The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms' Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.
Animals ; Male ; Testis ; Sertoli Cells/metabolism* ; Transcriptome ; Spermatogenesis/genetics* ; Primates ; Aging/genetics* ; Stem Cells

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
Humans ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Chemoradiotherapy ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy ; Prospective Studies ; Rectal Neoplasms/pathology* ; Thrombocytopenia/drug therapy* ; Treatment Outcome ; Adult ; Aged

Based on the characteristics of clinical symptoms of secretory otitis media in traditional Chinese and Western medicine,by reference to clinical diagnostic criteria,efforts were made to analyze and establish the Western medical diagnostic criteria and traditional Chinese medicine( TCM) syndrome differentiation criteria for secretory otitis media,and summarize the modeling methods and model characteristics of secretory otitis media animal models. According to the clinical diagnostic criteria and symptom characteristics,the coincidence degree between the existing animal models and clinical symptoms was evaluated,and its advantages and disadvantages were defined. On the basis of the statistical results,there were fewer methods for modeling secretory otitis media animal models,and only a specific relevant pathogenic mechanism could be revealed. Among them,the model with a higher coincidence degree was genetic engineering technology modeling and injection into the middle ear vesicles. The two modeling methods of bacterial factors highly coincided with the clinical symptoms of Western medicine,but both failed to reflect the TCM syndrome type. Therefore,establishing an animal model that simultaneously reflects the characteristics of clinical symptoms of secretory otitis media in traditional Chinese and Western medicine,and improving the evaluation criteria of secretory otitis media based on animal models are the main tasks of future studies on secretory otitis media.
Animals ; China ; Disease Models, Animal ; Medicine ; Medicine, Chinese Traditional ; Otitis Media with Effusion/drug therapy*

Moxa smoke plays an indispensable role in traditional Chinese medicine with the functions of dispelling poison, exorcizing evil and avoiding filth, dispelling cold, etc. It has been used to prevent pestilence for thousands of years. This paper reviewed the clinical application, mechanism and existing shortcomings of moxa smoke for preventing epidemic diseases, and found that moxa smoke can effectively inhibit a variety of pathogenic bacteria, fungi and viruses that cause infectious and epidemic diseases, and has good pharmacological effects of sterilization, antiviral and immunity enhancement, and has achieved remarkable effect in disease prevention, health care and plague prevention. It is suggested that attention should be paid to the air quality of moxibustion clinics in the future, it is urgent to establish a unified sanitary air quality standard system to create a good clinic environment. At the same time, the research on the clinical safe concentration range of moxa smoke should be strengthened to effectively avoid the occurrence of adverse reactions, give full play to the efficacy of moxa smoke in eliminating pathogenic factors and preventing epidemic, so as to provide the basis for the rational application and promotion of moxa smoke.

Angiotensin-Converting Enzyme 2/metabolism* ; COVID-19/virology* ; Disease Susceptibility ; Humans ; SARS-CoV-2/pathogenicity* ; Species Specificity

Cells, Cultured ; Cyclic Nucleotide Phosphodiesterases, Type 2 ; antagonists & inhibitors ; metabolism ; Fibroblasts ; drug effects ; metabolism ; Glucosides ; pharmacology ; Humans ; Lung ; cytology ; embryology ; Phenols ; pharmacology ; Phosphodiesterase Inhibitors ; pharmacology ; Tumor Suppressor Protein p53 ; metabolism

Aged ; China ; Forests ; Humans ; Life Style ; Pulmonary Disease, Chronic Obstructive ; therapy

Based on the clinical symptom characteristics of transient ischemic attack in Chinese and Western medicines, the existing models of transient ischemic attack were summarized and analyzed. Then the advantages and disadvantages of each model, the diagnostic criteria of traditional Chinese and Western medicine and clinical symptoms compliance were analyzed to put forward the evaluation method and improvement method of the corresponding animal models. It was found that there were many modeling methods of transient ischemic attack, but they can not reflect the transience, reversibility, recurrence and other typical characteristics of the disease, with significant differences with clinical symptoms. Moreover, there is lack of reasonable quantitative criteria for the success of the animal model. By combining the existing single factor animal models, a composite animal model that was more closely related to the clinical symptoms of transient ischemic attack was established to replicate an animal model that was more compatible with the characteristics of clinical symptoms. It is the future development directions of the transient ischemic attack animal models to establish reasonable quantitative standards, reflect the causes of Chinese and Western medicine symptoms and improving a series of systematic and complete model evaluation methods.

OBJECTIVE: In order to understand which kind of function genes play an important role for estimating wound age, the variation of difference genes' mRNA expression were compared after injury. METHODS: The mRNA expression levels of seven candidate genes (ICAM-1, NF-κB, MX2, MT1, MT2, sTnI, and Cox6c) were analyzed in contused rat skeletal muscle at different time points using real-time fluorescent quantitative PCR (RT-qPCR). The raw Ct values were normalized relative to that of RPL32 mRNA, and converted to standard Ct values. At each time point after injury, the standard deviations (SD) of the standard Ct values were calculated by SPSS. RESULTS: The expression trends of the seven genes were all found to be related to wound age, but there were lower variation coefficients and greater reliability of s TnI and Cox6c when compared with other genes. CONCLUSION The genes encoding structural proteins or proteins that perform basic functions can be suitable for wound age estimation.
Animals ; Contusions/genetics* ; Forensic Pathology ; Gene Expression Profiling ; Intercellular Adhesion Molecule-1 ; Muscle, Skeletal/metabolism* ; NF-kappa B ; Proteins ; RNA, Messenger/metabolism* ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Reproducibility of Results ; Time Factors ; Wound Healing/genetics*

OBJECTIVE: To investigate the relationship between the expression of secreted frizzled-related protein 5 (SFRP5) mRNA and the time interval after skeletal muscle injury in rats by real-time PCR. METHODS: A total of ninety SD rats were randomly divided into the contusion groups at different times including 4h, 8h, 12h, 16h, 20h, 24h, 28h, 32h, 36h, 40h, 44h, 48h after contusion, incision groups at different times including 4h and 8h after incision and the control group. The samples were taken from the contused zone at different time points. The total RNA was isolated from the samples and reversely transcribed to analyze the expression levels of SFRP5 mRNA. RESULTS: Compared to the control group, the expression of SFRP5 mRNA in contusion groups were down-regulated within 48 h after contusion and reached the lowest level at 20 h, and the expression of SFRP5 mRNA gradually increased from 20 h to 48 h after contusion. The expression of SFRP5 mRNA in the incised groups were significantly lower than that of the contusion groups at 4 h after injury. At the time of 8 h, the expression levels between the contusion and incision groups showed no statistically significant difference. CONCLUSION It is suggested that SFRP5 mRNA analysis may show regular expression and can be a marker for estimation of skeletal muscle injury age.
Animals ; Biomarkers/metabolism* ; Contusions/metabolism* ; Membrane Proteins/metabolism* ; Muscle, Skeletal/metabolism* ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction