Accessing Benzoazepine Derivatives via Photoinduced Radical Relay Formal [5 + 2] Reaction of Amide/Alkyne Enabled by Palladium Catalysis.

A novel class of alkyne-tethered amides facilitates an unprecedented photoinduced palladium-catalyzed radical relay formal [5 + 2] reaction. This innovative strategy allows for the rapid construction of diverse fused benzoazepine structures, yielding structurally novel and compelling compounds. With a broad substrate scope and excellent functional group tolerance, the methodology synthesizes biologically active compounds. Notably, the resulting tricyclic benzo[b]azepines offer diversification opportunities through simple transformations. DFT calculations elucidate a seven-membered ring closure mechanism involving the alkenyl radical and Pd(I) rebound alongside a concerted metalation-deprotonation (CMD) process.

Latest advances in the study of non-coding RNA-mediated circadian rhythm disorders causing endometrial cancer.

Endometrial cancer (EC) is one of the most common gynecological cancers, and its risk factors include obesity and metabolic, genetic, and other factors. Recently, the circadian rhythm has also been shown to be associated with EC, as the severity of EC was found to be related to night work and rhythm disorders. Therefore, circadian rhythm disorders (CRDs) may be one of the metabolic diseases underlying EC. Changes in the circadian rhythm are regulated by clock genes (CGs), which in turn are regulated by non-coding RNAs (ncRNAs). More importantly, the mechanism of EC caused by ncRNA-mediated CRDs is gradually being unraveled. Here, we review existing studies and reports and explore the relationship between EC, CRDs, and ncRNAs.

Effects of treatment with stem cell-derived extracellular vesicles in preclinical rodent models of intrauterine adhesion: A meta-analysis.

Background: Intrauterine adhesion (IUA) results from serious complications of intrauterine surgery or infection and mostly remains incurable. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have emerged as a potential new approach for the treatment of IUA; however, their impact is not fully understood. Here, we performed a meta-analysis summarizing the effects of sEVs on IUA in preclinical rodent models. Methods: This meta-analysis included searches of PubMed, EMBASE, Cochrane, and the Web of Science databases from January 1, 1997, to April 1, 2022, to identify studies reporting the therapeutic effect of sEVs on rodent preclinical animal models of IUA. We compared improvements in endometrial thickness, endometrial gland number, fibrosis area, embryo number, vascular endothelial growth factor (VEGF), transforming growth factor ß1 (TGFß1), and leukemia inhibitory factor (LIF) levels after treatment. Results: Our search included 100 citations, of which 7 met the inclusion criteria, representing 231 animals. Compared with that in the control group, the fibrosis area in the sEV-treated group was significantly reduced (standardized mean difference (SMD) = -6.87，95 % confidence interval (CI) = -9.67 to -4.07). The number of glands increased after the intervention (95 % CI, 3.72-7.68; P = 0.000). Endometrial thickness was significantly improved in the sEV-treated group (SMD = 2.57, 95 % CI, 1.62-3.52). Conclusions: This meta-analysis is highlighting that sEV treatment can improve the area of endometrial fibrosis, as well as VEGF, and LIF level, in a mouse IUA model. This knowledge of these findings will provide new insights into future preclinical research.

Acupuncture for ventilator-dependent patients at a hospital-based respiratory care center: A randomized controlled trial.

Background: In intensive care units, mechanical ventilation is an important therapy to help patients with dyspnea. However, long-term ventilator dependence would consume huge medical resources and increase the risk of morbidity and mortality. The aim of the study was to examine the efficacy of the acupuncture combined with western medical care on ventilator parameters in ventilator-dependent patients. Methods: In this clinical trial, 80 ventilator-dependent patients aged 20 to 80 years old were randomly assigned to acupuncture group and control group in the respiratory care center (RCC) of Changhua Christian Hospital. Besides regular medical care and therapy, participants in the acupuncture group received acupuncture therapy at the same 17 acu-points for 20 minutes once a day, a total of 12 sessions. The ventilator parameters were recorded to evaluate the respiratory efficiency for all participants. The primary outcome was rapid shallow breathing index (RSBI), and secondary outcomes were respiratory rate (RR), tidal volume (TV) and ventilation per minute (MV). Results: Though there was no significant difference in the parameter between the acupuncture group and the control group, we found the trend of decreasing RSBI in the acupuncture group. In subgroup analyses, the mean of RSBI significantly decreased 16.02 (with the SD in 60.84) in acupuncture group, while it increased 17.84 (with the SD in 39.38) in control group (p=0.036) after 12 sessions. Conclusion: Acupuncture treatment can improve breathing ability of patients with respirator dependence in respiratory care center.

