Combination therapy of lymphatic drug delivery and total body irradiation in a metastatic lymph node and lung mouse model.

Chemotherapy using a lymphatic drug delivery system (LDDS) targeting lymph nodes (LNs) in the early stage of metastasis has a superior antitumor effect to systemic chemotherapy. An LDDS produces a higher drug retention rate and tissue selectivity in LNs. To expand the therapeutic coverage of LDDS from local treatment of metastatic LNs to prevention of distant metastases, the combination of treatment with therapies that enhance systemic tumor immune effects is an important therapeutic strategy. Recently, total body irradiation (TBI) has been shown to activate immune responses and alter the tumor microenvironment. Here we show that combination therapy with TBI and LDDS improves the antitumor effect of metastatic LNs and lung metastasis. Tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis into the proper axillary LN (PALN) and lung in a mouse model. TBI was carried out on day 4 after inoculation using a gamma irradiator. Lymphatic drug delivery into the accessory axillary LN was used to treat PALN. In vivo bioluminescence imaging, high-frequency ultrasound, and histology showed that combination therapy using TBI (total dose 1.0 Gy once) and the LDDS suppressed tumor growth in LNs and lung metastases and was more effective than using LDDS or TBI alone. Quantitative RT-PCR of spleens after combination therapy revealed increased expression of CD4, CD8, and IL-12b, indicating an activated immune response. The results show that combination therapy with TBI and LDDS is a method to improve the efficacy of LN metastases and distant metastases therapy and is a promising novel approach to treat cancer patients.

Drug formulation augments the therapeutic response of carboplatin administered through a lymphatic drug delivery system.

Treatment of metastatic lymph nodes (LNs) is challenging due to their unique architecture and biophysical traits. Systemic chemotherapy fails to impede tumor progression in LNs due to poor drug uptake and retention by LNs, resulting in fatal systemic metastasis. To effectively treat LN metastasis, achieving specific and prolonged retention of chemotherapy drugs in the tumor-draining LNs is essential. The lymphatic drug-delivery system (LDDS) is an ultrasound-guided drug-delivery methodology for administration of drugs to LNs that addresses these requirements. However, early-stage metastatic LNs have an additional set of drug transport barriers, such as elevated intranodal pressure and viscosity, that negatively impact drug diffusion. In the present study, using formulations of elevated osmotic pressure and viscosity relative to saline, we sought to favorably alter the LN's physical environment and study its impact on pharmacokinetics and consequently the therapeutic efficacy of carboplatin delivered using the LDDS. Our study confirmed the capability of a drug formulation with elevated osmotic pressure and viscosity to alter the architecture of LNs, as it caused notable expansion of the lymphatic sinus. Additionally, the study delineated an optimal range of osmotic pressure and viscosity, centered around 1897 kPa and 11.5 mPa·s, above and below which therapeutic efficacy was found to decline markedly. These findings suggest that formulation osmotic pressure and viscosity are parameters that require critical consideration as they can both hinder and promote tumorigenesis. The facile formulation reported here has wide-ranging applicability across cancer spectrums and is thus anticipated to be of great clinical benefit.

Intranodal delivery of modified docetaxel: Innovative therapeutic method to inhibit tumor cell growth in lymph nodes.

Delivery of chemotherapeutic agents into metastatic lymph nodes (LNs) is challenging as they are unevenly distributed in the body. They are difficult to access via traditional systemic routes of drug administration, which produce significant adverse effects and result in low accumulation of drugs into the cancerous LN. To improve the survival rate of patients with LN metastasis, a lymphatic drug delivery system (LDDS) has been developed to target metastatic LN by delivering chemotherapy agents into sentinel LN (SLN) under ultrasound guidance. The LDDS is an advanced method that can be applied in the early stage of the progression of tumor cells in the SLN before tumor mass formation has occurred. Here we investigated the optimal physicochemical ranges of chemotherapeutic agents' solvents with the aim of increasing treatment efficacy using the LDDS. We found that an appropriate osmotic pressure range for drug administration was 700-3,000 kPa, with a viscosity < 40 mPa⋅s. In these physicochemical ranges, expansion of lymphatic vessels and sinuses, drug retention, and subsequent antitumor effects could be more precisely controlled. Furthermore, the antitumor effects depended on the tumor progression stage in the SLN, the injection rate, and the volumes of administered drugs. We anticipate these optimal ranges to be a starting point for developing more effective drug regimens to treat metastatic LN with the LDDS.

