Incidence and Characteristics of Cerebral Infarction After Microsurgical Clipping of Unruptured Anterior Circulation Cerebral Aneurysms: Diffusion-Weighted Imaging-Based Analysis of 600 Patients.

BACKGROUND AND OBJECTIVES: Postclipping cerebral infarction (PCI) remains a major concern after treatment for unruptured intracranial aneurysms (UIAs). However, studies of microsurgical clipping based on diffusion-weighted imaging are limited. We aimed to present the incidence, risk factors, and types of PCI and its radiological and clinical characteristics. METHODS: This was a retrospective single-center study in which patients were scheduled to undergo microsurgical clipping for anterior circulation UIAs. The overall incidence and risk factors were calculated. Based on the operation and relevant artery, we categorized PCI on diffusion-weighted imaging into 4 types and presented their radiological and clinical characteristics. RESULTS: We reviewed the radiological and clinical data of 605 patients. The overall incidence of PCI was 16.7% (101/605), of which asymptomatic infarction was 14.9% (90/605) and symptomatic infarction was 1.8% (11/605). Hypertension (adjusted odds ratio [aOR], 2.258; 95% confidence interval [CI]: 1.330-3.833), temporary clipping (aOR, 1.690; 95% CI: 1.034-2.760), multiple aneurysm locations (aOR, 1.832; 95% CI: 1.084-3.095), and aneurysm dome size (aOR, 1.094; 95% CI: 1.006-1.190) were independent risk factors for PCI. Type II (perianeurysmal perforator) infarction was the most common type of PCI (48.6%) and the most common cause of symptomatic infarction (72.7%). Types II and III (distal embolic) infarctions correlated with atherosclerotic changes in the aneurysm wall and temporary clipping (62.4% and 70.6%, respectively). The type IV (unrelated) infarction group had a higher incidence of systemic atherosclerosis (55%). CONCLUSION: Microsurgical clipping is a safe and viable option for the treatment of anterior circulation UIAs. However, modification of the surgical technique, preoperative radiological assessment, and patient selection are required to reduce the incidence of PCI.

Analysis of temperature effects on the protein accumulation of the FT-FD module using newly generated Arabidopsis transgenic plants.

Arabidopsis flowering is dependent on interactions between a component of the florigens FLOWERING LOCUS T (FT) and the basic leucine zipper (bZIP) transcription factor FD. These proteins form a complex that activates the genes required for flowering competence and integrates environmental cues, such as photoperiod and temperature. However, it remains largely unknown how FT and FD are regulated at the protein level. To address this, we created FT transgenic plants that express the N-terminal FLAG-tagged FT fusion protein under the control of its own promoter in ft mutant backgrounds. FT transgenic plants complemented the delayed flowering of the ft mutant and exhibited similar FT expression patterns to wild-type Col-0 plants in response to changes in photoperiod and temperature. Similarly, we generated FD transgenic plants in fd mutant backgrounds that express the N-terminal MYC-tagged FD fusion protein under the FD promoter, rescuing the late flowering phenotypes in the fd mutant. Using these transgenic plants, we investigated how temperature regulates the expression of FT and FD proteins. Temperature-dependent changes in FT and FD protein levels are primarily regulated at the transcript level, but protein-level temperature effects have also been observed to some extent. In addition, our examination of the expression patterns of FT and FD in different tissues revealed that similar to the spatial expression pattern of FT, FD mRNA was expressed in both the leaf and shoot apex, but FD protein was only detected in the apex, suggesting a regulatory mechanism that restricts FD protein expression in the leaf during the vegetative growth phase. These transgenic plants provided a valuable platform for investigating the role of the FT-FD module in flowering time regulation.

A straightforward strategy for reducing variability in flowering time at warm ambient temperatures.