Potential for NPY receptor-related therapies for polycystic ovary syndrome: an updated review.

Polycystic ovary syndrome (PCOS) is a complex endocrine disease that can cause female infertility and bring economic burden to families and to society. The clinical and/or biochemical manifestations include hyperandrogenism, persistent anovulation, and polycystic ovarian changes, often accompanied by insulin resistance and obesity. Although its pathogenesis is unclear, PCOS involves the abnormal regulation of the hypothalamic-pituitary-ovarian axis and the abnormal activation of GnRH neurons. Neuropeptide Y (NPY) is widely distributed in the arcuate nucleus of the hypothalamus and functions as the physiological integrator of two neuroendocrine systems, one governing feeding and the other controlling reproduction. In recent years, an increasing number of studies have focused on the improvement of the reproductive and metabolic status of PCOS through the therapeutic application of NPY and its receptors. In this review, we summarize the central and peripheral regulation of NPY and its receptors in the development of PCOS and discuss the potential for NPY receptor-related therapies for PCOS.

Aryl-to-alkyl radical relay Heck reaction of amides with vinyl arenes.

A palladium-catalyzed aryl-to-alkyl radical relay Heck reaction of amides at α-C(sp3)-H sites with vinyl arenes is described. This process displays a broad substrate scope with respect to both amide and alkene components and provides access to a diverse class of more complex molecules. The reaction is proposed to proceed via a hybrid palladium-radical mechanism. The core of the strategy is that the fast oxidative addition of aryl iodide and fast 1,5-HAT overcome the slow oxidative addition of alkyl halides, and the photoexcitation effect suppresses the undesired ß-H elimination. It is anticipated that this approach would inspire the discovery of new palladium-catalyzed alkyl-Heck methods.

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma.

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels. SIGNIFICANCE: Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial. This article is highlighted in the In This Issue feature, p. 517.

Melatonin enhances autologous adipose-derived stem cells to improve mouse ovarian function in relation to the SIRT6/NF-κB pathway.

BACKGROUND: Premature ovarian insufficiency (POI) is the main cause of female infertility. Adipose-derived stem cells (ADSCs) are ideal candidates for the treatment of POI. However, some deficient biological characteristics of ADSCs limit their utility. This study investigated whether melatonin (MLT)-pretreated autologous ADSCs were superior to ADSCs alone in the treatment of the POI mouse model. METHODS: Autologous ADSCs were isolated and cultured in MLT-containing medium. Surface markers of ADSCs were detected by flow cytometry. To determine the effect of MLT on ADSCs, CCK-8 assay was used to detect ADSCs proliferation and enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of cytokines. The POI model was established by intraperitoneal injection of cyclophosphamide and busulfan. Then, MLT-pretreated autologous ADSCs were transplanted into mice by intraovarian injection. After 7 days of treatment, ovarian morphology, follicle counts, and sex hormones levels were evaluated by hematoxylin and eosin (H&E) staining and ELISA, and the recovery of fertility was also observed. The expressions of SIRT6 and NF-κB were detected by immunohistochemical (IHC) staining and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Flow cytometry showed that autologous ADSCs expressed CD90 (99.7%) and CD29 (97.5%). MLT can not only promote the proliferation of ADSCs but also boost their secretory function, especially when ADSCs were pretreated with 5 µM MLT for 3 days, improving the interference effect. After transplantation of autologous ADSCs pretreated with 5 µM MLT, the serum hormone levels and reproductive function were significantly recovered, and the mean counts of primordial follicle increased. At the same time, the expression of SIRT6 was remarkably increased and the expression of NF-κB was significantly decreased in this group. CONCLUSIONS: MLT enhances several effects of ADSCs in restoring hormone levels, mean primordial follicle counts, and reproductive capacity in POI mice. Meanwhile, our results suggest that the SIRT6/NF-κB signal pathway may be the potential therapeutic mechanism for ADSCs to treat POI.

