Utilizing fNIRS to investigate the impact of Baduanjin training on attentional function in post-stroke cognitive impairment patients: a study protocol for a randomized controlled trial.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a prevalent complication among stroke survivors. It not only directly impacts patients' cognitive abilities but also hampers their capacity to regain independence in daily activities, consequently diminishing their quality of life. Among the various cognitive deficits following stroke, impaired attention is the most frequently observed, influencing not only daily functioning but also higher cognitive functions like working memory, executive functioning, and language.Emerging evidence indicates that Baduanjin, a traditional Chinese exercise, may have a positive impact on enhancing attention in older adults with mild cognitive impairment and stroke survivors. However, the precise mechanisms behind this effect remain unclear. In this study, we employed Baduanjin training as an intervention to address attention decline in post-stroke cognitive impairment patients and to delve into the potential mechanisms through which Baduanjin training may enhance attention in individuals with PSCI. METHODS: In this prospective randomized controlled trial, we plan to recruit 72 participants diagnosed with post-stroke cognitive impairment (PSCI). These participants will be randomly assigned in a 1:1:1 ratio to one of three groups: Baduanjin training(left hemisphere stroke and right hemisphere stroke) and conventional treatment.The conventional treatment group will receive standard rehabilitation sessions. In addition to conventional treatment, participants in the octogenarian training groups will undergo octogenarian training sessions lasting 40 min, five times a week, over a total period of 12 weeks.The primary outcome measures will include the Montreal Cognitive Assessment (MoCA) scale and the Attentional Lateralization Index. These assessments will be conducted by a trained evaluator before the start of the intervention and at weeks 6 and 12 after the intervention begins.Secondary outcome measures will be assessed using the baseline Mandarin version of the Oxford Cognitive Screening (OCS-P) scale, the simplified Fugl-Meyer Motor Function Assessment (FMA) scale, the Pittsburgh Rehabilitation Participation (PRPS) scale, and the Activities of Daily Living (ADL) scale before and after the intervention, respectively. DISCUSSION: This trial aims to examine the impact of Baduanjin training on attentional lateralization among patients with post-stroke cognitive impairment (PSCI). Functional brain imaging utilizing near-infrared spectroscopy will be employed to investigate how Baduanjin exercise influences the structural and functional connectivity of distinct brain regions or brain networks. TRIAL REGISTRATION: Chictr.org.cn, ID: ChiCTR2300076533 . Registered on 11 October 2023.

Hydrogel-mediated tumor T cell infiltration and immune evasion to reinforce cancer immunotherapy.

Cancer immunotherapy has received increasing attention in tumor therapy. However, insufficient infiltration of T cells and over-expressed PD-L1 checkpoint in tumor cells severely impede cancer immunotherapy. Here, an injectable hydrogel was designed to reinforce T cell infiltration and inactivate PD-L1 for powerful cancer immunotherapy. The hydrogel was created by sodium alginate (SA) as the gelator, where linagliptin particles and BMS-202 particles were present in hydrogel micropores. After gelation in the tumor site, the linagliptin powerfully suppressed chemokine CXCL10 degradation, enabling the introduced CXCL10 to realize sustainable chemotaxis towards strong T cell infiltration. Meanwhile, the BMS-202 inactivated PD-L1 of tumor cells, thereby eliminating the PD-L1-governed immune evasion. Therefore, the hydrogel in combination with CXCL10 demonstrated powerful cancer immunotherapy against primary and distant tumors, along with efficient inhibition of lung metastasis. Our study not only offers a potent platform against tumors, but also provides a conceptually new approach to reinforce cancer immunotherapy.

A single-shot prophylactic tumor vaccine enabled by an injectable biomembrane hydrogel.

