Sex Difference in the Effect of Bifidobacterium longum on Repeated Water Avoidance Stress-induced Gut Dysbiosis in Wistar Rats.

Dysbiosis in gut microbiota is known to contribute to development of irritable bowel syndrome. We tried to investigate the effect of Bifidobacterium longum on repeated water avoidance stress (WAS) in a Wistar rat model. The three groups (no-stress, WAS, and WAS with B. longum) of rats were allocated to sham or WAS for 1 hour daily for 10 days, and B. longum was administered through gavage for 10 days. Fecal pellet numbers were counted at the end of each 1-hour session of WAS. After 10 days of repeated WAS, the rats were eutanized, and the feces were collected. WAS increased fecal pellet output (FPO) significantly in both sexes (P < 0.001), while the female B. longum group showed significantly decreased FPO (P = 0.005). However, there was no consistent change of myeloperoxidase activity and mRNA expression of interleukin-1ß and TNF-α. Mast cell infiltration at colonic submucosa increased in the female WAS group (P = 0.016). In terms of fecal microbiota, the repeated WAS groups in both sexes showed different beta-diversity compared to control and WAS with B. longum groups. WAS-induced mast cell infiltration was reduced by the administration of B. longum in female rats. Moreover, administration of B. longum relieved WAS-caused dysbiosis, especially in female rats. In conclusion, B. longum was beneficial for WAS-induced stress in rats, especially in females.

Design of PD-L1-Targeted Lipid Nanoparticles to Turn on PTEN for Efficient Cancer Therapy.

Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue-specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor-targeting peptides into the LNPs; the programmed death ligand 1 (PD-L1) binding peptides are conjugated to PEGylated lipids via a copper-free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD-L1 proteins, which leads to the uptake of LNPs into PD-L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN-deficient triple-negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy-mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor-targeted LNPs for mRNA-based cancer therapy.

A Prospective Multi-Centered Registry-Based Observational Study for Patients With Cancer: Design and Rationale for Korean Medicine Cancer Registry (KMCARE).

BACKGROUND: Cancer is one of the leading causes of death in most countries with an expected increased burden on healthcare systems. Since integrative medical treatments are not collected within the scope of existing cancer registries, the establishment of the Korean Medicine Cancer Registry (KMCARE), gathering integrative therapies, including conservative care and Korean medicine, is warranted. METHODS: A prospective observational study based on the registry will be conducted in 5 Korean medical hospitals. A total of 650 eligible participants undergoing Korean medicine treatments within 1 month of a diagnosis of lung, colorectal, stomach, or breast cancer are anticipated to be enrolled in the registry. Data collected in the KMCARE can be classified into patient information, received treatments, and outcomes. The primary outcome is the Functional Assessment of Cancer Therapy-General Questionnaire score at 3 months. Secondary outcomes include the MD Anderson Symptom Inventory-Core and the Body Constitution Questionnaire at 3 and 6 months. After 6 months of follow-up periods, survival surveillance will be continued for additional 18 months. Descriptive and statistical analysis of primary and secondary outcomes, baseline data, safety, survival, and prognostic factors will be performed. DISCUSSION: This is the first prospective, multi-centered, registry-based observational study of cancer patients in Korean medicine hospitals, which could reveal the current status of cancer patients receiving integrative cancer therapies, and provide better insight into the role of Korean medicine in palliative care for patients with cancer. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0007447.

Corrigendum: Comparative efficacy of Jaungo, a traditional herbal ointment, and a water-in-oil type non-steroidal moisturizer for radiation-induced dermatitis in patients with breast cancer: a prospective, randomized, single-blind, pilot study.

[This corrects the article DOI: 10.3389/fphar.2023.1216668.].

Exploring the origins of decreased sound tolerance in tinnitus patients.

This study aimed to confirm the characteristics of auditory function alterations in tinnitus patients with concomitant decreased sound tolerance (ST) and provide insights for developing tailored therapeutic approaches. A retrospective analysis was conducted on patient records from a tertiary university hospital's tinnitus clinic between March 2020 and June 2023. Demographic attributes and audiological profiles were reviewed. Patients were categorized into Group 1 if loudness discomfort level test outcomes were 77 dB or below, measured using an average of frequencies from 250 Hz to 8 kHz. The remaining patients were allocated to Group 2. Among the 434 tinnitus patients, 115 (26.5%) demonstrated decreased ST and were classified as Group 1. This group exhibited higher DPOAE amplitudes (p < 0.001), shortened latency, and decreased threshold of ABR wave V bilaterally (p < 0.05). No significant disparities were observed in gender, age, tinnitus handicap inventory, visual analog scale, and pure-tone audiometry results except subjective hyperacusis. Binary logistic regression analysis utilizing the forward conditional method revealed that the difference between groups was independently linked to DPOAE response at 7,277 Hz on the left side [B = 0.093, p < 0.001, EXP(B) = 1.07, 95% CI = 1.044-1.153]. Increased DPOAE amplitude and shorter and decreased ABR wave V in tinnitus patients with decreased ST might suggest a possible association with lesions in or around the superior olivary complex or higher central auditory pathway, potentially linked to the inhibition of medial olivocochlear efferents.

The Possible Preventative Role of Lactate- and Butyrate-Producing Bacteria in Colorectal Carcinogenesis.

Background/Aims: : The gut microbiome has emerged as a key player that mechanistically links various risk factors to colorectal cancer (CRC) etiology. However, the role of the gut microbiome in CRC pathogenesis remains unclear. This study aimed to characterize the gut microbiota in healthy controls (HCs) and patients with colorectal adenoma (AD) and CRC in subgroups based on sex and age. Methods: : Study participants who visited the hospital for surveillance of CRC or gastrointestinal symptoms were prospectively enrolled, and the gut microbiome was analyzed based on fecal samples. Results: : In terms of HC-AD-CRC sequence, commensal bacteria, including lactate-producing (Streptococcus salivarius) and butyrate-producing (Faecalibacterium prausnitzii, Anaerostipes hadrus, and Eubacterium hallii) bacteria, were more abundant in the HC group than in the AD and CRC groups. In the sex comparison, the female HC group had more lactate-producing bacteria (Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Lactobacillus ruminis) than the male HC group. In age comparison, younger subjects had more butyrate-producing bacteria (Agathobaculum butyriciproducens and Blautia faecis) than the older subjects in the HC group. Interestingly, lactate-producing bacteria (B. catenulatum) were more abundant in females than males among younger HC group subjects. However, these sex- and age-dependent differences were not observed in the AD and CRC groups. Conclusions: : The gut microbiome, specifically lactate- and butyrate-producing bacteria, which were found to be abundant in the HC group, may play a role in preventing the progression of CRC. In particular, lactate-producing bacteria, which were found to be less abundant in healthy male controls may contribute to the higher incidence of CRC in males.

Post-insertion technique to introduce targeting moieties in milk exosomes for targeted drug delivery.

BACKGROUND: Recently, increased attention has been given on exosomes as ideal nanocarriers of drugs owing to their intrinsic properties that facilitate the transport of biomolecular cargos. However, large-scale exosome production remains a major challenge in the clinical application of exosome-based drug delivery systems. Considering its biocompatibility and stability, bovine milk is a suitable natural source for large-scale and stable exosome production. Because the active-targeting ability of drug carriers is essential to maximize therapeutic efficacy and minimize side effects, precise membrane functionalization strategies are required to enable tissue-specific delivery of milk exosomes with difficulty in post-isolation modification. METHODS: In this study, the membrane functionalization of a milk exosome platform modified using a simple post-insertion method was examined comprehensively. Exosomes were engineered from bovine milk (mExo) with surface-tunable modifications for the delivery of tumor-targeting doxorubicin (Dox). The surface modification of mExo was achieved through the hydrophobic insertion of folate (FA)-conjugated lipids. RESULTS: We have confirmed the stable integration of functionalized PE-lipid chains into the mExo membrane through an optimized post-insertion technique, thereby effectively enhancing the surface functionality of mExo. Indeed, the results revealed that FA-modified mExo (mExo-FA) improved cellular uptake in cancer cells via FA receptor (FR)-mediated endocytosis. The designed mExo-FA selectively delivered Dox to FR-positive tumor cells and triggered notable tumor cell death, as confirmed by in vitro and in vivo analyses. CONCLUSIONS: This simple and easy method for post-isolation modification of the exosomal surface may be used to develop milk-exosome-based drug delivery systems.

Butylparaben promotes phosphatidylserine exposure and procoagulant activity of human red blood cells via increase of intracellular calcium levels.

Parabens are widely used as preservatives, added to products commonly used by humans, and to which individuals are exposed orally or dermally. Once absorbed into the body, parabens move into the bloodstream and travel through the systemic circulation. We investigated the potential impact of parabens on the enhanced generation of thrombin by red blood cells (RBCs), which are the principal cellular components of blood. We tested the effects of methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), butylparaben (BuP), and p-hydroxybenzoic acid on freshly isolated human RBCs. BuP and simultaneous exposure to BuP and PrP significantly increased phosphatidylserine (PS) externalization to the outer membranes of RBCs. PS externalization by BuP was found to be mediated by increasing intracellular Ca2+ levels in RBCs. The morphological changes in BuP-treated RBCs were observed under an electron microscope. The BuP-exposed RBCs showed increased thrombin generation and adhesion to endothelial cells. Additionally, the externalization of PS exposure and thrombin generation in BuP-treated RBCs were more susceptible to high shear stress, which mimics blood turbulence under pathological conditions. Collectively, we observed that BuP induced morphological and functional changes in RBCs, especially under high shear stress, suggesting that BuP may contribute to the thrombotic risk via procoagulant activity in RBCs.

The Protective Effect of Roseburia faecis Against Repeated Water Avoidance Stress-induced Irritable Bowel Syndrome in a Wister Rat Model.

Roseburia faecis, a butyrate-producing, gram-positive anaerobic bacterium, was evaluated for its usefulness against repeated water avoidance stress (WAS)-induced irritable bowel syndrome (IBS) in a rat model, and the underlying mechanism was explored. We divided the subjects into three groups: one without stress exposure, another subjected to daily 1-hour WAS for 10 days, and a third exposed to the same WAS regimen while also receiving two different R. faecis strains (BBH024 or R22-12-24) via oral gavage for the same 10-day duration. Fecal pellet output (FPO), a toluidine blue assay for mast cell infiltration, and fecal microbiota analyses were conducted using 16S rRNA metagenomic sequencing. Predictive functional profiling of microbial communities in metabolism was also conducted. FPO and colonic mucosal mast cell counts were significantly higher in the WAS group than in the control group (male, P = 0.004; female, P = 0.027). The administration of both BBH024 (male, P = 0.015; female, P = 0.022) and R22-12-24 (male, P = 0.003; female, P = 0.040) significantly reduced FPO. Submucosal mast cell infiltration in the colon showed a similar pattern in males. In case of fecal microbiota, the WAS with R. faecis group showed increased abundance of the Roseburia genus compared to WAS alone. Moreover, the expression of a gene encoding a D-methionine transport system substrate-binding protein was significantly elevated in the WAS with R. faecis group compared to that in the WAS (male, P = 0.028; female, P = 0.025) group. These results indicate that R. faecis is a useful probiotic for treating IBS and colonic microinflammation.

Design of siRNA Bioconjugates for Efficient Control of Cancer-Associated Membrane Receptors.

Research on siRNA delivery has seen tremendous growth over the past few decades. As one of the major delivery strategies, siRNA bioconjugates offer the potential to enhance and extend the pharmacological properties of siRNAs while minimizing toxicity. In this paper, we suggest the development of a siRNA conjugate platform with peptides and proteins that are ligands of target receptors for cancer treatment. The siRNA bioconjugates target and block the receptor membrane proteins, enter the cells through receptor-mediated endocytosis, and inhibit the expression of that same target membrane receptor, thereby doubly controlling the function of the membrane proteins. The three kinds of bioconjugates targeting CD47, PD-L1, and EGFR were synthesized via two different copper-free click chemistry reactions. Results showed the cellular uptake of each conjugate, reduction of target gene expression, and efficient functional control of receptor proteins. This platform provides an effective approach for regulating membrane proteins in various diseases beyond cancer.

Applying the concept of niche breadth to understand urban tree mortality in the UK.

Accelerated climate change has raised concerns about heightened vulnerability of urban trees, spurring the need to reevaluate their suitability. The urgency has also driven the widespread application of climatic niche-based models. In particular, the concept of niche breadth (NB), the range of environmental conditions that species can tolerate, is commonly estimated based on species occurrence data over the selected geographic range to predict species response to changing conditions. However, in urban environments where many species are cultivated out of the NB of their natural distributions, additional empirical evidence beyond presence and absence is needed not only to test the true tolerance limits but also to evaluate species' adaptive capacity to future climate. In this research, mortality trends of Acer and Quercus species spanning a 21-year period (2000-2021) from tree inventories of three major UK botanic gardens - the Royal Botanic Gardens, Kew (KEW), Westonbirt, the National Arboretum (WESB), and the Royal Botanic Garden Edinburgh (RBGE) - were analyzed in relation to their NB under long-term drought stress. As a result, Acer species were more responsive to drought and heat stress. For Acer, positioning below the lower limits of the precipitation of warmest quarter led to an increase in the probability of annual mortality by 1.2 and 1.3 % at KEW and RBGE respectively. In addition, the mean cumulative mortality rate increased corresponding to an increase in the number of niche positions below the lower limits of the selected bioclimatic variables. On the other hand, Quercus species in general exhibited comparable resilience regardless of their niche positions. Moreover, Mediterranean oaks were most tolerant, with cumulative mortality rates that were lower than those of native oaks in the UK. These findings further highlight the importance of incorporating ecological performance and recognizing species-specific adaptive strategies in climatic niche modeling.

Mono-(2-ethylhexyl)-phthalate potentiates methylglyoxal-induced blood-brain barrier damage via mitochondria-derived oxidative stress and bioenergetic perturbation.

Phthalates in contaminated foods and personal care products are one of the most frequently exposed chemicals with a public health concern. Phthalate exposure is related to cardiovascular diseases, including diabetic vascular complications and cerebrovascular diseases, yet the mechanism is still unclear. The blood-brain barrier (BBB) integrity disruption is strongly associated with cardiovascular and neurological disease exacerbation. We investigated BBB damage by di-(2-ethylhexyl) phthalate (DEHP) or its metabolite mono-(2-ethylhexyl) phthalate (MEHP) using brain endothelial cells and rat models. BBB damage by the subthreshold level of MEHP, but not a DEHP, significantly increased by the presence of methylglyoxal (MG), a reactive dicarbonyl compound whose levels increase in the blood in hyperglycemic conditions in diabetic patients. Significant potentiation in apoptosis and autophagy activation, mitochondria-derived reactive oxygen species (ROS) production, and mitochondrial metabolic disturbance were observed in brain ECs by co-exposure to MG and MEHP. N-acetyl cysteine (NAC) restored autophagy activation as well as tight junction protein impairment induced by co-exposure to MG and MEHP. Intraperitoneal administration of MG and MEHP significantly altered mitochondrial membrane potential and tight junction integrity in rat brain endothelium. This study may provide novel insights into enhancing phthalate toxicity in susceptible populations, such as diabetic patients.

Imaging of Facial Nerve With 3D-DESS-WE-MRI Before Parotidectomy: Impact on Surgical Outcomes.