Ambient temperature is one of the major environmental factors affecting flowering. As the temperature rises, most plants, including Arabidopsis, flower more rapidly. In addition, phenotypic variability in flowering time tends to increase at warm ambient temperatures. The increased variability of flowering time at warm temperatures prevents accurate flowering time measurements, particularly when evaluating the flowering time of Arabidopsis plants under short-day conditions in order to restrict the photoperiodic effect. Here, we propose a simple method for reducing the variability of flowering time at warm temperatures. Instead of growing plants at different temperatures from germination, the strategy of first vegetative growth at cool temperatures and then shifting to warm temperatures allows plants to respond more stably and robustly to warm temperatures. Consistent with flowering time measurements, plants grown under the modified growth condition exhibited higher levels of FLOWERING LOCUS T (FT) gene expression than plants grown exclusively at warm temperatures. This approach enables more precise thermo-response studies of flowering time control in Arabidopsis.

Hederacolchiside A1 Suppresses Autophagy by Inhibiting Cathepsin C and Reduces the Growth of Colon Cancer.

While autophagy degrades non-functional or unnecessary cellular components, producing materials for synthesizing cellular components, it can also provide energy for tumor development. Hederacolchiside A1 (HA1) derived from anemone raddeana has anticancer effects on several carcinomas by inducing apoptosis or exhibiting cytotoxicity, but the relationship with autophagy has not been studied. We investigated the association between HA1 and autophagy and evaluated its anticancer effect on colon cancer. HA1 induced accumulation of the autophagy-related markers LC3B and SQSTM1, with distinct vacuolar formation, unlike other autophagy inhibitors; the effects were similar to those of chloroquine. In addition, HA1 decreased the expression and proteolytic activity of lysosomal protein cathepsin C, reduced the growth of colon cancer cells in vitro, and inhibited tumor growth in vivo. It also reduced the expression of Ki-67 and cathepsin C in mouse tissues and reduced the growth of spheroids and organoids composed of cancer cells. Taken together, these results imply that HA1 regulates cell growth and autophagy and has potential as a promising therapeutic agent in colon cancer.

Decursin inhibits tumor progression in head and neck squamous cell carcinoma by downregulating CXCR7 expression in vitro.

CXC chemokine receptor 7 (CXCR7) is frequently overexpressed in cancer and plays a significant role in tumor growth and metastasis. Consequently, inhibition of CXCR7 is important for treatment strategies. However, little is known concerning the biological role of CXCR7 and its underlying mechanisms in head and neck squamous cell carcinoma (HNSCC). The present study investigated the role of CXCR7 in HNSCC, as well as the effects of decursin, a pyranocoumarin compound isolated from Angelica gigas Nakai, on CXCR7 and its downstream signaling. Expression levels of CXCR7 in HNSCC cells were examined using flow cytometry, reverse transcriptase PCR, western blot analysis, and immunofluorescence. The effects of CXCR7 on cell proliferation, migration, and invasion were studied using CCK­8, gap closure, and transwell assays. The results revealed that decursin significantly reduced CXCR7 expression and inhibited cell proliferation, migration, and invasion of human HNSCC cell lines. In addition, decursin induced G0/G1 cell cycle arrest in CXCR7­overexpressing cells and decreased the levels of cyclin A, cyclin E, and CDK2. Furthermore, CXCR7 promoted cancer progression via the STAT3/c­Myc pathway in HNSCC; suppression of CXCR7 with decursin prevented this effect. These results suggest that CXCR7 promotes cancer progression through the STAT3/c­Myc pathway and that the natural compound decursin targets CXCR7 and may be valuable in the treatment of HNSCC.

MITF Promotes Cell Growth, Migration and Invasion in Clear Cell Renal Cell Carcinoma by Activating the RhoA/YAP Signal Pathway.

Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor involved in the lineage-specific regulation of melanocytes, osteoclasts and mast cells. MITF is also involved in the progression of melanomas and other carcinomas, including the liver, pancreas and lung. However, the role of MITF in clear cell renal cell carcinoma (ccRCC) is largely unknown. This study investigates the functional role of MITF in cancer and the molecular mechanism underlying disease progression in ccRCC. MITF knockdown inhibited cell proliferation and shifted the cell cycle in ccRCC cells. In addition, MITF knockdown reduced wound healing, cell migration and invasion compared with the controls. Conversely, MITF overexpression in SN12C and SNU482 cells increased cell migration and invasion. Overexpression of MITF activated the RhoA/YAP signaling pathway, which regulates cell proliferation and invasion, and increased YAP signaling promoted cell cycle-related protein expression. Additionally, tumor formation was impaired by MITF knockdown and enhanced by MITF overexpression in vivo. In summary, MITF expression was associated with aggressive tumor behavior, and increased the migratory and invasive capabilities of ccRCC cells. These effects were reversed by MITF suppression. These results suggest that MITF is a potential therapeutic target for the treatment of ccRCC.

Decursin inhibits cell growth and autophagic flux in gastric cancer via suppression of cathepsin C.

Autophagy plays an important role in the survival of cancer cells under stressful conditions, such as nutrient or oxygen deficiency. Therefore, autophagy inhibition is being considered as a novel therapeutic strategy for cancer. Decursin is a natural compound derived from Angelica gigas; it has been used in the treatment of various diseases, including cancer. However, the mechanism by which decursin regulates autophagy in gastric cancer and other carcinomas remains unclear. Here, we demonstrated that decursin reduced the growth and induced cell cycle arrest in gastric cancer cells in vitro. Decursin blocked autophagic flux by reducing the expression of lysosomal protein cathepsin C (CTSC) and attenuating its activity, thereby causing autophagic dysregulation (i.e., accumulation of LC3 and SQSTM1). Decursin also inhibited cell proliferation and cell cycle progression by inhibiting CTSC and E2F3, both of which were linked to gastric cancer aggressiveness. The antitumor effects of decursin were confirmed in vivo. We established spheroid and patient-derived organoid models and found that decursin decreased the growth of spheroids and patient-derived gastric organoids, as well as modulated the expression of CTSC and autophagy-related proteins. Hence, our findings uncovered a previously unknown mechanism by which decursin regulates cell growth and autophagy and suggests that decursin may act as a potential therapeutic agent that simultaneously inhibits cell growth and autophagy.

A prion-like domain in ELF3 functions as a thermosensor in Arabidopsis.

Temperature controls plant growth and development, and climate change has already altered the phenology of wild plants and crops1. However, the mechanisms by which plants sense temperature are not well understood. The evening complex is a major signalling hub and a core component of the plant circadian clock2,3. The evening complex acts as a temperature-responsive transcriptional repressor, providing rhythmicity and temperature responsiveness to growth through unknown mechanisms2,4-6. The evening complex consists of EARLY FLOWERING 3 (ELF3)4,7, a large scaffold protein and key component of temperature sensing; ELF4, a small α-helical protein; and LUX ARRYTHMO (LUX), a DNA-binding protein required to recruit the evening complex to transcriptional targets. ELF3 contains a polyglutamine (polyQ) repeat8-10, embedded within a predicted prion domain (PrD). Here we find that the length of the polyQ repeat correlates with thermal responsiveness. We show that ELF3 proteins in plants from hotter climates, with no detectable PrD, are active at high temperatures, and lack thermal responsiveness. The temperature sensitivity of ELF3 is also modulated by the levels of ELF4, indicating that ELF4 can stabilize the function of ELF3. In both Arabidopsis and a heterologous system, ELF3 fused with green fluorescent protein forms speckles within minutes in response to higher temperatures, in a PrD-dependent manner. A purified fragment encompassing the ELF3 PrD reversibly forms liquid droplets in response to increasing temperatures in vitro, indicating that these properties reflect a direct biophysical response conferred by the PrD. The ability of temperature to rapidly shift ELF3 between active and inactive states via phase transition represents a previously unknown thermosensory mechanism.

CXCR7 promotes migration and invasion in head and neck squamous cell carcinoma by upregulating TGF-ß1/Smad2/3 signaling.

