor of postoperative prognosis than muscle weakness based on grip strength.

Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging-Related Muscle Weakness in Male Mice.

Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin-(1-7), respectively, is the primary process that counteracts activation of the canonical renin-angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging-related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild-type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS-associated genes, inflammation-associated genes, and senescence-associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging-associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging-associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.

A pressor dose of angiotensin II has no influence on the angiotensin-converting enzyme 2 and other molecules associated with SARS-CoV-2 infection in mice.

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.

Differential effects of pre-exercise on cancer cachexia-induced muscle atrophy in fast- and slow-twitch muscles.

We hypothesized that pre-exercise may effectively prevent cancer cachexia-induced muscle atrophy in both fast- and slow-twitch muscle types. Additionally, the fast-twitch muscle may be more affected by cancer cachexia than slow-twitch muscle. This study aimed to evaluate the effects of pre-exercise on cancer cachexia-induced atrophy and on atrophy in fast- and slow-twitch muscles. Twelve male Wistar rats were randomly divided into sedentary and exercise groups, and another 24 rats were randomly divided into control, pre-exercise, cancer cachexia induced by intraperitoneal injections of ascites hepatoma AH130 cells, and pre-exercise plus cancer cachexia groups. We analyzed changes in muscle mass and in gene and protein expression levels of major regulators and indicators of muscle protein degradation and synthesis pathways, angiogenic factors, and mitochondrial function in both the plantaris and soleus muscles. Pre-exercise inhibited muscle mass loss, rescued protein synthesis, prevented capillary regression, and suppressed hypoxia in the plantaris and soleus muscles. Pre-exercise inhibited mitochondrial dysfunction differently in fast- and slow-twitch muscles. These results suggested that pre-exercise has the potential to inhibit cancer-cachexia-induced muscle atrophy in both fast- and slow-twitch muscles. Furthermore, the different progressions of cancer-cachexia-induced muscle atrophy in fast- and slow-twitch muscles are related to differences in mitochondrial function.

Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors.

Cysteinyl leukotriene G protein-coupled receptors CysLT1 and CysLT2 regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT1R has been used for treating asthma and associated diseases for over two decades, CysLT2R has recently started to emerge as a potential drug target against atopic asthma, brain injury and central nervous system disorders, as well as several types of cancer. Here, we describe four crystal structures of CysLT2R in complex with three dual CysLT1R/CysLT2R antagonists. The reported structures together with the results of comprehensive mutagenesis and computer modeling studies shed light on molecular determinants of CysLTR ligand selectivity and specific effects of disease-related single nucleotide variants.

Angiotensin 1-7 alleviates aging-associated muscle weakness and bone loss, but is not associated with accelerated aging in ACE2-knockout mice.

The angiotensin-converting enzyme 2 (ACE2)-angiotensin 1-7 (A1-7)-A1-7 receptor (Mas) axis plays a protective role in the renin-angiotensin system (RAS). We recently found that ACE2 knockout (ACE2KO) mice exhibit earlier aging-associated muscle weakness, and that A1-7 alleviates muscle weakness in aging mice. In the present study, we investigated the role of the A1-7-Mas pathway in the effect of ACE2 on physiological aging. Male wild-type, ACE2KO, and Mas knockout (MasKO) mice were subjected to periodical grip strength measurement, followed by administration of A1-7 or vehicle for 4 weeks at 24 months of age. ACE2KO mice exhibited decreased grip strength after 6 months of age, while grip strength of MasKO mice was similar to that of wild-type mice. A1-7 improved grip strength in ACE2KO and wild-type mice, but not in MasKO mice. Muscle fibre size was smaller in ACE2KO mice than that in wild-type and MasKO mice, and increased with A1-7 in ACE2KO and WT mice, but not in MasKO mice. Centrally nucleated fibres (CNFs) and expression of the senescence-associated gene p16INK4a in skeletal muscles were enhanced only in ACE2KO mice and were not altered by A1-7. ACE2KO mice, but not MasKO mice, exhibited thinning of peripheral fat along with increased adipose expression of p16INK4a A1-7 significantly increased bone volume in wild-type and ACE2KO mice, but not in MasKO mice. Our findings suggest that the impact of ACE2 on physiological aging does not depend on the endogenous production of A1-7 by ACE2, while overactivation of the A1-7-Mas pathway could alleviate sarcopenia and osteoporosis in aged mice.

Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.

We hypothesized that low-intensity endurance exercise might be more effective in preventing cancer cachexia-induced muscle atrophy through both an increase in protein synthesis and a decrease in protein degradation. The purpose of present study was to evaluate the effects and to clarify the mechanism of low-intensity endurance exercise on cancer cachexia-induced muscle atrophy. Twenty-four male Wistar rats were randomly divided into 4 groups: control (Cont), Cont plus exercise (Ex), AH130-induced cancer cachexia (AH130), and AH130 plus Ex. Cancer cachexia was induced by intraperitoneal injections with AH130 Yoshida ascites hepatoma cells; we analyzed the changes in muscle mass and the gene and protein expression levels of major regulators or indicators of skeletal muscle protein degradation and synthesis pathway in the soleus muscles. Low-intensity exercise inhibited the muscle mass loss through a suppression of the ubiquitin-proteasome pathway, increased hypoxia-inducible factor- 1α and phosphorylated AMPK, and inhibited the deactivation of mammalian target of rapamycin pathway in the soleus muscle, which contributed to the prevention of cancer cachexia-induced muscle atrophy. These results suggest that low-intensity exercise has the potential to become an effective therapeutic intervention for the prevention of cancer cachexia-induced muscle atrophy.-Tanaka, M., Sugimoto, K., Fujimoto, T., Xie, K., Takahashi, T., Akasaka, H., Kurinami, H., Yasunobe, Y., Matsumoto, T., Fujino, H., Rakugi, H. Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.

Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice.

BACKGROUND: A pharmacologic strategy for age-related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1-7, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2-angiotensin 1-7 in age-related muscle weakness remains undetermined. Here, we investigated whether deletion of ACE2 alters the development of muscle weakness by aging and whether angiotensin 1-7 reverses muscle weakness in older mice. METHODS: After periodic measurement of grip strength and running distance in male ACE2KO and wild-type mice until 24 months of age, we infused angiotensin 1-7 or vehicle for 4 weeks, and measured grip strength, and excised tissues. Tissues were also excised from younger (3-month-old) and middle-aged (15-month-old) mice. Microarray analysis of RNA was performed using tibialis anterior (TA) muscles from middle-aged mice, and some genes were further tested using RT-PCR. RESULTS: Grip strength of ACE2KO mice was reduced at 6 months and was persistently lower than that of wild-type mice (p < 0.01 at 6, 12, 18, and 24-month-old). Running distance of ACE2KO mice was shorter than that of wild-type mice only at 24 months of age [371 ± 26 vs. 479 ± 24 (m), p < 0.01]. Angiotensin 1-7 improved grip strength in both types of older mice, with larger effects observed in ACE2KO mice (% increase, 3.8 ± 1.5 and 13.3 ± 3.1 in wild type and ACE2KO mice, respectively). Older, but not middle-aged ACE2KO mice had higher oxygen consumption assessed by a metabolic cage than age-matched wild-type mice. Angiotensin 1-7 infusion modestly increased oxygen consumption in older mice. There was no difference in a wheel-running activity or glucose tolerance between ACE2KO and wild-type mice and between mice with vehicle and angiotensin 1-7 infusion. Analysis of TA muscles revealed that p16INK4a, a senescence-associated gene, and central nuclei of myofibers increased in middle-aged, but not younger ACE2KO mice. p16INK4a and central nuclei increased in TA muscles of older wild-type mice, but the differences between ACE2KO and wild-type mice remained significant (p < 0.01). Angiotensin 1-7 did not alter the expression of p16INK4a or central nuclei in TA muscles of both types of mice. Muscle ACE2 expression of wild-type mice was the lowest at middle age (2.6 times lower than younger age, p < 0.05). CONCLUSIONS: Deletion of ACE2 induced the early manifestation of muscle weakness with signatures of muscle senescence. Angiotensin 1-7 improved muscle function in older mice, supporting future application of the peptide or its analogues in the treatment of muscle weakness in the elderly population.