Effects of acute- and long-term aerobic exercises at different intensities on bone in mice.

INTRODUCTION: Exercise intensity determines the benefits of aerobic exercise. Our objectives were, in aerobic exercise at different intensities, to determine (1) changes in bone metabolism-related genes after acute exercise and (2) changes in bone mass, strength, remodeling, and bone formation-related proteins after long-term exercise. MATERIALS AND METHODS: Total 36 male C57BL/6J mice were divided into a control group and exercise groups at 3 different intensities: low, moderate, or high group. Each exercise group was assigned to acute- or long-term exercise groups. Tibias after acute exercise were evaluated by real-time PCR analysis. Furthermore, hindlimbs of long-term exercise were assessed by micro-CT, biomechanical, histological, and immunohistochemical analyses. RESULTS: Acute moderate-intensity exercise decreased RANKL level as bone resorption marker, whereas low- and high-intensity exercise did not alter it. Additionally, only long-term exercise at moderate intensity increased bone mass and strength. Moderate-intensity exercise promoted osteoblast activity and suppressed osteoclast activity. After low- and high-intensity exercise, osteoblast and osteoclast activity were unchanged. An increase in the number of ß-catenin-positive cells and a decrease in sclerostin-positive cells were observed in the only moderate group. CONCLUSION: These results showed that moderate-intensity exercise can inhibit bone resorption earlier, and long-term exercise can increase bone mass and strength through promoted bone formation via the Wnt/ß-catenin activation. High-intensity exercise, traditionally considered better for bone, may fail to stimulate bone remodeling, leading to no change in bone mass and strength. Our findings suggest that moderate-intensity exercise, neither too low nor high, can maintain bone health.

Design and synthesis of novel thiazole-derivatives as potent ALK5 inhibitors.

TGF-ß is an immunosuppressive cytokine and plays a key role in progression of cancer by inducing immunosuppression in tumor microenvironment. Therefore, inhibition of TGF-ß signaling pathway may provide a potential therapeutic intervention in treating cancers. Herein, we report the discovery of a series of novel thiazole derivatives as potent inhibitors of ALK5, a serine-threonine kinase which is responsible for TGF-ß signal transduction. Compound 29b was identified as a potent inhibitor of ALK5 with an IC50 value of 3.7 nM with an excellent kinase selectivity.

Effects of different exercise modes and intensities on cognitive performance, adult hippocampal neurogenesis, and synaptic plasticity in mice.

Exercise can induce beneficial improvements in cognition. However, the effects of different modes and intensities of exercise have yet to be explored in detail. This study aimed to identify the effects of different exercise modes (aerobic and resistance) and intensities (low and high) on cognitive performance, adult hippocampal neurogenesis and synaptic plasticity in mice. A total of 40 C57BL/6J mice were randomised into 5 groups (n = 8 mice per group): control, low-intensity aerobic exercise, high-intensity aerobic exercise, low-intensity resistance exercise, and high-intensity resistance exercise. The aerobic exercise groups underwent treadmill training, while the resistance exercise groups underwent ladder climbing training. At the end of the exercise period, cognitive performance was assessed by the Y-maze and Barnes maze. In addition, adult hippocampal neurogenesis was evaluated immunohistochemically by 5-bromo-2'-deoxyuridine (BrdU)/ neuronal nuclei (NeuN) co-labeling. The levels of synaptic plasticity-related proteins in the hippocampus, including synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), were analyzed by western blotting. Our results showed no significant differences in cognitive performance among the groups. However, high-intensity aerobic exercise significantly increased hippocampal adult neurogenesis relative to the control. A trend towards increased adult neurogenesis was observed in the low-intensity aerobic group compared to the control group. No significant changes in synaptic plasticity were observed among all groups. Our results indicate that high-intensity aerobic exercise may be the most potent stimulator of adult hippocampal neurogenesis.

Effects of different combinations of mechanical loading intensity, duration, and frequency on the articular cartilage in mice.

