Long-term Therapeutic Effects Research Articles

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

Evaluation of embedded modular branched stent graft in treating aortic arch aneurysm using imaging-based computational flow analysis

Embedded modular branched stent graft (EMBSG) was a new option for aortic arch aneurysm. However, the therapeutic effect of this innovative stenting technique has not been fully assessed. Computational fluid dynamics and three-dimensional structural analyses were performed on three patients (Patient I, Patient II and Patient III) with aortic arch aneurysm, both before and after EMBSG implantation. Patient-specific alterations from preoperative to postoperative were analyzed via morphological and functional metrics. Patient I and Patient II showed notable curvature changes and area reduction after intervention procedure. Three patients showed an increase in flow velocity after EMBSG implantation, while the pressure drop from ascending aorta to the aortic arch was remarkable in Patient I and Patient II with the value of 7.09 ​mmHg, and 10.95 ​mmHg, respectively. Patient I and Patient II also showed elevated time-averaged wall shear stress (TAWSS) in the stenting region, while Patient III showed a trivial change in TAWSS after intervention procedure. Three patients showed low relative residence time after EMBSG insertion. The short-term results of EMBSG in treating aortic arch aneurysm were promising. Hemodynamic parameters have the potential to assist in the outcome evaluation and might be used to guide the stent graft design and wise selection, thereby improving the long-term therapeutic effect in managing complex vascular disease.

Tandem peptide lipid CRISPR-Cas9 complex combating APP and APOE4 gene abnormality in Alzheimer's disease

Alzheimer's attacks 24 million global population and dominates 60-80% of existing cases of dementia. It causes the accumulation of beta-amyloid (Aβ) plaques in the hippocampus and entorhinal cortex, resulting in decreased mass from the brain. Recent studies have shown that the manifestation of this disease is due to an overaccumulation of abnormal Aβ protein due to abnormalities in the APP and APOE4 genes. Point mutations in the APP gene will create the toxic form of Aβ protein, namely Aβ42, and the toxic APOE4 gene will accelerate the onset of Aβ42 deposition and pro-inflammatory activity that exacerbates the degenerative process of the brain. Gene editing as a potential definitive therapy was recently a concern by researchers. CRISPR-Cas9 repairs the APP gene and substitutes the APOE4 gene with APOE3 by modifying the gene's DNA sequence. Nano complex CRISPR-Cas9 tandem peptide lipid is a model for clinicians to target brain nerve cells. In vivo research on an Alzheimer's mouse model proved the potential of nano-complex-based peptides as carriers of CRISPR-Cas9 in brain nerve cells. This engineering technology offers satisfactory results with high precision, minimal side effects, and a relatively low price for long-term therapeutic effects and even a lifetime.

Long-term effects of adenotonsillectomy in children with attention deficit hyperactivity disorder.

Adenotonsillectomy (AT) improves short-term symptoms of attention deficit hyperactivity disorder (ADHD) in children; however, its long-term effects remain unclear. We aimed to verify the therapeutic long-term effects of AT in children with ADHD. This retrospective control study included children ages < 18 years who were diagnosed with ADHD and receiving ADHD medications. Participants were divided into groups depending on whether AT was performed (AT [+] or AT [-] groups) and matched 1:1 for age, sex, and year and month of diagnosis using randomized nonreplacement selection. Among patients with ADHD (n = 171,112), 3,615 underwent AT. In both groups, the number of drugs taken gradually increased before and decreased after the AT date (ATD). There was no difference in the number of drugs used before (P = .88) and after ATD (P = .06). Before ATD, the average number of outpatient visits (nOV) did not change in both groups (AT [+]: P = .12; AT [-]: P = .71). After ATD, the average number of outpatient visits decreased only in the AT (+) group (P = .001). However, there was no difference in the average number of outpatient visits between the two groups before (P = .47) and after ATD (P = .17). Before ATD, methylphenidate doses between the groups were not different (P = .06); however, a significant increase was noted after ATD in the AT (+) group (P < .001). AT does not result in significant long-term therapeutic effects in terms of medication use and health care utilization in children with ADHD. Lee J, Choi A, Kim S, Kim K. Long-term effects of adenotonsillectomy in children with attention deficit hyperactivity disorder. J Clin Sleep Med. 2024;20(5):727-733.