OBJECTIVE: The intra-parotid facial nerve (FN) can be visualized using three-dimensional double-echo steady-state water-excitation sequence magnetic resonance imaging (3D-DESS-WE-MRI). However, the clinical impact of FN imaging using 3D-DESS-WE-MRI before parotidectomy has not yet been explored. We compared the clinical outcomes of parotidectomy in patients with and without preoperative 3D-DESS-WE-MRI. MATERIALS AND METHODS: This prospective, non-randomized, single-institution study included 296 adult patients who underwent parotidectomy for parotid tumors, excluding superficial and mobile tumors. Preoperative evaluation with 3D-DESS-WE-MRI was performed in 122 patients, and not performed in 174 patients. FN visibility and tumor location relative to FN on 3D-DESS-WE-MRI were evaluated in 120 patients. Rates of FN palsy (FNP) and operation times were compared between patients with and without 3D-DESS-WE-MRI; propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to adjust for surgical and tumor factors. RESULTS: The main trunk, temporofacial branch, and cervicofacial branch of the intra-parotid FN were identified using 3D-DESS-WE-MRI in approximately 97.5% (117/120), 44.2% (53/120), and 25.0% (30/120) of cases, respectively. The tumor location relative to FN, as assessed on magnetic resonance imaging, concurred with surgical findings in 90.8% (109/120) of cases. Rates of temporary and permanent FNP did not vary between patients with and without 3D-DESS-WE-MRI according to PSM (odds ratio, 2.29 [95% confidence interval {CI} 0.64-8.25] and 2.02 [95% CI: 0.32-12.90], respectively) and IPTW (odds ratio, 1.76 [95% CI: 0.19-16.75] and 1.94 [95% CI: 0.20-18.49], respectively). Conversely, operation time for surgical identification of FN was significantly shorter with 3D-DESS-WE-MRI (median, 25 vs. 35 min for PSM and 25 vs. 30 min for IPTW, P < 0.001). CONCLUSION: Preoperative FN imaging with 3D-DESS-WE-MRI facilitated anatomical identification of FN and its relationship to the tumor during parotidectomy. This modality reduced operation time for FN identification, but did not significantly affect postoperative FNP rates.

mRNA: A promising platform for cancer immunotherapy.

Messenger RNA (mRNA) is now in the limelight as a powerful tool for treating various human diseases, especially malignant tumors, thanks to the remarkable clinical outcomes of mRNA vaccines using lipid nanoparticle technology during the COVID-19 pandemic. Recent promising preclinical and clinical results that epitomize the advancement in mRNA and nanoformulation-based delivery technologies have highlighted the tremendous potential of mRNA in cancer immunotherapy. mRNAs can be harnessed for cancer immunotherapy in forms of various therapeutic modalities, including cancer vaccines, adoptive T-cell therapies, therapeutic antibodies, and immunomodulatory proteins. This review provides a comprehensive overview of the current state and prospects of mRNA-based therapeutics, including numerous delivery and therapeutic strategies.

Traditional herbal medicine for anorexia in patients with cancer: a systematic review and meta-analysis of randomized controlled trials.

Background: The purpose of this systematic review and meta-analysis was to evaluate the efficacy and safety of traditional herbal medicine (THM) for improving anorexia in patients with cancer. Methods: We searched for randomized controlled trials (RCTs) that evaluated orally administered THM for cancer-related anorexia using 10 databases from the inception to 1 August 2021. The primary outcome was an improvement in anorexia, measured with the total effective rate (TER) or visual analog scale (VAS). The secondary outcomes were the changes in body weight, the Karnofsky performance scale, acylated ghrelin, and adverse events. We used the Cochrane risk of bias assessment tool and the Grading of Recommendations Assessment, Development, and Evaluation method to assess the quality of the studies and the quality of the evidence. Results: A total of 26 RCTs were included, of which 23 were subjected to quantitative analysis. THM showed a significant improvement in anorexia measured with the TER [risk ratio (RR) 1.12, 95% confidence intervals (CI) 1.04-1.20] than appetite stimulants with moderate quality evidence and in the Karnofsky performance scale (RR 1.38, 95% CI 1.12-1.70) with low quality evidence but not in body weight gain (RR 0.98, 95% CI 0.80-1.20). THM showed a significant improvement in anorexia measured with the TER (RR 1.74, 95% CI 1.23-2.48) compared with usual care with low-quality evidence but did not significantly improve the VAS score (mean difference 0.72, 95% CI 0.00-1.43) or the level of acylated ghrelin (mean difference 0.94, 95% CI 1.08-2.97). There were no serious adverse events. Conclusion: This review suggests that THM may be considered a safe alternative therapeutic option for improving anorexia in patients with cancer. Nonetheless, more rigorous RCTs are needed due to methodological limitations. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42021276508.

Comparative efficacy of Jaungo, a traditional herbal ointment, and a water-in-oil type non-steroidal moisturizer for radiation-induced dermatitis in patients with breast cancer: a prospective, randomized, single-blind, pilot study.

Background: Radiation-induced dermatitis (RID) is one of the most prevalent side-effects of conventional cancer therapies; however, there is no standard treatment for its prevention. Therefore, this study aimed to evaluate the comparative efficacy and safety of Jaungo (mainly composed of Lithospermum erythrorhizon Siebold & Zucc. and Angelica sinensis (Oliv.) Diel) and the water-in-oil-type non-steroidal moisturizer for the prevention of RID in patients with breast cancer (BC). Methods: This is a prospective, single-blind, pilot randomized controlled trial. Between March 2021 and July 2022, 50 patients were randomly selected to use Jaungo or the moisturizer while undergoing postoperative radiation therapy (RT). Assessments were conducted nine times-every week while the patients underwent RT and 2 weeks after the end of therapy. The primary outcome was the incidence rate of RID grade ≥2. The secondary outcomes were the incidence rate of maximum grade RID, time to RID onset, RID-related quality of life (QOL) score, pain intensity, and adverse events. Results: The incidence rate of RID grade ≥2 was 24.0% and 20.0% in the Jaungo and the moisturizer groups, respectively, with no significant difference between the groups (p = 0.733). Regarding the secondary outcomes, the incidence rate of maximum grade RID (p = 0.890), mean time to RID onset (p = 0.092), cumulative incidence rate of RID (p = 0.280), RID-related QOL score, and maximum pain intensity (p = 0.844) also did not differ significantly between the groups. None of the subjects in either group experienced severe adverse effects, although one participant in the moisturizer group had mild fever and insomnia. Conclusion: These findings suggest that Jaungo has preventive efficacy without severe side-effects against RID in patients with BC that is comparable to that of the water-in-oil type non-steroidal moisturizer. Further extensive randomized controlled trials with larger sample sizes are warranted to validate our findings. Clinical Trial Registration: Clinical Research Information Service (CRIS), https://cris.nih.go.kr, identifier KCT0005971.

Postoperative rehabilitation using a digital healthcare system in patients with total knee arthroplasty: a randomized controlled trial.

INTRODUCTION: Digital healthcare systems based on augmented reality (AR) show promise for postoperative rehabilitation. We compared the effectiveness of AR-based rehabilitation and conventional rehabilitation after total knee arthroplasty (TKA). MATERIALS AND METHODS: We randomly allocated 56 participants to digital healthcare rehabilitation group (DR group) and conventional rehabilitation group (CR group). Participants in the CR group performed brochure-based home exercises for 12 weeks, whereas those in the DR group performed AR-based home exercises that showed each motion on a monitor and provided real-time feedback. The primary outcome was change in 4-m gait speed. The secondary outcomes were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, health-related quality of life [assessed by the EuroQoL 5-Dimension 5-Level (EQ5D5L) questionnaire], pain [measured using a numeric rating scale (NRS)], Berg Balance Scale (BBS), range of motion (ROM), and muscle strength. Outcomes were measured at baseline (T0) and 3 (T1), 12 (T2), and 24 (T3) weeks after randomization. RESULTS: There was no significant difference in baseline characteristics of participants between two groups, except age and body mass index. No group difference was observed in 4-m gait speed (0.37 ± 0.19 and 0.42 ± 0.28 for the DR and CR groups, respectively; p = 0.438). The generalized estimating equation model revealed no significant group by time interaction regarding for 4-m gait speed, WOMAC, EQ5D5L, NRS, BBS, ROM, and muscle strength score. All outcomes were significantly improved in both groups (p < 0.001). CONCLUSION: The use of a digital healthcare system based on AR improved the functional outcomes, pain, and quality of life of patients after TKA. AR-based rehabilitation may be useful treatment as an alternative to conventional rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT04513353). Registered on August 9, 2020. http://clinicaltrials.gov/ct2/show/NCT04513353 .

A randomized controlled trial of postoperative rehabilitation using digital healthcare system after rotator cuff repair.