BACKGROUND: Understanding how healthy articular cartilage responds to mechanical loading is critical. Moderate mechanical loading has positive effects on the cartilage, such as maintaining cartilage homeostasis. The degree of mechanical loading is determined by a combination of intensity, frequency, and duration; however, the best combination of these parameters for knee cartilage remains unclear. This study aimed to determine which combination of intensity, frequency, and duration provides the best mechanical loading on healthy knee articular cartilage in vitro and in vivo. METHODS AND RESULTS: In this study, 33 male mice were used. Chondrocytes isolated from mouse knee joints were subjected to different cyclic tensile strains (CTSs) and assessed by measuring the expression of cartilage matrix-related genes. Furthermore, the histological characteristics of mouse tibial cartilages were quantified using different treadmill exercises. Chondrocytes and mice were divided into the control group and eight intervention groups: high-intensity, high-frequency, and long-duration; high-intensity, high-frequency, and short-duration; high-intensity, low-frequency, and long-duration; high-intensity, low-frequency, and short-duration; low-intensity, high-frequency, and long-duration; low-intensity, high-frequency, and short-duration; low-intensity, low-frequency, and long-duration; low-intensity, low-frequency, and short-duration. In low-intensity CTSs, chondrocytes showed anabolic responses by altering the mRNA expression of COL2A1 in short durations and SOX9 in long durations. Furthermore, low-intensity, low-frequency, and long-duration treadmill exercises minimized chondrocyte hypertrophy and enhanced aggrecan synthesis in tibial cartilages. CONCLUSION: Low-intensity, low-frequency, and long-duration mechanical loading is the best combination for healthy knee cartilage to maintain homeostasis and activate anabolic responses. Our findings provide a significant scientific basis for exercise and lifestyle instructions.

Increased intramuscular adipose tissue of the quadriceps at admission is more strongly related to activities of daily living recovery at discharge compared to muscle mass loss in older patients with aspiration pneumonia.

BACKGROUND: Recent studies reported that an increase in intramuscular adipose tissue of the quadriceps in older patients negatively affects the recovery of activities of daily living (ADL) more than the loss of muscle mass. However, whether intramuscular adipose tissue of the quadriceps in older patients with aspiration pneumonia is related to ADL recovery remains unclear. This study aimed to determine the relationship between intramuscular adipose tissue of the quadriceps and ADL recovery in older patients with aspiration pneumonia. METHODS: Thirty-nine older inpatients who were diagnosed with aspiration pneumonia participated in this prospective study. The main outcome of this study was ADL at discharge. ADL were assessed using the Barthel Index (BI). The intramuscular adipose tissue and muscle mass of the quadriceps were evaluated at admission using echo intensity and muscle thickness observed on ultrasound images. A multiple linear regression analysis was performed to confirm whether the quadriceps echo intensity was related to the BI score at discharge, even after adjusting for confounding factors. RESULTS: The medians [interquartile range] of the BI score at admission and discharge were 15.0 [0.0-35.0] and 20.0 [5.0-55.0], respectively. The BI score at discharge was significantly higher than that at admission (p = 0.002). The quadriceps echo intensity (ß = - 0.374; p = 0.036) and BI score at admission (ß = 0.601; p < 0.001) were independently and significantly related to the BI score at discharge (R2 = 0.718; f2 = 2.546; statistical power = 1.000). In contrast, the quadriceps thickness (ß = - 0.216; p = 0.318) was not independently and significantly related to the BI score at discharge. CONCLUSIONS: Increased intramuscular adipose tissue of the quadriceps at admission is more strongly and negatively related to ADL recovery at discharge than the loss of muscle mass among older patients with aspiration pneumonia. Interventions targeting the intramuscular adipose tissue of the quadriceps may improve ADL among these patients.

[Three Cases of Preoperative Chemotherapy(FOLFOXIRI plus Bevacizumab)for Locally Advanced Colorectal Cancer with Urinary Bladder Invasion].

Radical cystectomy for locally advanced colorectal cancer with urinary bladder invasion significantly reduces the quality of life in exchange for a cure. We performed preoperative chemotherapy with FOLFOXIRI plus bevacizumab for 3 patients with locally advanced colorectal cancer with urinary bladder invasion to avoid radical cystectomy and to achieve local control for urinary bladder preservation. Grade 3 neutropenia was observed in 2 patients as an adverse reaction to the preoperative chemotherapy, but all 3 patients showed good tumor regression. All 3 patients underwent laparoscopic high anterior rectal resection and partial cystectomy, and all were able to undergo R0 resections with urinary bladder preservation. One patient had anastomotic leakage as a postoperative complication. One patient had local recurrence in the urinary bladder, and 2 had recurrence with peritoneal dissemination during their postoperative courses. Preoperative chemotherapy(FOLFOXIRI plus bevacizumab)for locally advanced colorectal cancer with urinary bladder invasion is considered to be a useful treatment option because of its potential for tumor shrinkage and bladder preservation.

[A Case of Postoperative Recurrence of Bilateral Breast Cancer in Which Stable Disease Condition Was Achieved by Olaparib].