Systemic immune-inflammation index predicts the clinical outcomes in patients with acute uncomplicated type-B aortic dissection undergoing optimal medical therapy

BackgroundOptimal medical therapy (OMT) for uncomplicated type B aortic dissection (uTBAD) provides excellent short-term outcomes during follow up; however, its long-term therapeutic effectiveness is unsatisfactory. This study evaluated the predictive value of systemic immune-inflammation index (SII) for adverse events among patients with acute uTBAD undergoing OMT.MethodsWe performed a retrospective analysis of a prospectively maintained database between 2013 and 2020. The primary end point in this study was composite outcomes including aortic intervention, all-cause mortality, retrograde type A aortic dissection (rTAAD) and aortic diameter growth > 5 mm. The patients were divided into high and low SII groups according to the optimal cut-off value of SII as determined using the receiver operating characteristic curve. Cox proportional hazards models were constructed to estimate the hazards ratios and identify the predictors of composite outcomes.ResultsA total of 124 patients with acute uTBAD who underwent OMT were enrolled. One patient died during hospitalisation. At the end of a mean follow-up duration of 51 ± 23 months, 53 (43.1%) patients experienced composite outcomes, 15 patients (12.2%) died, 31 (25.2%) underwent aortic intervention, 21 (17.1%) exhibited diameter growth of > 5 mm, and 2 developed rTAAD. The patients were divided into low SII group (n = 78, 62.9%) and high SII group (n = 46, 37.1%) as per the optimal cut-off SII value of 1449. The incidence of composite outcomes in high SII group was significantly higher than that in low SII (28 [60.9%] vs. 26[33.3%], p < 0.01). Patients with high SII demonstrated significantly higher mortality rate than those with a low SII (11 [23.9%] vs. 5 [6.4%], respectively; p < 0.01). In addition, the high SII group had significantly higher rate of aortic-related reinterventions than the low SII group (16 [34.8%] vs. 15 [19.2%], p = 0.03). Multivariable Cox analyses showed that a high SII score was independently associated with composite outcomes rate (hazard ratio, 2.15; 95% confidence interval, 1.22–3.78; p < 0.01).ConclusionsThe long-term therapeutic effectiveness of OMT alone in patients with acute uTBAD is unsatisfactory. An SII > 1449 at the time of diagnosis is an independent predictor of OMT failure.

Spinal Neuromodulation for Peripheral Arterial Disease of Lower Extremities: A Ten-Year Retrospective Analysis.

This long-term retrospective study evaluated the survival and amputation outcome of subjects who received neuromodulation therapy for the management of peripheral arterial disease (PAD). The study reviews the health data of a single cohort of 51 patients who received spinal neuromodulation (spinal cord stimulation [SCS] or dorsal root ganglion stimulation [DRG-S]) for PAD from 2007 to 2022 in a single German center. Survival rate and major amputation rate were determined. Pain, quality of life, walking distance, and opioid usage were assessed before implantation (baseline), one, six, and 12 months (M) after implantation, and then annually (during a follow-up visit). Implant-related complications also were documented. In total, 51 patients (37 men [mean age 68.9± 10.2 years], 14 women [mean age (68.7± 14.6 years]) underwent SCS (n= 49) or DRG-S (n= 2) implantation owing to persistent ischemic pain. The follow-up mean years± SD is 4.04± 2.73. At baseline, patients were classified as Rutherford's category 3 (n= 23), category 4 (n= 15) or category 5 (n= 9). At 24 M, 42 of 47 patients did not require a major amputation after the implant. All the patients reported nearly complete pain relief from pain at rest. A total of 75% of patients were able to walk >200 m, and 87% of patients who used opioids at baseline were off this medication at 24 M. Overall, 93% of patients reported an improvement in their overall health assessment. These improved outcomes were sustained through years three to 10 for patients who have reported outcomes. Our single-center data support the efficacy of spinal neuromodulation for improvements in limb salvage, pain relief, mobility, and quality of life. The data also show that neuromodulative therapy has a long-term therapeutic effect in patients with chronic limb pain with Rutherford category 3, 4, and 5 PAD.