A digital healthcare system based on augmented reality (AR) has promising uses for postoperative rehabilitation. We compare effectiveness of AR-based and conventional rehabilitation in patients after rotator cuff repair (RCR). This study randomly allocates 115 participants who underwent RCR to digital healthcare rehabilitation group (DR group) and conventional rehabilitation group (CR group). The DR group performs AR-based home exercises using UINCARE Home+, whereas the CR group performs brochure-based home exercises. The primary outcome is a change in the Simple Shoulder Test (SST) score between baseline and 12 weeks postoperatively. The secondary outcomes are the Disabilities of the Arm, Shoulder and Hand (DASH) score; Shoulder Pain And Disability Index (SPADI) score; EuroQoL 5-Dimension 5-Level (EQ5D5L) questionnaire score; pain; range of motion (ROM); muscle strength; and handgrip strength. The outcomes are measured at baseline, and at 6, 12, and 24 weeks postoperatively. The change in SST score between baseline and 12 weeks postoperatively is significantly greater in the DR group than in the CR group (p = 0.025). The SPADI, DASH, and EQ5D5L scores demonstrate group×time interactions (p = 0.001, = 0.04, and = 0.016, respectively). However, no significant differences over time are observed between the groups in terms of pain, ROM, muscle strength, and handgrip strength. The outcomes show significant improvement in both groups (all p < 0.001). No adverse events are reported during the interventions. AR-based rehabilitation shows better improvement in terms of shoulder function after RCR compared to conventional rehabilitation. Therefore, as an alternative to the conventional rehabilitation, the digital healthcare system is effective for postoperative rehabilitation.

Exosome-guided direct reprogramming of tumor-associated macrophages from protumorigenic to antitumorigenic to fight cancer.

Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance. In particular, tumor-associated macrophages (TAMs), as the predominant infiltrated immune cells in a tumor, play a pivotal role in regulating the immunosuppressive tumor microenvironment. As a potential therapeutic strategy to counteract TAMs, here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages. Exosomes derived from M1-type macrophages (M1-Exo) promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency. Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability, potentiating antitumor immunity surrounding the tumor. Strikingly, these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II, offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.

Impact of traditional East Asian medicine as an add-on therapy on survival and recurrence after surgery for breast cancer: A systematic review and meta-analysis.

Background: Breast cancer is the most common cancer in women. Patients with cancer increasingly incorporate complementary and alternative medicines, including traditional East Asian medicine (TEAM), for cancer prevention and treatment. This review aimed to determine the effectiveness and safety of TEAM for survival and recurrence after surgery in patients with breast cancer. Methods: We searched nine electronic databases up to 25 August 2022, for randomized controlled trials (RCTs) of TEAM to prevent the recurrence of breast cancer in female patients after mastectomy or breast-conserving surgery. The primary outcome was 5-year disease-free survival (DFS), and secondary outcomes were 5-year overall survival, locoregional and distant recurrence rates, and toxicity. This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to evaluate the quality of evidence. Results: From 368 citations, data from nine studies reporting on a total of 1240 patients were included in the systematic review, and eight studies were deemed suitable for the meta-analysis. TEAM combined with adjuvant chemotherapy showed a significant improvement in DFS (odds ratio [OR] 0.42%, 95% confidence interval [CI] 0.28 to 0.61, p < 0.00001) and overall survival (OR 0.44%, 95% CI 0.27 to 0.73, p = 0.001) compared to adjuvant chemotherapy alone. The reduction in the rate of total recurrence was favorable for TEAM combined with adjuvant chemotherapy compared to adjuvant chemotherapy alone (Risk ratio 0.49%, 95% CI 0.35 to 0.70; p < 0.0001). TEAM after adjuvant chemotherapy showed a significant advantage in DFS compared to no TEAM (OR 0.61%, 95% CI 0.41 to 0.92, p = 0.02). No severe adverse events related to TEAM were reported. The overall certainty of the evidence for DFS, overall survival, and the total recurrence rate were moderate when postoperative breast cancer patients used TEAM combined with adjuvant chemotherapy. Conclusion: Moderate-quality evidence suggests TEAM as an add-on therapy to adjuvant chemotherapy. TEAM may have the potential to improve long-term survival and prevent postoperative recurrence in patients with breast cancer. In future, more rigorous RCTs should be conducted to confirm these findings.