The patient is a 51-year-old female with comorbidity of schizophrenia. At the age of 41, she underwent surgery for bilateral breast cancer. Both sides were of the Luminal type, with Stage ⅢC on the right and Stage 0 on the left. She started to receive adjuvant chemotherapy but it was interrupted according to her wish. Approximately 3 years ago, she developed carcinomatous pleuritis, multiple liver metastases, and bone metastases. Despite receiving chemotherapy, her condition worsened. A BRACAnalysis revealed pathogenic variants in BRCA2. Upon initiating treatment with olaparib, both her liver metastases and carcinomatous pleuritis have shown reductions, and her tumor markers have also started to decline. Approximately 5 months after treatment with olaparib, it has been possible to continue without any side effects. Olaparib has shown good results in patients with germline BRCA1/2 mutation-positive HER2-negative advanced/recurrent breast cancer who have a history of receiving anthracycline and taxane-based therapies. It was considered that even in recurrent breast cancer, the presence or absence of BRCA1/2 mutations should be actively sought even in advanced cases, and the administration of olaparib should be considered.

[A Case of Resection of Right Axillary Accessory Breast Cancer with Skin Invasion].

A 56-year-old female was referred to our hospital for further examination and treatment because of her increasing right axillary mass for 1 year. Based on histological examination diagnosing the right axillary mass as carcinoma and radiological examination showing no evidence of distal metastasis, we decided to perform a radical resection. The patient underwent right axillary mass resection, axillary lymph node dissection, and latissimus dorsi musculocutaneous flap reconstruction. Right-sided breast cancer was diagnosed based on histopathological examination. The diagnosis was similar to that of breast cancer. The patient underwent adjunctive chemotherapy and is currently undergoing endocrine therapy. The incidence of accessory breast cancer is 0.2-0.6% among all breast cancers and is relatively rare. Postoperative adjuvant pharmacotherapy has no consensus. However, endocrine therapy, chemotherapy, and molecular target therapy are performed in cases of conventional breast cancer. Herein, we describe a case of right axillary accessory breast cancer with skin invasion successfully treated with radical resection.

Development of patellofemoral osteoarthritis with knee joint malalignment and lateral patellar dislocation after hindlimb suspension in growing rats.

Knee malalignment is a risk factor for patellar instability and patellofemoral osteoarthritis (PFOA), but etiologies remain unknown. We investigated the potential effects of decreased weight loading during growth on knee alignments and patellofemoral (PF) joint pathology. Hindlimb suspension (HS) was performed in 4-week-old female rats for 2, 4, and 8 weeks (HS groups). Age-matched rats were used as controls. Three-dimensional reconstructed images of the knee were obtained using X-ray computed tomography. Tibial tubercle-trochlear groove (TT-TG) distance, patellar tilt angle, and bisect offset were measured as indices of knee alignment. Histological analysis was also performed to evaluate the changes in cartilage and synovium in the PF joints. At Week 8, TT-TG distance, patella tilt angle, and bisect offset were significantly larger in the HS group than in the control group, respectively, indicating tibial external rotation, outward patellar tilt, and external displacement of the patella. Lateral patellar dislocation was frequently found in the HS group at Week 8 (five of eight knee joints, p < 0.05). Degenerative changes in the cartilage of the trochlear groove were observed at Week 8, and synovial changes such as hypertrophy and synovitis were observed at Weeks 4 and 8. Correlation analyses revealed significant relationships between the Mankin score and bisect offset, and between the OARSI synovitis score and all knee alignments indices. These results suggest that decreased weight loading on the lower extremities in growing rats resulted in knee malalignments characterized by external rotation of tibia and high incidence of lateral patellar dislocation with concomitant PFOA.

Thoracoscopic endoscopic cooperative surgery for gastric tube cancer after esophagectomy: a case report.

The incidence of gastric tube cancer (GTC) is increasing due to the improved prognosis of patients after esophagectomy for esophageal cancer. Total resection of the gastric tube is expected to be curative for patients with GTC. However, several studies have reported that this procedure is associated with high mortality and morbidity rates. We here present a case of GTC without lymph node metastasis in a patient who underwent partial resection of a gastric tube via thoracoscopic-endoscopic cooperative surgery. No postoperative complications or recurrence was observed. This procedure is a favorable and minimally invasive procedure for GTC without lymph node metastasis.

Impact of Arteriosclerosis on Reconstruction-related Complications After Esophagectomy and Usefulness of Tailor-made Reconstruction Technique.