Onabotulinum toxin a treatment for posttraumatic trigeminal neuropathic pain: case series and literature review

This case series aimed to assess the treatment outcomes of onabotulinum toxin A (BTX-A) in patients with refractory posttraumatic trigeminal neuropathic pain (PTNP) and to conduct a narrative review of the evidence for BTX-A in PTNP. Thirteen patients were treated with BTX-A infiltrations. Patient demographic and pain characteristics, BTX-A administration, and treatment outcomes were retrospectively analyzed. Papers retrieved after a literature search of articles on PTNP treatment using BTX-A were reviewed. Six patients reported an improvement in pain 3 months after the initial BTX-A injection, with 4 patients reporting a 50% reduction. Two patients achieved an 80% reduction in pain score over 3 years of BTX-A therapy. Three patients reported temporary ipsilateral facial muscle weakness. The literature review revealed five case reports on the use of BTX-A in PTNP patients that reported similar effectiveness to the present cohort study. BTX-A may be a potential treatment modality for refractory PTNP, thus reducing the need for polypharmacy. Multiple intraoral BTX-A injections administered over the painful sites are well tolerated, safe and easily practiced. High-quality studies are required to evaluate the long-term therapeutic efficacy and side effects of BTX-A therapy.

Sprayable, thermosensitive hydrogels for promoting wound healing based on hollow, porous and pH-sensitive ZnO microspheres.

A solvothermal method and the subsequent heat treatment process were developed to fabricate hollow ZnO particles with hierarchical pores on a large scale. The as-obtained hollow, porous ZnO microspheres with tunable sizes, high specific surface areas, pH sensitivity, antibacterial properties, and high adsorption capacities showed significant advantages for drug delivery. Sprayable hydrogels containing hollow, porous ZnO microspheres and curcumin nanoparticles (CNPs) were prepared to accelerate wound healing. The water-dispersed CNPs promoted both the migration of fibroblasts and angiogenesis and an aqueous solution of Pluronic F127 (a temperature-sensitive phase-change hydrogel material) was shown to be an effective choice for medical dressings. The experimental data suggest that hollow, porous ZnO microspheres can be loaded with additional CNPs to achieve continuous long-term therapeutic effects.

Short-term and long-term efficacy in robot-assisted treatment for mid and low rectal cancer: a systematic review and meta-analysis

ObjectiveThis study aims to conduct a meta-analysis to evaluate the short-term and long-term therapeutic effects of robot-assisted laparoscopic treatment in patients with mid and low rectal cancer.MethodsA comprehensive search strategy was employed to retrieve relevant literature from PubMed, NCBI, Medline, and Springer databases, spanning the database inception until August 2023. The focus of this systematic review was on controlled studies that compared the treatment outcomes of robot-assisted (Rob) and conventional laparoscopy (Lap) in the context of mid and low rectal cancer. Data extraction and literature review were meticulously conducted by two independent researchers (HMW and RKG). The synthesized data underwent rigorous analysis utilizing RevMan 5.4 software, adhering to established methodological standards in systematic reviews. The primary outcomes encompass perioperative outcomes and oncological outcomes. Secondary outcomes include long-term outcomes.ResultA total of 11 studies involving 2239 patients with mid and low rectal cancer were included (3 RCTs and 8 NRCTs); the Rob group consisted of 1111 cases, while the Lap group included 1128 cases. The Rob group exhibited less intraoperative bleeding (MD = −40.01, 95% CI: −57.61 to −22.42, P < 0.00001), a lower conversion rate to open surgery (OR = 0.27, 95% CI: 0.09 to 0.82, P = 0.02), a higher number of harvested lymph nodes (MD = 1.97, 95% CI: 0.77 to 3.18, P = 0.001), and a lower CRM positive rate (OR = 0.46, 95% CI: 0.23 to 0.95, P = 0.04). Additionally, the Rob group had lower postoperative morbidity rate (OR = 0.66, 95% CI: 0.53 to 0.82, P < 0.0001) and a lower occurrence rate of complications with Clavien–Dindo grade ≥ 3 (OR = 0.60, 95% CI: 0.39 to 0.90, P = 0.02). Further subgroup analysis revealed a lower anastomotic leakage rate (OR = 0.66, 95% CI: 0.45 to 0.97, P = 0.04). No significant differences were observed between the two groups in the analysis of operation time (P = 0.42), occurrence rates of protective stoma (P = 0.81), PRM (P = 0.92), and DRM (P = 0.23), time to flatus (P = 0.18), time to liquid diet (P = 0.65), total hospital stay (P = 0.35), 3-year overall survival rate (P = 0.67), and 3-year disease-free survival rate (P = 0.42).ConclusionRobot-assisted laparoscopic treatment for mid and low rectal cancer yields favorable outcomes, demonstrating both efficacy and safety. In comparison to conventional laparoscopy, patients experience reduced intraoperative bleeding and a lower incidence of complications. Notably, the method achieves comparable short-term and long-term treatment results to those of conventional laparoscopic surgery, thus justifying its consideration for widespread clinical application.