Prophylactic tumor vaccines hold great promise against tumor occurrence. However, their clinical efficacy remains low due to inadequate activation of strong-sustainable immunity. Herein, a biomembrane hydrogel was designed as a powerful single-shot prophylactic tumor vaccine. Mannose-decorated hybrid biomembrane (MHCM) modified with oxidized sodium alginate (OSA) was designed as a gelator (O-MHCM), where the hybrid biomembrane (HCM) is a hybridization of bacterial outer membrane vesicles (OMV) and tumor cell membranes (TCM). The O-MHCM enables quick gelation subcutaneously where the cysteine protease inhibitor E64 is encapsulated in hydrogel micropores. After a single vaccination of E64@O-MHCM hydrogel, MHCM and E64 are released sustainably due to OSA moiety degradation. The MHCM enables active targeting to dendritic cells (DC) and effective DC maturation. Meanwhile, the E64 enables sufficient antigen availability for subsequent cross presentation. Ultimately, strong and sustainable T lymphocyte-mediated immunity was elicited, demonstrating a strong prophylactic effect against breast tumors. This study provides a long-lasting platform to prevent tumor occurrence, opening an innovative avenue for the design of a single-shot prophylactic tumor vaccine. STATEMENT OF SIGNIFICANCE: Developing a single-shot prophylactic tumor vaccine to elicit strong-sustainable immunity is of great interest clinically. Here, a prophylactic tumor vaccine was designed using an injectable biomembrane hydrogel for achieving strong-sustainable immunity. The mannose-tailored hybrid biomembrane was modified with oxidized sodium alginate to result in a gelator, which enabled the formation of the hydrogel after subcutaneous injection. Cysteine protease inhibitor E64 was incorporated into the micropores of the hydrogel. The hydrogel induced strong-sustainable immunity through the continuous release of active components. This was facilitated by the mannose moiety, which enabled active targeting, as well as the antigen and adjuvant function of biomembrane, and the E64-enabled suppression of antigen degradation. The biomembrane hydrogel demonstrated powerful prevention of 4T1 breast tumors. This study offers an attractive strategy for designing a single-shot prophylactic tumor vaccine.

Tumor lysates-constructed hydrogel to potentiate tumor immunotherapy.

T cell-based immunotherapy (TCBI) is an emerging approach to combat tumors. However, the outcome of TCBI is still far from satisfaction clinically, owing to stumbling blocks from insufficient immunogenicity, T cell exhaustion and immune evasion from programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway. Herein, an injectable tumor lysates-constructed hydrogel is reported to address these issues. Chemically modified tumor lysates are, for the first time, designed as the gelator to intratumorally construct hydrogel, achieving a robust antigen reservoir to induce strong immunogenicity. Meanwhile, hydrogel-encapsulated nicotinamide riboside and SB415286 enable strong mitophagy in T cells to prevent their exhaustion as well as powerfully genetical suppression of PD-1 expression to regulate immune evasion. Thus, our injectable hydrogel creates a robust immune niche within tumor, enabling to significantly potentiate TCBI. Our strategy pharmacologically regulates body's own T cells in situ, demonstrating potent immunotherapeutic effects and offering a conceptually new approach for TCBI.

A photodynamic-mediated glutamine metabolic intervention nanodrug for triple negative breast cancer therapy.

"Glutamine addiction" is a unique feature of triple negative breast cancer (TNBC), which has a higher demand for glutamine and is more susceptible to glutamine depletion. Glutamine can be hydrolyzed to glutamate by glutaminase (GLS) for synthesis of glutathione (GSH), which is an important downstream of glutamine metabolic pathways in accelerating TNBC proliferation. Consequently, glutamine metabolic intervention suggests potential therapeutic effects against TNBC. However, the effects of GLS inhibitors are hindered by glutamine resistance and their own instability and insolubility. Therefore, it is of great interest to harmonize glutamine metabolic intervention for an amplified TNBC therapy. Unfortunately, such nanoplatform has not been realized. Herein, we reported a self-assembly nanoplatform (BCH NPs) with a core of the GLS inhibitor Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and photosensitizer Chlorin e6 (Ce6) and a shell of human serum albumin (HSA), enabling effective harmonization of glutamine metabolic intervention for TNBC therapy. BPTES inhibited the activity of GLS to block the glutamine metabolic pathways, thereby inhibiting the production of GSH to amplify the photodynamic effect of Ce6. While Ce6 not only directly killed tumor cells by producing excessive reactive oxygen species (ROS), but also deplete GSH to destroy redox balance, thus enhancing the effects of BPTES when glutamine resistance occurred. BCH NPs effectively eradicated TNBC tumor and suppressed tumor metastasis with favorable biocompatibility. Our work provides a new insight for photodynamic-mediated glutamine metabolic intervention against TNBC.

Radiotherapy-mediated redox homeostasis-controllable nanomedicine for enhanced ferroptosis sensitivity in tumor therapy.