BACKGROUND/AIM: Anastomotic leakage is one of the most common and serious postoperative complications following esophagectomy. This study analyzed the effect of risk factors, such as the degree of arteriosclerosis, comorbidities, and patient characteristics on the incidence of reconstruction-related complications including anastomotic leakage. Furthermore, the usefulness of tailor-made reconstruction methods was clarified using wide gastric conduit. PATIENTS AND METHODS: Patients who underwent esophagectomy with a gastric conduit for esophageal cancer between 2011 and 2018 were enrolled. In the initial group that underwent esophagectomy between August 2011 and February 2016, gastrointestinal reconstruction was performed using a narrow gastric conduit. In the latter group, reconstruction using subtotal gastric conduit was selected for high-risk patients between March 2016 and March 2018. Postoperative complications including reconstruction-related complications were assessed. RESULTS: The occurrence of anastomotic leakage was significantly associated with the patient's risk in the initial group. The rates of anastomotic leakage and reconstruction-related complications were significantly lower in the latter group than in the initial group (3.2% vs. 23.0%, p=0.001; 27.0% vs. 44.3%, p=0.044). The incidence of all complications was significantly lower in the latter group than in the initial group (28.6% vs. 59.0%, p=0.001). The change in bodyweight loss one year after the operation was significantly lower in the latter group than in the initial group (p=0.042). CONCLUSION: Tailor-made reconstruction using wide gastric conduit for high-risk cases of esophageal cancer could reduce the occurrence of anastomotic leakage and promote a better quality of life after surgery.

Initial 12 Cases of Robot-Assisted Gastrectomy for Gastric Cancer Using the Hinotori Surgical Robot System: Tips for the Efficient Introduction of a New Surgical Robot.

Introduction: The use of robotic platform for gastrectomy for gastric cancer is rapidly increasing. This study aimed to describe the perioperative outcomes of 12 patients who underwent robotic gastrectomy for gastric cancer using the hinotori™ surgical robot system (hinotori), a novel robot-assisted surgical platform, and compare the outcomes with the existing system, the da Vinci® Surgical System (DVSS). Methods: This study included 12 consecutive patients with gastric cancer who underwent robotic gastrectomy for gastric cancer using the hinotori between March 2023 and September 2023 at our institution. The comprehensive perioperative outcomes of these patients were retrospectively analyzed and compared to 11 patients who underwent robotic gastrectomy using the DVSS during the same period. Results: The median age and body mass index were 71 years (range: 56-86) and 22.7 kg/m2 (range: 16.1-26.7). Distal and total gastrectomy were performed in 8 and 4 patients, respectively. The median console time and operation times were 187 (range: 112-270) and 252 minutes (range: 173-339), respectively. The median blood loss was 3 mL (range: 2-5). No intra- or postoperative complications were observed. There were no significant differences in perioperative outcomes between the hinotori and the DVSS. Conclusions: Robotic gastrectomy for gastric cancer using the hinotori is a feasible procedure and achieved perioperative outcomes similar to that using the DVSS. Clinical Trial Registration number: 114167-1.

Chemoprevention of esophageal adenocarcinoma in a rat surgical model by a cysteinyl leukotriene receptor­1 antagonist.

Reflux of gastroduodenal contents into the esophagus leads to the development of esophagitis and inflammation-associated pathologies, such as Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). The role of the lipoxygenase (LOX) pathway in carcinogenesis has been recently reported; however, its involvement in esophageal carcinogenesis remains unclear. To address this, the present study investigated the potential of pranlukast, a cysteinyl leukotriene receptor-1 antagonist, to suppress the progression of BE and EAC in a rat duodenogastroesophageal reflux (DGER) model. Male Wistar rats that underwent DGER were divided into two groups. One group was fed commercial chow (control group), and the other was fed experimental chow containing pranlukast (pranlukast group). The rats were sacrificed at 10, 20, 30 and 40 weeks after surgery, and their esophagi were examined. Expression levels of 5-LOX, CD68, IL-8, VEGF and Ki-67 were investigated using immunohistochemistry, and apoptosis was analyzed using the TUNEL method. In the pranlukast group, esophagitis was milder, and the incidence of BE and EAC was significantly lower (P<0.05) compared with that in the control group at 40 weeks after surgery. The number of cells positive for IL-8 and VEGF were significantly lower in the pranlukast group compared with the control group. Proliferative activity was also lower in the pranlukast group compared with the control group (P<0.05). Pranlukast treatment increased apoptosis (P<0.05). Overall, Pranlukast suppressed esophageal carcinogenesis in a rat DGER model, decreasing inflammatory cytokines such as IL-8 and VEGF.