Regulatory effects and clinical application of panax-based compound formula on chronic diseases

Hypertension, diabetes, and hyperlipidemia are common chronic diseases today and can lead to severe complications. Panax-based compound formula, as a comprehensive traditional Chinese medicine formulation, incorporates various components such as Panax, exerting multiple pharmacological effects, including nourishing the kidney qi, strengthening the heart, vasodilation, and increasing blood flow. Through the study of multiple cases, including patients with hypotension, heart disease, diabetes, hyperlipidemia, as well as early and long-term hypertension, preliminary evidence has been provided, indicating the potential positive effects of this compound in different types of hypertensive and diabetic patients. It demonstrates clear antiarrhythmic effects and effectively reduces blood pressure, improves heart failure, and alleviates hyperlipidemia. However, further research and clinical trials are required to verify its long-term therapeutic effects and safety. It is crucial to develop personalized treatment plans when using this compound formula.

Abstract 13272: Acute Effects of Enhanced External Counterpulsation in Adults With Fontan Circulation

Background: Patients who have undergone Fontan palliation for single ventricle CHD exhibit reduced cardiac output. Aims: To study the safety and acute hemodynamic effects of enhanced external counterpulsation (EECP) in a cohort of Fontan patients. Methods: Pilot study of adult Fontan patients recruited through the ambulatory clinic at a single, large-volume ACHD center. Patients underwent TTE and measurement of pulmonary blood flow (PBF), a surrogate for cardiac output, followed by 1 hour of EECP divided into 20-minute stages (80 mmHg, 160 mmHg, 240 mmHg). TTE and PBF measurement were repeated at each stage and 15-30 minutes after completion of EECP. Patients were monitored for symptoms throughout the visit. A repeated measures linear-mixed-model (robust to non-normality) was used to estimate the mean at each time point and to test for differences across time points. Results: There were 23 patients enrolled (52% male, 91% cis-gender, 74% White). Mean age at enrollment and at Fontan completion was 33.0 ± 7.8 years and 5.1 ± 4.1 years, respectively. Six patients (26%) had a pacemaker. Twenty-two (96%) completed a full hour of EECP. Pressure was reduced in the third stage for 3 patients due to discomfort. No patients reported chest pain or increased dyspnea during EECP. PBF was increased at each stage of EECP compared to baseline and returned to baseline post-EECP (Fig. 1). There was a small qualitative improvement in ventricular systolic function in the second and third stages of EECP compared to baseline (160 mmHg: p=0.048; 240 mmHg: p=0.024). O 2 saturation was increased at each stage of EECP compared to baseline (baseline: 93.0%, 80 mmHg: 94.3% [p=0.008], 160 mmHg: 94.6% [p=&lt;0.001], 240 mmHg: 94.6% [p=&lt;0.001]). Mean arterial pressure and heart rate did not change. Conclusions: EECP is well-tolerated in adult Fontan patients and acutely improves PBF at pressures as low as 80 mmHg. Further study is warranted to explore long-term therapeutic effects of EECP in these patients.

Unleashing the Potential of Nrf2: A Novel Therapeutic Target for Pulmonary Vascular Remodeling.