The chemokine receptor CXCR7 has been suggested to play important roles in the progression of several types of cancers. However, few studies have investigated the biological roles of CXCR7 in head and neck squamous cell carcinoma (HNSCC). CXCR7 expression and its clinical implications were examined in 103 HNSCC tissues using immunohistochemistry (IHC). The biological roles and mechanisms of CXCR7-mediated signaling pathways were investigated in HNSCC cells through CXCR7 overexpression in vitro and in vivo. High expression of CXCR7 was significantly associated with tumor size (P = 0.007), lymph node metastasis (P = 0.004), and stage (P = 0.020) in HNSCC. Overexpression of CXCR7 in HNSCC cells enhanced cell migration and invasion in vitro and promoted lymph node metastasis in vivo. CXCR7 also induced epithelial-mesenchymal transition through PI3K/AKT. CXCR7 increased secretion of transforming growth factor-ß1 (TGF-ß1) and promoted EMT through phosphorylated Smad2/3. Taken together, our results provide functional and mechanistic roles of CXCR7 as a master regulator of oncogenic TGF-ß1/Smad2/3 signaling in HNSCC, suggesting that CXCR7 might be a therapeutic target for the treatment of HNSCC.

Decursin inhibits tumor growth, migration, and invasion in gastric cancer by down-regulating CXCR7 expression.

CXC chemokine receptor 7 (CXCR7) is highly expressed in various type of cancers and promotes cancer progression and metastasis. However, the biological role and regulation of CXCR7 in gastric cancer remains unclear, and little is known about compounds that modulate CXCR7. Here, we investigated the role of CXCR7 in gastric tumorigenesis, and the effects of decursin, which is derived from Angelica gigas Nakai, on CXCR7. Our results showed that CXCR7 significantly promoted growth of gastric cancer cells and increased migration and invasion, which was mediated by the STAT3/c-Myc pathway. We also confirmed that decursin had an antitumor effect through down-regulating the expression of CXCR7 in gastric cancer. Furthermore, apoptotic cell death was induced through the reduction of anti-apoptotic factors such as Bcl-2 in vitro and in vivo. Our findings show that CXCR7 in gastric cancer promotes cancer progression through the STAT3/c-Myc pathway and that decursin is a natural compound that may target CXCR7 in gastric cancer treatment.

Anti-cancer activity of the novel 2-hydroxydiarylamide derivatives IMD-0354 and KRT1853 through suppression of cancer cell invasion, proliferation, and survival mediated by TMPRSS4.

Elevated expression of transmembrane serine protease 4 (TMPRSS4) correlates with poor prognosis in non-small cell lung cancer, gastric cancer, colorectal cancer, prostate cancer, and other cancer patients. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, proliferation, and metastasis. In addition, we reported novel 2-hydroxydiarylamide derivatives, IMD-0354 and KRT1853, as TMPRSS4 serine protease inhibitors. Here, we further evaluated the effects of the representative derivatives on TMPRSS4-mediated cellular function and signaling. IMD-0354 and KRT1853 inhibited cancer cell invasion, migration, and proliferation in TMPRSS4-expressing prostate, colon, and lung cancer cells. Both compounds suppressed TMPRSS4-mediated induction of Sp1/3, AP-1, and NF-κB transcription factors. Furthermore, TMPRSS4 promoted cancer cell survival and drug resistance, and both compounds enhanced anoikis sensitivity as well as reduced bcl-2 and survivin levels. Importantly, KRT1853 efficiently reduced tumor growth in prostate and colon cancer xenograft models. These results strongly recommend KRT1853 for further development as a novel anti-cancer agent.

Relief of knee flexion contracture and gait improvement following adaptive training for an assist device in a transtibial amputee: A case study.