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system.

Lymph node (LN) metastasis is thought to account for 20-30% of deaths from head and neck cancer. The lymphatic drug delivery system (LDDS) is a new technology that enables the injection of drugs into a sentinel LN (SLN) during the early stage of tumor metastasis to treat the SLN and secondary metastatic LNs. However, the optimal physicochemical properties of the solvent used to carry the drug have not been determined. Here, we show that the osmotic pressure and viscosity of the solvent influenced the antitumor effect of cisplatin (CDDP) in a mouse model of LN metastasis. Tumor cells were inoculated into the proper axillary LN (PALN), and the LDDS was used to inject CDDP solution into the subiliac LN (SiLN) to treat the tumor cells in the downstream PALN. CDDP dissolved in saline had no therapeutic effects in the PALN after it was injected into the SiLN using the LDDS or into the tail vein (as a control). However, CDDP solution with an osmotic pressure of ~ 1,900 kPa and a viscosity of ~ 12 mPa⋅s suppressed tumor growth in the PALN after it was injected into the SiLN using the LDDS. The high osmotic pressure dilated the lymphatic vessels and sinuses to enhance drug flow in the PALN, and the high viscosity increased the retention of CDDP in the PALN. Our results demonstrate that optimizing the osmotic pressure and viscosity of the solvent can enhance the effects of CDDP, and possibly other anticancer drugs, after administration using the LDDS.

Intranodal pressure of a metastatic lymph node reflects the response to lymphatic drug delivery system.

Cancer metastasis to lymph nodes (LNs) almost certainly contributes to distant metastasis. Elevation of LN internal pressure (intranodal pressure, INP) during tumor proliferation is associated with a poor prognosis for patients. We have previously reported that a lymphatic drug delivery system (LDDS) allows the direct delivery of anticancer drugs into the lymphatic system and is a promising treatment strategy for early-stage LN metastasis. However, methods for evaluating the treatment effects have not been established. Here, we used a mouse model of MXH10/Mo-lpr/lpr, which develops a systemic swelling of LNs, and murine malignant fibrous histiocytoma-like (KM-Luc/GFP) cells or murine breast cancer (FM3A-Luc) cells inoculated into the subiliac LN of mice to produce a tumor-bearing LN model. The changes in INP during intranodal tumor progression and after treatment with cis-dichlorodiammineplatinum(II) (CDDP) using an LDDS were measured. We found that tumor progression was associated with an increase in INP that occurred independently of LN volume changes. The elevation in INP was suppressed by CDDP treatment with the LDDS when intranodal tumor progression was significantly inhibited. These findings indicate that INP is a useful parameter for monitoring the therapeutic effect in patients with LN metastasis who have been given drugs using an LDDS, which will serve to manage cancer metastasis treatment and contribute to an improved quality of life for cancer patients.

In vivo delivery of an exogenous molecule into murine T lymphocytes using a lymphatic drug delivery system combined with sonoporation.

Physical delivery of exogenous molecules into lymphocytes is extremely challenging because conventional methods have notable limitations. Here, we evaluated the potential use of acoustic liposomes (ALs) and sonoporation to deliver exogenous molecules into lymphocytes within a lymph node (LN). MXH10/Mo-lpr/lpr (MXH10/Mo/lpr) mice, which show systemic LN swelling, were used as the model system. After direct injection into the subiliac LN, a solution containing both ALs and TOTO-3 fluorophores (molecular weight: 1355) was able to reach the downstream proper axillary LN (PALN) via the lymphatic vessels (LVs). This led to the accumulation of a high concentration of TOTO-3 fluorophores and ALs in the lymphatic sinuses of the PALN, where a large number of lymphocytes were densely packed. Exposure of the PALN to >1.93 W/cm2 of 970-kHz ultrasound allowed the solution to extravasate into the parenchyma and reach the large number of lymphocytes in the sinuses. Flow cytometric analysis showed that TOTO-3 molecules were delivered into 0.49 ± 0.23% of CD8+7AAD- cytotoxic T lymphocytes. Furthermore, there was no evidence of tissue damage. Thus, direct administration of drugs into LVs combined with sonoporation can improve the delivery of exogenous molecules into primary lymphocytes. This technique could become a novel approach to immunotherapy.

Lymph node resection induces the activation of tumor cells in the lungs.

Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment, and for predicting patient survival. Activation of lung metastatic lesions after LN dissection has been described for head and neck cancer and breast cancer. Preclinical studies have reported that dissection of a tumor-bearing LN is involved in the activation and rapid growth of latent tumor metastases in distant organs, but it is also important to understand how normal (non-tumor-bearing) LN resection influences secondary cancer formation. Here, we describe how the resection of tumor-bearing and non-tumor-bearing LN affects distant metastases in MXH10/Mo-lpr/lpr mice. Tumor cells were administered intravenously and/or intranodally into the right subiliac lymph node (SiLN) to create a mouse model of lung metastasis. Luciferase imaging revealed that tumor cells in the lung were activated after resection of the SiLN, irrespective of whether it contained tumor cells. No luciferase activity was detected in the lungs of mice that did not undergo LN resection (excluding the intravenous inoculation group). Our results indicate that resection of an LN can activate distant metastases regardless of whether the LN contains tumor cells. Hence, lung metastatic lesions are suppressed while metastatic LN are present but activated after LN resection. If this phenomenon occurs in patients with cancer, it is likely that lung metastatic lesions may be activated by elective LN dissection in clinical N0 cases. The development of minimally invasive cancer therapy without surgery would help to minimize the risk of activation of distant metastatic lesions by LN resection.

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed destructive arthritis and enthesitis.

BACKGROUND: McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop destructive arthritis and enthesitis in the ankle. There is no published data that drug treatment has been trialed on these mice. This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of arthritis and enthesitis in McH-lpr/lpr-RA1 mice. METHODS: Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines. RESULTS: Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at 14 and 17 weeks of age. The kappa coefficient was 0.77. However, progression of entheseal ossification persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups. CONCLUSIONS: Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for destructive arthritis and enthesitis. IL-6 signal blockade could contribute to the treatment of destructive arthritis, and further studies should be carried out to confirm its potential in the prevention of enthesopathy developed to ossification.

Why does the Quiet Eye improve aiming accuracy? Testing a motor preparation hypothesis with brain potential.

The purpose of the present study was to determine whether the Quiet Eye (QE) acquired over time is associated with motor preparation processes by using movement-related cortical potentials (MRCPs). Eighteen male, right-handed college students voluntarily participated in this study. Participants performed a dart throw while wearing an eye-tracking system and electrode cap to measure electroencephalogram waveforms (EEG). After performing the dart task, participants were randomly assigned to a Quiet Eye training group (QET) or control training group (CT). Six subjects were excluded due to incomplete electroencephalography (EEG) data. MRCPs were analysed separately within 4 QE categories: High performance score and Long fixation time (HL), High performance score and Short fixation time (HS), Low performance score and Long fixation time (LL), and Low performance score and Short fixation time (LS). Results revealed that although the QET group acquired QE characteristics, MRCPs did not differ between the two groups. Thus, a longer-term experimental design may be necessary to observe EEG changes. Furthermore, QE durations may relate to not only motor programming but also online control.

The Effect of Choice on Motor Learning for Learners With Different Levels of Intrinsic Motivation.

This study examines whether the positive effect of choice on motor learning in a dart-throwing task varies by intrinsic motivation. Participants were allocated to a highly motivated or less-motivated group based on measured task motivation and randomly to a Choice or No Choice group. In Experiment 1, participants in the Choice group chose their dart color. In Experiment 2, they chose when to observe a model demonstration. Results showed that the effect of choice on motor learning differed between highly and less-motivated participants in Experiment 1 (i.e., interaction between motivation and choice) but not Experiment 2 (i.e., main effects of motivation and choice). Specifically, motor learning was enhanced in less-motivated but not highly motivated participants when choosing dart color, while it was enhanced regardless of initial intrinsic motivation when choosing model-demonstration time. Therefore, external provision of choice in a motor-learning situation may not be equally effective across learners.

Evaluation of metastatic niches in distant organs after surgical removal of tumor-bearing lymph nodes.

BACKGROUND: Surgical removal of primary tumors can promote the incidence of tumor metastasis. However, molecular mechanisms underlying this process remain unclear. METHODS: We inoculated tumor cells expressing luciferase gene  into subiliac lymph node (SiLN) of the MXH10/Mo-lpr/lpr mice. The tumor-bearing SiLNs were surgically removed at a certain period of time after inoculation. RESULTS: In vivo bioluminescence imaging system and histological staining revealed metastasis in lung, proper axillary lymph node (PALN) and liver. The lung metastasis rate in SiLN removal groups was significantly higher than in the control group using Fisher exact test. Mann-Whitney U-test indicated that the luciferase-positive tumor cells in the lung and liver were significantly higher than in the control groups. The lung samples in SiLN removal groups had strong expression of lysine oxidase (LOX). Moreover, the number of CD11b+ cells in the lung and liver in the SiLN removal groups was significantly increased, which was positively correlated with LOX expression level. In addition, the condition of LOX and CD11b in liver was similar to lung. In the SiLN surgical removal groups, the matrix metalloproteinase (MMP)-2 and VEGFA expression in the lung tissues was significantly higher than in the control groups; the collagen fibers per area around the pulmonary vessels was quite significantly lower and negatively correlated with the expression of MMP-2 by Spearman's analysis. Our data indicated that the reticular fibers were deposited and disordered in the tumor tissues of the lungs in the removal groups, and the reticular fibers per area was higher than in the control groups. The tumor cells in the PALN of control groups were significantly higher than in the SiLN removal groups, and CD169+ and CD11c+ cells were also higher than in the SiLN removal groups. CONCLUSIONS: Altogether, surgical removal of the tumor-bearing lymph node promoted tumor metastasis through changing the niche in lung and liver. Treatment targeting the metastatic niche might be an effective strategy to prevent tumor metastasis, thereby possibly increasing the survival and reducing the incidence of metastasis in cancer patients.

Therapeutic effect of cisplatin given with a lymphatic drug delivery system on false-negative metastatic lymph nodes.

Systemic administration of drugs into the blood circulation is standard treatment for prevention of metastasis. However, systemic delivery cannot maintain sufficiently high concentrations of anticancer drugs in lymph nodes (LN). Here, we show that giving cisplatin (CDDP) using a lymphatic drug delivery system (LDDS) has the potential to treat false-negative metastatic LN. We found that in MXH10/Mo-lpr/lpr mice, which develop systemic swelling of LN up to 10 mm in diameter, accumulation of indocyanine green (ICG), which has a similar molecular weight to CDDP, in a target LN was greater for lymphatic delivery of ICG than for systemic (i.v.) administration. Furthermore, CDDP administration with a LDDS inhibited tumor growth in false-negative metastatic LN and produced fewer adverse effects than systemically given CDDP. We anticipate that drug delivery using a LDDS will, in time, replace systemic chemotherapy for the treatment of false-negative metastatic LN.

Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis.

Most solid cancers spread to new sites via the lymphatics before hematogenous dissemination. However, only a small fraction of an intravenously administered anti-cancer drug enters the lymphatic system to reach metastatic lymph nodes (LN). Here, we show that the enhanced permeability and retention (EPR) effect is not induced during the early stages of LN metastasis. Luciferase-expressing tumor cells were injected into the subiliac LN of the MXH10/Mo-lpr/lpr mouse to induce metastasis to the proper axillary LN (PALN). In vivo biofluorescence imaging was used to confirm metastasis induction and to quantify the EPR effect, measured as PALN accumulation of intravenously injected indocyanine green (ICG) liposomes. PALN blood vessel volume changes were measured by contrast-enhanced high-frequency ultrasound imaging. The volume and density of blood vessels in the PALN increased until day 29 after inoculation, whereas the LN volume remained constant. ICG retention was first detected on day 29 post-inoculation. While CD31-positive cells increased up to day 29 post-inoculation, α-smooth muscle actin-positive cells were detected on day 29 post-inoculation for the first time. These results suggest that the EPR effect was not induced in the early stages of LN metastasis; therefore, systemic chemotherapy would likely not be beneficial during the early stages of LN metastasis. The development of an alternative drug delivery system, independent of the EPR effect, is required for the treatment of LN metastasis.

Early diagnosis of lymph node metastasis: Importance of intranodal pressures.

Regional lymph node status is an important prognostic indicator of tumor aggressiveness. However, early diagnosis of metastasis using intranodal pressure, at a stage when lymph node size has not changed significantly, has not been investigated. Here, we use an MXH10/Mo-lpr/lpr mouse model of lymph node metastasis to show that intranodal pressure increases in both the subiliac lymph node and proper axillary lymph node, which are connected by lymphatic vessels, when tumor cells are injected into the subiliac lymph node to induce metastasis to the proper axillary lymph node. We found that intranodal pressure in the subiliac lymph node increased at the stage when metastasis was detected by in vivo bioluminescence, but when proper axillary lymph node volume (measured by high-frequency ultrasound imaging) had not increased significantly. Intravenously injected liposomes, encapsulating indocyanine green, were detected in solid tumors by in vivo bioluminescence, but not in the proper axillary lymph node. Basic blood vessel and lymphatic channel structures were maintained in the proper axillary lymph node, although sinus histiocytosis was detected. These results show that intranodal pressure in the proper axillary lymph node increases at early stages when metastatic tumor cells have not fully proliferated. Intranodal pressure may be a useful parameter for facilitating early diagnosis of lymph node metastasis.

Activation of latent metastases in the lung after resection of a metastatic lymph node in a lymph node metastasis mouse model.

Iatrogenic induction of regional and distant cancer metastases is a risk associated with clinical resection of tumor-positive sentinel lymph nodes. However, there have been no studies of this risk in a mouse model of cancer metastasis. Here, we report that resection of a tumor-bearing subiliac lymph node (SiLN) enhanced lung metastasis in a mouse model of lymph node metastasis. Bioluminescence imaging revealed that metastatic tumor cells in the secondary lymph node continued to grow after resection of the SiLN, and that the probability of metastasis to the lungs was increased when the interval between SiLN inoculation and resection was reduced. Futhermore, histological analysis demonstrated that latents in the lung were stimulated to grow after resection of the SiLN. Fluorescence imaging indicated that the route of tumor cell dissemination from SiLN to the lung was the venous system located over the SiLN. We speculate that our mouse model will be useful for studying the mechanisms of tumor cell latency, with a view to improving the detection and treatment of latent metastases.

Potential of rapid adjustment of brief interceptive action using predicted information.

Interceptive actions, such as hitting a ball in baseball or tennis, feature a moving target whose parameters (i.e., velocity or trajectory) differ across trials. This means that players are required to make rapid trial-by-trial adjustments. The purpose of this study was to determine whether a brief interceptive action could be adjusted using predicted sensory consequence of movement (pSCM) information, even under severe time constraints where the participants could not adjust their movement using only visual feedback. Participants performed an interceptive action for targets with two different velocities with different occurrence probabilities (20%, 50%, and 80%). Prior to movement onset, we applied transcranial magnetic stimulation (TMS) to the supplementary motor area (SMA), as TMS of the SMA is known to disrupt pSCM activity. We hypothesized that if pSCM information were used to adjust the motor parameters of a brief interception, then TMS would significantly increase the constant temporal error (i.e., the difference between the sum of reaction time and movement time and the total target visible time) for a target velocity with a low probability (20%). This hypothesis is based on the previous findings that the pSCM plays an important role in the adjustment of relatively brief interception. We found that while interceptions that lasted about 250 ms after movement onset were unaffected, interceptions that lasted about 350 ms after movement onset could be influenced by TMS. However, TMS interfered with performance provided that the delivery of the pulse occurred 100 ms before movement onset. This finding suggests that pSCM information that is used for a rapid adjustment is generated only in that specific time interval.

Guanine nucleotide-binding protein 1 is one of the key molecules contributing to cancer cell radioresistance.

Standard fractionated radiotherapy for the treatment of cancer consists of daily irradiation of 2-Gy X-rays, 5 days a week for 5-8 weeks. To understand the characteristics of radioresistant cancer cells and to develop more effective radiotherapy, we established a series of novel, clinically relevant radioresistant (CRR) cells that continue to proliferate with 2-Gy X-ray exposure every 24 h for more than 30 days in vitro. We studied three human and one murine cell line, and their CRR derivatives. Guanine nucleotide-binding protein 1 (GBP1) gene expression was higher in all CRR cells than their corresponding parental cells. GBP1 knockdown by siRNA cancelled radioresistance of CRR cells in vitro and in xenotransplanted tumor tissues in nude mice. The clinical relevance of GBP1 was immunohistochemically assessed in 45 cases of head and neck cancer tissues. Patients with GBP1-positive cancer tended to show poorer response to radiotherapy. We recently reported that low dose long-term fractionated radiation concentrates cancer stem cells (CSCs). Immunofluorescence staining of GBP1 was stronger in CRR cells than in corresponding parental cells. The frequency of Oct4-positive CSCs was higher in CRR cells than in parental cells, however, was not as common as GBP1-positive cells. GBP1-positive cells were radioresistant, but radioresistant cells were not necessarily CSCs. We concluded that GBP1 overexpression is necessary for the radioresistant phenotype in CRR cells, and that targeting GBP1-positive cancer cells is a more efficient method in conquering cancer than targeting CSCs.