Pulmonary vascular remodeling, characterized by the thickening of all three layers of the blood vessel wall, plays a central role in the pathogenesis of pulmonary hypertension (PH). Despite the approval of several drugs for PH treatment, their long-term therapeutic effect remains unsatisfactory, as they mainly focus on vasodilation rather than addressing vascular remodeling. Therefore, there is an urgent need for novel therapeutic targets in the treatment of PH. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor that regulates endogenous antioxidant defense and emerges as a novel regulator of pulmonary vascular remodeling. Growing evidence has suggested an involvement of Nrf2 and its downstream transcriptional target in the process of pulmonary vascular remodeling. Pharmacologically targeting Nrf2 has demonstrated beneficial effects in various diseases, and several Nrf2 inducers are currently undergoing clinical trials. However, the exact potential and mechanism of Nrf2 as a therapeutic target in PH remain unknown. Thus, this review article aims to comprehensively explore the role and mechanism of Nrf2 in pulmonary vascular remodeling associated with PH. Additionally, we provide a summary of Nrf2 inducers that have shown therapeutic potential in addressing the underlying vascular remodeling processes in PH. Although Nrf2-related therapies hold great promise, further research is necessary before their clinical implementation can be fully realized.

Injectable hyperbranched PEG crosslinked hyaluronan hydrogel microparticles containing mir-99a-3p modified subcutaneous ADSCs-derived exosomes was beneficial for long-term treatment of osteoarthritis

Exosomes (Exos) secreted by adipose-derived stem cells (ADSCs) have shown potential in alleviating osteoarthritis (OA). Previous studies indicated that infrapatellar fat pad (IPFP) derived stem cells (IPFSCs) may be more suitable for the treatment of OA than subcutaneous adipose tissue (ScAT) derived stem cells (ScASCs). However, it remains unclear which type of Exos offers superior therapeutic benefit for OA. This study first compared the differences between Exos derived from IPFP stem cells (ExosIPFP) and ScAT stem cells (ExosScAT) in OA treatment. Results suggested that ExosIPFP significantly inhibit the degradation of cartilage extracellular matrix (ECM) than ExosScAT, following this, the differences in microRNA (miRNA) expression between the two types of Exos using small RNA sequencing were performed. Subsequently, miR-99 b-3p was chosen and over-expressed in ExosScAT (ExosScAT−99b−3p), both in vivo and in vitro experiments demonstrated its efficacy in inhibiting the expression of ADAMTS4, promoting the repair of the ECM in OA. Finally, microfluidic technology was performed to fabricate a hyaluronan-based hydrogel microparticles (HMPs) for encapsulating Exos (HMPs@exos), the injectability, sustained release of Exos and long-term therapeutic effect on OA were validated. In summary, these results suggest miR-99 b-3p regulates the degradation of cartilage ECM by targeting ADAMTS4, the upregulation of miR-99 b-3p in ExosScAT would enable them to exhibit comparable or even superior effectiveness to ExosIPFP for OA treatment, making it a promising approach for OA treatment. Considering the abundant resources of ScAT and the limited availability of IPFP, ScAT harvested through liposuction could be genetically engineered to yield Exos for OA treatment. Furthermore, the encapsulation of Exos in HMPs provides an injectable sustained local drug release system, which could potentially enhance the efficacy of Exos and hold potential as future therapeutic strategies.

Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model

Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2months and will be tested for up to a year in ongoing studies.

A peptidic network antibody inhibits both angiogenesis and inflammatory response

Corneal neovascularization (CNV) is a global threat to human health. Traditional anti-angiogenesis agent may have therapy effect, while the inflammation in disease area remains unsolved. Herein, we reported two binding-induced fibrillogenesis (BIF) peptides as peptidic network antibodies for high-efficient and long-lasting anti-angiogenesis with reduced inflammatory response. BIF peptides could self-assemble into nanoparticles and further perform BIF behavior through binding Ca2+. In vitro, the migration of integrin αvβ3 highly expressed endothelial cells was inhibited by BIF peptides. In vivo, one BIF peptide (0.012 mg/Kg) exhibited higher anti-angiogenesis effect than monoclonal antibody bevacizumab (0.96 mg/Kg) in a CNV rabbit model on day 14, despite that the dose of BIF was only 1.3% of bevacizumab. Meanwhile, the inflammatory response, such as PI3 kinase/Akt pathway in CNV was successfully inhibited as well. The peptidic network antibody could block integrin αvβ3 via a long-term retention mode, which led to long-term therapeutic effect. The study provides BIF peptides as promising therapeutic agents for both anti-angiogenesis and reduced inflammatory response.