Ferroptosis has received increasing attentions in cancer therapy owing to its unique advantages over apoptosis. However, ferroptosis is governed by the efficiency of reactive oxygen species (ROS) production and the tumor cell antioxidant microenvironment that compromises therapeutic efficacy of ferroptosis. It is of great significance to develop a strategy that can both achieve high-efficiency ROS production and modulate tumor cell antioxidant microenvironment to amplify ferroptosis. However, until now, such a strategy has rarely been realized. Here, we, for the first time, reported a radiotherapy -mediated redox homeostasis-controllable nanomedicine for amplifying ferroptosis sensitivity in tumor therapy. The nanomedicine is constructed by co-assembling a ferroptosis inducer hemin and a thioredoxin 1 (Trx-1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) with human serum albumin. For our nanomedicine, hemin converts H2O2 to ROS via Fenton reaction to induce ferroptosis while PX-12 effectively inhibits the activity of antioxidant Trx-1 to suppress ROS depletion, resulting in amplified ferroptosis. Particularly, combining radiotherapy with the nanomedicine, radiotherapy depletes the other key antioxidant glutathione and generates additional radiotherapy-induced ROS, further boosting the ferroptosis effect. Therefore, our strategy can simultaneously ensure efficient ROS production and regulation of tumor cell antioxidant microenvironment, thereby enhancing efficacy of ferroptosis in tumor therapy. Our work offers an innovative approach to amplify ferroptosis sensitivity against tumors by simultaneously promoting ROS production and regulating redox homeostasis. STATEMENT OF SIGNIFICANCE: The antioxidants such as thioredoxin 1 (Trx-1) and glutathione (GSH) in tumor cells, are significantly upregulated by the innate cancer cellular redox homeostasis, severely restricting the reactive oxygen species (ROS)-based therapy and compromising the effect of Fenton reaction-induced ferroptosis against tumors. It is urgent to develop a strategy to simultaneously achieve Fenton reaction-induced ferroptosis and regulate the cancer cellular redox homeostasis against upregulated levels of Trx-1 and GSH. A radiotherapy-mediated redox homeostasis-regulatable nanomedicine was designed for amplifying ferroptosis sensitivity in tumor therapy, where the therapeutic efficacy of ferroptosis against tumors can be significantly amplified by integrating Fenton reaction-induced and radiotherapy-induced ferroptosis as well as PX-12-enabled inhibition of antioxidant Trx-1 and radiotherapy-induced downregulation of antioxidant GSH levels.

Effect of high-frequency repetitive transcranial magnetic stimulation under different intensities upon rehabilitation of chronic pelvic pain syndrome: protocol for a randomized controlled trial.

INTRODUCTION: Nearly one in seven women worldwide suffers from chronic pelvic pain syndrome (CPPS) each year. Often, CPPS necessitates a combination of treatments. Studies have shown the good therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) upon CPPS. We wish to undertake a randomized controlled trial (RCT) to observe the effect of high-frequency rTMS at different intensities upon CPPS. METHODS AND ANALYSES: In this prospective, double-blinded RCT, 63 female CPPS participants will be recruited and randomized (1:1:1) to high-intensity rTMS, low-intensity rTMS, or sham rTMS. The control group will receive a 10-day course of conventional pelvic floor (PF) rehabilitation (neuromuscular stimulation, magnetic therapy, or light therapy of the PF). On the basis of conventional treatment, participants in the high-intensity rTMS group will receive pulses of 10 Hz with a resting motor threshold (RMT) of 110% for a total of 15,000 pulses. Participants in the low-intensity rTMS group will receive pulses of 10 Hz with an RMT of 80% with 15,000 pulses. The sham rTMS group will be subjected to sham stimulation with the same sound as produced by the real magnetic stimulation coil. The primary outcome will be determined using a visual analog scale, the Genitourinary Pain Index, Zung Self-Rating Anxiety Scale, and Zung Self-Rating Depression Scale. The secondary outcome will be determined by electromyography of the surface of PF muscles at baseline and after treatment completion. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee of Bao'an People's Hospital, Shenzhen, Guangdong Province (approval number: BYL20211203). The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences (Protocol version 1.0-20220709). TRIAL REGISTRATION: Chictr.org.cn, ID: ChiCTR2200055615. Registered on 14 January 2022, http://www.chictr.org.cn/showproj.aspx?proj=146720 . Protocol version 1.0-20220709.