Docetaxel administered through a novel lymphatic drug delivery system (LDDS) improved treatment outcomes for lymph node metastasis.

Recently, sentinel lymph nodes (LNs) have been recognized as a starting point of hematogenous metastasis; thus, an increase in the control rate of LN metastasis is expected to improve the survival rate. Although surgical treatment and radiation therapy are commonly used for the radical treatment of LNs, these treatments are associated with lymphedema, pain, and an extended hospital stay. In a recent mouse study, activation of metastatic tumors in distant organs was reported after removing LNs, with or without metastasis to the LNs. Thus, there is the necessity for cancer treatment that can replace LN removal. Here, we evaluated the treatment efficacy of lymphatic drug delivery system (LDDS) with osmotic pressure and viscosity escalated Docetaxel at the early stage of LN metastasis. MXH10/Mo/lpr mice were inoculated with mouse breast cancer cells into Subiliac LN to create the metastatic mouse model. Docetaxel was injected into mouse mammary carcinoma cells inoculated LN as a single shot (SS) or double shot (DS) to understand the therapeutic mechanism of a single shot or double shot intervention using an in vivo imaging system, histology, and qPCR. The results showed that the DS administration of docetaxel at 1,960 kPa (12 mPa∙s) had better therapeutic outcomes with increased complete response and improved survival with reduced adverse events. The results also revealed that administration of a DS of docetaxel enhances differentiation of T helper cells, and improves survival and therapeutic outcomes. From a safety perspective, LDDS-administered DS of low-concentration docetaxel without any other anticancer treatments to LNs a novel approach to cancer management of LN metastasis. We emphasize that LDDS is a groundbreaking method of delivering anticancer drugs specifically to cancer susceptible LNs and is designed to enhance the effectiveness of cancer treatment while minimizing side effects.

Fast-ball sports experts depend on an inhibitory strategy to reprogram their movement timing.

The purpose of our study was to clarify whether an inhibitory strategy is used for reprogramming of movement timing by experts in fast-ball sports when they correct their movement timing due to unexpected environmental changes. We evaluated the influence of disruption of inhibitory function of the right inferior frontal gyrus (rIFG) on reprogramming of movement timing of experts and non-experts in fast-ball sports. The task was to manually press a button to coincide with the arrival of a moving target. The target moved at a constant velocity, and its velocity was suddenly either increased or decreased in some trials. The task was performed either with or without transcranial magnetic stimulation (TMS), which was delivered to the region of the rIFG. Under velocity change conditions without TMS, the experts showed significantly smaller timing errors and a higher rate of reprogramming of movement timing than the non-experts. Moreover, TMS application during the task significantly diminished the expert group's performance, but not the control group, particularly in the condition where the target velocity decreases. These results suggest that experts use an inhibitory strategy for reprogramming of movement timing. In addition, the rIFG inhibitory function contributes to the superior movement correction of experts in fast-ball sports.

Intralymphatic injection of chemotherapy drugs modulated with glucose improves their anticancer effect.

Lymph node metastasis (LNM) has a significant impact on cancer prognosis, emphasizing the need for effective treatment strategies. This study investigated the potential use of high osmotic pressure drug solutions with low viscosity administration using a lymphatic drug delivery system (LDDS) to improve LNM treatment outcomes. The hypothesis was that injection of epirubicin or nimustine at high osmotic pressure but without altered viscosity would enhance drug retention and accumulation in LNs, thereby improving the efficacy of treatment. Biofluorescence analysis revealed enhanced drug accumulation and retention in LNs after administration using LDDS compared to intravenous (i.v) injection. Histopathological results demonstrated minimal tissue damage in the LDDS groups. Pharmacokinetic analysis revealed an improved treatment response with higher drug accumulation and retention in LNs. The LDDS approach offers the potential for greatly reduced side effects of chemotherapy drugs, lower dosage requirements and crucially increased drug retention in LNs. The results highlight the promise of high osmotic pressure drug solutions with low viscosity administrated using the LDDS for enhancing the treatment efficacy of LN metastasis. Further research and clinical trials are warranted to validate these results and optimize the clinical translation of this novel treatment technique.