Carrier-Free Nanovaccine: An Innovative Strategy for Ultrahigh Melanoma Neoantigen Loading.

In personalized cancer immunotherapy, developing an effective neoantigen nanovaccine with high immunogenicity is a significant challenge. Traditional nanovaccine delivery systems often require nanocarriers, which can hinder the delivery of the neoantigen and cause significant toxicity. In this study, we present an innovative strategy of carrier-free nanovaccine achieved through direct self-assembly of 2'-fluorinated CpG (2'F-CpG) with melanoma neoantigen peptide (Obsl1). Molecular dynamics simulations demonstrated that the introduction of a fluorine atom into CpG increases the noncovalent interaction between 2'F-CpG and Obsl1, which enhanced the loading of Obsl1 on 2'F-CpG, resulting in the spontaneous formation of a hybrid 2'F-CpG/Obsl1 nanovaccine. This nanovaccine without extra nanocarriers showed ultrahigh Obsl1 loading up to 83.19 wt %, increasing the neoantigen peptide uptake by antigen-presenting cells (APCs). In C57BL/6 mice models, we demonstrated the long-term preventive and therapeutic effects of the prepared 2'F-CpG/Obsl1 nanovaccine against B16F10 melanoma. Immunocellular analysis revealed that the nanovaccine activated innate and adaptive immune responses to cancer cells. Hence, this study established a simple, safe, and effective preparation strategy for a carrier-free neoantigen nanovaccine, which could be adapted for the future design of personalized cancer vaccines in clinical settings.

Efficacy and safety of total glucosides of paeony in the treatment of recurrent aphthous ulcers: a single-center, double-blind, randomized, placebo-controlled clinical trial.

Introduction: There has been a lack of treatments available to lower the frequency of recurrent aphthous ulcers (RAUs) until now. Total glucosides of paeony (TGP) is a botanical drug extracted from the dried roots of Paeonia lactiflora Pall. [Ranunculaceae; Paeoniae Radix Alba]. This study aims to evaluate the efficacy and safety of TGP in the treatment of RAU. Methods: This study was registered with the Chinese Clinical Trial Registry (ChiCTR1900025623). Patients were randomly assigned to the TGP or placebo group and treated with 1.8g/day for 24weeks. Participants were observed for a total of 36weeks and were asked to record ulcer severity, medication, and adverse reactions in the form of diaries or apps every day. The primary outcome was the monthly ulcer-free interval. Results: A total of 79 individuals were enrolled, with 40 assigned to the TGP group and 39 to the placebo group. The dropout rate was 18.18%. In the TGP group, the monthly ulcer-free interval was significantly longer than baseline (median, 9.6days) since weeks 13-24 (median, 18.5days) (p < 0.05), and after discontinuation, it was further prolonged (median, 24.7days) than in weeks 13-24 (p < 0.05). In addition, the monthly ulcer-free interval was longer in the TGP group than in the placebo group (median, 15.9days) at weeks 25-36 (p < 0.001). There were better improvements in the monthly number of ulcers and monthly area of ulcers, and visual analog scoring in the TGP group at weeks 25-36 (p < 0.001). Conclusion: TGP had a good long-term therapeutic effect on RAU with frequent occurrence. Systematic Review Registration: www.chictr.org.cn, identifier ChiCTR1900025623.

Application of Cyclodextrin for Cancer Immunotherapy.