Clinical Evaluation of Autologous and Allogeneic Stem Cell Therapy for Intrauterine Adhesions: A Systematic Review and Meta-Analysis.

Objective: Intrauterine adhesions (IUAs) are a major cause of female infertility. Stem cells can be used to restore endometrial function owing to their regenerative abilities. We compared the safety and efficacy of autologous and allogeneic stem cell treatments in patients with recurrent IUA after conventional therapy based on a systematic review of the related literature. Methods: The PubMed, Embase, and Cochrane databases were systematically searched. All analysis were performed using Review Manager 5.4. We compared improvements in endometrial thickness, pregnancy rates, menstruation, and side effects after autologous and allogeneic stem cell therapy. The study was registered with PROSPERO, CRD 42022322870. Results: Our search returned 154 reports, 10 of which met the inclusion criteria, representing 116 patients. Of these, 44 patients in two studies were treated with allogeneic stem cells and 72 patients in eight studies were treated with autologous stem cells. Improvements in endometrial thickness and pregnancy rates after intrauterine device treatment were compared between the autologous and allogeneic stem cell groups. Endometrial thickness increased more after autologous stem cell IUA treatment (mean difference, 1.68; 95% confidence interval [CI]: 1.30-2.07; P < 0.00001), and the pregnancy rate was also improved (relative risk, 1.55; 95% CI: 1.19-2.02, P < 0. 001). No obvious and serious adverse reactions were observed during stem cell therapy in either group. Conclusions: This meta-analysis and systematic review of the results of randomized trials of autologous and allogeneic stem cell treatments for IUA suggests that autologous stem cells have a better effect in improving the endometrium thickness and pregnancy rate. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022322870.

Therapeutic options for premature ovarian insufficiency: an updated review.

Primary ovarian insufficiency (POI) is a rare gynecological condition. This disease causes menstrual disturbances, infertility, and various health problems. Historically, hormone replacement therapy is the first-line treatment for this disorder. Women diagnosed with POI are left with limited therapeutic options. In order to remedy this situation, a new generation of therapeutic approaches, such as in vitro activation, mitochondrial activation technique, stem cell and exosomes therapy, biomaterials strategies, and platelet-rich plasma intra-ovarian infusion, is being developed. However, these emerging therapies are yet in the experimental stage and require precise design components to accelerate their conversion into clinical treatments. Thus, each medical practitioner bears responsibility for selecting suitable therapies for individual patients. In this article, we provide a timely analysis of the therapeutic strategies that are available for POI patients and discuss the prospects of POI therapy.

The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous.

Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs.

Scalable Synthesis of Ultrathin Polyimide Covalent Organic Framework Nanosheets for High-Performance Lithium-Sulfur Batteries.

Development of new porous materials as hosts to suppress the dissolution and shuttle of lithium polysulfides is beneficial for constructing highly efficient lithium-sulfur batteries (LSBs). Although 2D covalent organic frameworks (COFs) as host materials exhibit promising potential for LSBs, their performance is still not satisfactory. Herein, we develop polyimide COFs (PI-COF) with a well-defined lamellar structure, which can be exfoliated into ultrathin (∼1.2 nm) 2D polyimide nanosheets (PI-CONs) with a large size (∼6 µm) and large quantity (40 mg/batch). Explored as new sulfur host materials for LSBs, PI-COF and PI-CONs deliver high capacities (1330 and 1205 mA h g-1 at 0.1 C, respectively), excellent rate capabilities (620 and 503 mA h g-1 at 4 C, respectively), and superior cycling stability (96% capacity retention at 0.2 C for PI-CONs) by virtue of the synergy of robust conjugated porous frameworks and strong oxygen-lithium interactions, surpassing the vast majority of organic/polymeric lithium-sulfur battery cathodes ever reported. Our finding demonstrates that ultrathin 2D COF nanosheets with carbonyl groups could be promising host materials for LSBs with excellent electrochemical performance.

The tongue features associated with chronic kidney disease.

BACKGROUND: Traditional Chinese medicine (TCM) tongue diagnosis plays an important role in differentiation of symptoms because the tongue reflects the physiological and pathological condition of the body. The automatic tongue diagnosis system (ATDS), which noninvasively captures tongue images, can provide objective and reliable diagnostic information. Chronic kidney disease (CKD) currently is an important global public health problem and contributor to morbidity and mortality from non-communicable diseases. Thus, it is interesting to analyze and probe the relationship between tongue examination and CKD. METHODS: This protocol is a cross-sectional, case-controlled observational study investigating the usefulness of the ATDS in clinical practice by examining its efficacy as a diagnostic tool for CKD. Volunteers over 20 years old with and without CKD will be enrolled. Tongue images will be captured and the patients divided into 2 groups: CKD group and healthy group. Nine primary tongue features will be extracted and analyzed, including tongue shape, tongue color, tooth mark, tongue fissure, fur color, fur thickness, saliva, ecchymosis, and red dots. RESULT: The results of this study will systematically evaluate tongue manifestations of patients and examine its efficacy as an early detection and diagnosis of CKD. DISCUSSION: The aim of this protocol is to investigate discriminating tongue features to distinguish between CKD and normal people, and establish differentiating index to facilitate the noninvasive detection of CKD. TRIAL REGISTRIES: ClinicalTrials.gov; Identifier: NCT04708743.

A Perspective on Tongue Diagnosis in Patients with Breast Cancer.

INTRODUCTION: Breast cancer (BC) is the most common cancer in women and patients with BC often undergo complex treatment. In Taiwan, nearly 80% of patients with BC seek traditional Chinese medicine (TCM) during adjuvant chemotherapy to relieve discomfort and side effects. This study investigated tongue features and pattern differentiation through noninvasive TCM tongue diagnosis in patients with BC. MATERIALS AND METHODS: This cross-sectional, case-controlled, retrospective observational study collected patient data through a chart review. The tongue features were extracted using the automatic tongue diagnosis system (ATDS). Nine tongue features, including tongue shape, tongue color, fur thickness, fur color, saliva, tongue fissures, ecchymoses, teeth marks, and red dots, were analyzed. Results and Discussion. Objective image analysis techniques were used to identify significant differences in the many tongue features between BC patients and non-BC individuals. A significantly larger proportion of patients with BC had a small tongue (p < 0.001), pale tongue (p < 0.001), thick fur (p < 0.001), yellow fur (p < 0.001), wet saliva (p < 0.001), thick tongue fur (p < 0.001), fissures (p=0.040), and ecchymoses in the heart-lung area (p=0.013). According to logistic regression, small tongue shape, pale tongue color, yellow fur color, wet saliva, and the amounts of fissures were associated with a significantly increased odds ratio for BC. CONCLUSIONS: This study showed significant differences in tongue features, such as small tongue shape, pale tongue color, thick fur, yellow fur color, wet saliva, fissure, and ecchymoses in the heart-lung area in patients with BC. These tongue features would imply yin deficiency, deficiencies of blood, stagnation of heat, and phlegm/blood stasis in TCM theory. There is a need to investigate effective and safe treatment to enhance the role of TCM in integrated medical care for patients with BC.

Effect of electroacupuncture on restless legs syndrome (RLS) in hemodialysis patients: A protocol for systematic review and meta-analysis.

BACKGROUND: Restless legs syndrome (RLS) is frequent in dialysis patients and occurs predominantly in its most severe forms. The aim of the present study was to evaluate the effects of electroacupuncture (EA) in hemodialysis patients with RLS by heart rate variability (HRV) monitor. METHODS: One hundred twelve subjects who were hemodialysis patients with RLS will be divided into 2 groups: experimental and control. Each subject will receive the treatment relevant to their group 2 times a week for 4 weeks. After 4 weeks of treatment the subject will enter a 2-week washout period, after which the subjects will switch groups. Measurements will include HRV recordings, International Restless Legs Syndrome Rating Scale (IRLSRS) and Insomnia Severity Index (ISI). RESULT: The results of this study will systematically evaluate the effectiveness and safety of electoracupuncture intervention for hemodialysis patients with RLS. DISCUSSION: This study is the first investigation to analyze the relationship between EA and the change of HRV by an objective monitor. If the findings of the current trial are positive, this study will also help support an effective, safe and cheap approach to clinical treatment of this challenging disorder, help foster improved understanding the relationship between autonomic nervous system and RLS, and ultimately contribute to elucidate the mechanisms of EA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04356794; registration date: April 22, 2020.