BACKGROUND: Management of a knee contracture is important for regaining gait ability in transtibial amputees. However, there has been little study of prosthesis training for enhancing mobility and improving range of motion in cases of restricted knee extension. OBJECTIVE: This study aimed to evaluate the effects of adaptive training for an assist device (ATAD) for a transtibial amputee with a knee flexion contracture (KFC). A male transtibial amputee with KFC performed 4 months of ATAD with a multidisciplinary team. During the ATAD, the passive range of motion (PROM) in the knee, amputee mobility predictor (AMP) assessment, center of pressure (COP) on a force plate-equipped treadmill, gait features determined by three-dimensional motion analysis, and Short-Form 36 Item Health Survey (SF-36) scores were evaluated. RESULTS: Following ATAD, PROM showed immediate improvement (135.6 ± 2.4° at baseline, 142.5 ± 1.7° at Step 1, 152.1 ± 1.8° at Step 2, 165.8 ± 1.9° at Step 3, and 166.0 ± 1.4° at Step 4); this was followed by an enhanced COP. Gradually, gait features also improved. Additionally, the AMP score (5 at baseline to 29 at Step 4) and K-level (K0 at baseline to K3 at Step 4) increased after ATAD. Along with these improvements, the SF-36 score also improved. CONCLUSIONS: ATAD could be beneficial for transtibial amputees by relieving knee contractures and improving gait.

Evaluation of physical and emotional responses to vibrotactile stimulation of the forearm in young adults, the elderly, and transradial amputees.

Vibrotactile stimulation (VS) is widely used in the biomedical and biomechanics fields. Most studies have attempted to verify the effects and/or function of VS, but few studies have evaluated emotional response (ER) to VS, although emotions play a critical role in human behavior. This study aimed to evaluate the subjective response (SR) to VS in young, elderly, and amputee adults and to verify whether VS on the forearm evokes displeasure. Twenty-four young adults (YM: male 13, YF: female 11), 31 elderly subjects (EM: male 15, EF: female 16), and 19 transradial amputees (AM: male 11, AF: female 8) participated. Eight equally spaced vibration motors were attached around the circumference of the forearm (channels 1-4 on the lateral site and channels 5-8 on the medial site) and were located 25% of the proximal forearm. Vibration stimuli with frequencies ranging from 37Hz to 258Hz were applied. An SR 10-level test and ER (displeasure or not) test were performed. In all 3 groups, SRs to the lateral site were higher than those to the medial site (YM group, p<0.001; YF group, p=0.002; EM group, p<0.001; EF group, p=0.031; AM group, p<0.001; AF group, p=0.021). Additionally, SRs were saturated at certain frequencies (YM group, 149Hz; YF and EM groups, 198Hz; EF and AM groups, 120Hz; AF group, 176Hz). Several subjects (YM group, 7; YF group, 4; EM group, 2; EF group, 6; AM group, 3; AF group, 1) expressed displeasure, and ERs were different according to sex, age, or amputation. As a result, the lateral site was more sensitive to VS than the medial site, regardless of sex, age, or amputation. Furthermore, VS may evoke displeasure.

Lumbopelvic kinematic characteristics of golfers with limited hip rotation.

BACKGROUND: While the biomechanical characteristics of the golf swing are well established, the lumbopelvic kinematic characteristics of professional golfers with limited hip internal rotation warrant further investigation. PURPOSE: The specific aim was to ascertain mechanical differences in lumbopelvic-hip movement of asymptomatic professional golfers with and without limited hip internal rotation during the golf swing. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty professional male golfers (aged 25-35 years and 0 handicap matched) were classified into either the limited hip internal motion (LHIM) group (range of motion<20°) or the normal hip internal motion (NHIM) group (range of motion≥30°). All participants underwent clinical tests (muscle strength, muscle length, and range of motion) and a biomechanical assessment using 8 infrared optic cameras in a motion analysis system. Independent t tests were performed to determine potential mean differences in muscle strength, length, and range of motion and lumbopelvic kinematics at P<.05. RESULTS: Kinematic analysis revealed that the LHIM group showed significantly greater lumbar flexion (P<.001), right and left axial rotation (P<.025), and right-side lateral bending (P=.003) than the NHIM group. A greater pelvic posterior tilt was observed in the LHIM group when compared with the NHIM group (P=.021). Clinical tests showed reduced internal rotator muscle strength and shorter muscle length in the iliopsoas (P=.017) and hamstring (P<.001) among those in the LHIM group when compared with the NHIM group. CLINICAL RELEVANCE: The study data suggest that constraints to hip joint internal rotation, along with muscle strength imbalances between the agonist and antagonist muscles and muscle tightness, are associated with substantially greater lumbopelvic movement during the golf swing.

Assessment of forearm and plantar foot load in the elderly using a four-wheeled walker with armrest and the effect of armrest height.

BACKGROUND: Patients with hand and/or wrist pathology are recommended to have a four-wheeled walker with an arm rest (FWW-AR) rather than a standard walker or a standard four-wheeled walker (FWW). However, only a few quantitative studies have been performed to compare upper and lower extremity weight bearing. The aim of this study was to evaluate forearm and foot weight bearing using a FWW-AR and the effect of the armrest height. METHODS: Eleven elderly women (mean age 80.1±5.3 years; mean height 148.5±4.0 cm; mean weight 51.2±9.0 kg) were enrolled. The subjects walked with an FWW-AR, with the elbow in either 90 degree (D90) or 130 degree (D130) flexion, for a distance of 10 m. Surface electromyographic signals were recorded for the upper, middle, and lower trapezius, anterior deltoid, and erector spinae muscles; walking velocity was measured with the subjects weight bearing on their feet and forearms while walking. Simultaneously, the maximum plantar and forearm loads during walking with an FWW-AR were measured. RESULTS: The normalized foot plantar loads were lower at D90 than at D130, while the normalized forearm load was higher at D90 than at D130 (all P<0.05; left foot, 7.9±0.1 N/kg versus 8.8±0.1 N/kg; right foot, 8.6±0.2 N/kg versus. 9.6±0.1 N/kg; left forearm, 1.8±0.5 N/kg versus 0.8±0.2 N/kg; and right forearm, 2.0±0.5 N/kg versus 1.0±0.2 N/kg, respectively). The surface electromyographic activity of the muscles involved in shoulder elevation and the walking velocity were both lower with the elbow at D90 than at D130 (all P<0.05; left upper trapezius, 98.7%±19.5% versus 132.6%±16.9%; right upper trapezius, 83.4%±10.6% versus 108.1%±10.5%; left anterior deltoid, 94.1%±12.8% versus 158.6%±40.4%; right anterior deltoid, 99.1%±15.0% versus 151.9%±19.4%; and velocity, 0.6±0.1 m/sec versus 0.7±0.1 m/sec, respectively). CONCLUSION: Weight bearing on the lower extremities is significantly reduced when the upper extremities are supported during walking with an FWW-AR. Furthermore, the weight bearing profile is dependent on the armrest height.

Linear- and nonlinear-electromyographic analysis of supracutaneous vibration stimuli of the forearm using diverse frequencies and considering skin physiological properties.

Numerous studies have reported the efficacy of vibration in sensory feedback or substitution devices for users of myoelectric hand prostheses. Although most myoelectric hand prostheses are presently manipulated by a surface electromyogram (sEMG), only a few studies have been conducted on the effect of vibration on an sEMG. This study aimed to determine whether vibration stimulation affects the linear and nonlinear properties of surface electromyography (sEMG) considering the skin properties. The vibration stimuli, with frequencies ranging from 37 to 258 Hz, were applied to the proximal part of the arms of the eight female and seven male subjects. The skinfold thickness, hardness, and vibration threshold at the stimuli loci were measured. The root mean square (rms) and fractal dimension (DF) of the sEMG were measured at a distance of 1 cm in the upward direction from the stimuli loci. Above 223 Hz there were no differences between the rms of the genders in between the vibration stimuli (p > 0.05). Moreover, no differences were observed between the DF of the genders for any frequency (p > 0.05). Above 149 Hz, there were correlations between the rms and the skin hardness in the females. Otherwise, no correlations were observed between the rms and DF and the skin properties in both genders for most of the frequencies (all p > 0.05). These results suggest that vibration stimuli affect the linear properties of the sEMG, but not the nonlinear properties.