Tumor immunotherapy, compared with other treatment strategies, has the notable advantage of a long-term therapeutic effect for preventing metastasis and the recurrence of tumors, thus holding great potential for the future of advanced tumor therapy. However, due to the poor water solubility of immune modulators and immune escape properties of tumor cells, the treatment efficiency of immunotherapy is usually significantly reduced. Cyclodextrin (CD) has been repeatedly highlighted to be probably one of the most investigated building units for cancer therapy due to its elegant integration of an internal hydrophobic hollow cavity and an external hydrophilic outer surface. The application of CD for immunotherapy provides new opportunities for overcoming the aforementioned obstacles. However, there are few published reviews, to our knowledge, summarizing the use of CD for cancer immunotherapy. For this purpose, this paper provides a comprehensive summary on the application of CD for immunotherapy with an emphasis on the role, function, and reported strategies of CD in mediating immunotherapy. This review summarizes the research progress made in using CD for tumor immunotherapy, which will facilitate the generation of various CD-based immunotherapeutic delivery systems with superior anticancer efficacy.

A sustained-release phospholipid-based phase separation gel loaded with berberine for treating rheumatoid arthritis.

Berberine (BBR) has a long history of use in the treatment of Rheumatoid arthritis (RA) and is considered one of the most promising natural product for the treatment of RA. However, oral administration of berberine has low bioavailability and requires frequent administration, resulting in poor patient compliance. In this study, we developed a BBR-loaded phospholipid-based phase separation gel (BBR-PPSG) to achieve sustained drug release and long-term therapeutic effect. The stability of BBR-PPSG was verified and it was found that it can be stored for a long time. The pharmacokinetic study on rats and rabbits showed that BBR-PPSG not only achieved 1-month of sustained release, but also significantly increased the area under the curve (AUC) by nearly 9-fold and prolonged the half-life (t1/2) by 10-fold. By constructing rat and rabbit models of RA, we also proved that BBR-PPSG administration once a month effectively alleviated joint swelling, and significantly reduce TNF-α levels in AIA rats and OIA rabbits. Histopathological analysis of rabbit joint sections revealed that after intra-articular injection of BBR-PPSG, the synovial cell layer remained intact, while in the model group, the synovial cells were significantly reduced and exhibited necrosis. MicroCT data analysis showed that the values of Tb.N and Tb. Sp in the BBR-PPSG group were significantly better than those in the model group (p < 0.05). This study addressed the limitations of frequent administration of BBR by developing a phospholipid-based phase separation gel system for berberine delivery, achieving long-term sustained release. The BBR-PPSG demonstrated good biocompatibility, simple preparation and excellent stability, thus holding potential as a novel pharmaceutical formulation for RA treatment.

Therapeutic properties of Helicobacter pylori-derived vacuolating cytotoxin A in an animal model of chronic allergic airway disease

BackgroundIt has previously been shown that the Helicobacter pylori (H. pylori)-derived molecule vacuolating cytotoxin A (VacA) could be suitable for the treatment of allergic airway disease. The therapeutic activity of the protein, which acts through modulation of dendritic cells (DC) and regulatory T cells (Tregs), was demonstrated in murine short-term acute models. The aim of this study is to further evaluate the therapeutic potential of VacA by determining the effectiveness of different application routes and the suitability of the protein for treating the chronic phase of allergic airway disease.MethodsVacA was administered by the intraperitoneal (i.p.), oral (p.o.) or intratracheal (i.t.) routes, and long-term therapeutic effectiveness, allergic airway disease hallmarks, and immune phenotype were analyzed in murine models of acute and chronic allergic airway disease.ResultsAdministration of VacA via the i.p., p.o or i.t. routes was associated with a reduction in airway inflammation. The i.p. route showed the most consistent effect in reducing airway inflammation and i.p. treatment with VacA was the only treatment that significantly reduced mucus cell hyperplasia. In a murine model of chronic allergic airway disease, both short- and long-term treatment with VacA showed a therapeutic effect, with a reduction in a variety of asthma hallmarks, including bronchoalveolar lavage eosinophilia, lung inflammation and goblet cell metaplasia. Short-term treatment was associated with induction of Tregs, while repetitive long-term administration of VacA influenced immunological memory in the lung.ConclusionsIn addition to showing therapeutic efficacy in short-term models, treatment with VacA also appeared to be effective in suppressing inflammation in a chronic airway disease model. The observation that treatment was effective after administration via several different routes highlights the potential of VacA as a therapeutic agent with different routes of administration in humans.