Nanotechnology Education for the Global World: Training the Leaders of Tomorrow.

Nanoscience is one of the fastest growing and most impactful fields in global scientific research. In order to support the continued development of nanoscience and nanotechnology, it is important that nanoscience education be a top priority to accelerate research excellence. In this Nano Focus, we discuss current approaches to nanoscience training and propose a learning design framework to promote the next generation of nanoscientists. Prominent among these are the abilities to communicate and to work across and between conventional disciplines. While the United States has played leading roles in initiating these developments, the global landscape of nanoscience calls for worldwide attention to this educational need. Recent developments in emerging nanoscience nations are also discussed. Photo credit: Jae Hyeon Park.

Diabetes with pyogenic liver abscess--A perspective on tongue assessment in traditional Chinese medicine.

BACKGROUND: This novel study provides a time series analysis of tongue features extracted from a diabetic patient with pyogenic liver abscess (PLA), treated with the integration of western medicine and traditional Chinese medicine (TCM). The features, namely, tongue color, tongue fur thickness and fur color, identified from a series of tongue images taken every two days, exhibit significant transitions matching closely with the progression of disease. These tongue features could serve as effective, non-intrusive indices for different progression stages of diabetes with PLA. CASE PRESENTATION: A 76-year-old male diabetic patient was admitted for hyperglycemic hyperosmolar state. Intermittent fever and abdominal discomfort were noted. After performing abdominal computed tomography and laboratory studies, the results indicated pyeogenic liver abscess, Klebsiella pneumoniae ssp. pneumoniae related. As PLA progressed, the patient suffered spiking fever and right upper abdominal pain. Tongue examination revealed features with red tongue, white-yellow and thick fur. After receiving pigtail catheter drainage, the fever subsided and the pus-like fluid was drained smoothly. During the course of this process, gradually dwindled tongue fur witnessed through periodic tongue examination coincides consistently with laboratory data, namely, body temperature, fasting plasma glucose and plasma glucose level gathered. CONCLUSION: This is the first time series analysis of applying tongue examination to the progression of a specific disease. Through a series of tongue images taken periodically, tongue color, tongue fur thickness and fur color are identified to closely linked to the progression of diabetes with PLA, as indicated by data gathered through means of plasma glucose and abdominal sonographic follow-ups. Based on this promising finding, our future study will further extend the application of tongue assessment to evaluate the tongue characteristics of diabetic patients.

High-Performance Seizure Detection System Using a Wavelet-Approximate Entropy-fSVM Cascade With Clinical Validation.

The classification of electroencephalography (EEG) signals is one of the most important methods for seizure detection. However, verification of an atypical epileptic seizure often can only be done through long-term EEG monitoring for 24 hours or longer. Hence, automatic EEG signal analysis for clinical screening is necessary for the diagnosis of epilepsy. We propose an EEG analysis system of seizure detection, based on a cascade of wavelet-approximate entropy for feature selection, Fisher scores for adaptive feature selection, and support vector machine for feature classification. Performance of the system was tested on open source data, and the overall accuracy reached 99.97%. We further tested the performance of the system on clinical EEG obtained from a clinical EEG laboratory and bedside EEG recordings. The results showed an overall accuracy of 98.73% for routine EEG, and 94.32% for bedside EEG, which verified the high performance and usefulness of such a cascade system for seizure detection. Also, the prediction model, trained by routine EEG, can be successfully generalized to bedside EEG of independent patients.

Bio-signal analysis system design with support vector machines based on cloud computing service architecture.

Today, many bio-signals such as Electroencephalography (EEG) are recorded in digital format. It is an emerging research area of analyzing these digital bio-signals to extract useful health information in biomedical engineering. In this paper, a bio-signal analyzing cloud computing architecture, called BACCA, is proposed. The system has been designed with the purpose of seamless integration into the National Taiwan University Health Information System. Based on the concept of. NET Service Oriented Architecture, the system integrates heterogeneous platforms, protocols, as well as applications. In this system, we add modern analytic functions such as approximated entropy and adaptive support vector machine (SVM). It is shown that the overall accuracy of EEG bio-signal analysis has increased to nearly 98% for different data sets, including open-source and clinical data sets.