The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α ₂-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α ₂-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.
Humans ; Immunotherapy, Adoptive/methods* ; Receptors, Chimeric Antigen/immunology* ; Signal Transduction/immunology* ; T-Lymphocytes/immunology* ; Neoplasms/immunology* ; Animals

Metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by fatty acid overload, secondary chronic inflammation, and fibrosis, has become the most prevalent chronic liver disease globally. While no effective pharmacotherapy exists for MAFLD, mitigating inflammatory responses represents a promising approach to preventing the progression from steatosis to severe steatohepatitis. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which detects endogenous danger and stress signals, has emerged as a significant target for inflammatory disease treatment, as transcriptional inactivation of its components demonstrates the therapeutic potential for MAFLD. Natural products targeting NLRP3 inflammasome activation have shown promising efficacy in MAFLD therapy. This review synthesizes the current understanding of NLRP3 inflammasome activation and therapeutic targets for NLRP3 homeostasis. Additionally, natural products reported to inhibit NLRP3 inflammasome for MAFLD improvement are categorized according to their mechanisms of action. The review also addresses limitations and future directions regarding natural products targeting NLRP3 inflammasome in MAFLD treatment. Enhanced understanding of NLRP3 inflammasome activation mechanisms in MAFLD and the identification of novel natural products supported by mechanistic research will significantly advance MAFLD treatment.
Humans ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology* ; Inflammasomes/metabolism* ; Biological Products/therapeutic use* ; Animals ; Fatty Liver/immunology*

There are millions of patients with taxane-induced peripheral neuropathy （TIPN）， and there is no effective treatment or prevention measure in clinical practice. The occurrence of TIPN may be related to the dosage form of paclitaxel drugs， genetic and molecular markers， drug dosage and chemotherapy cycle， patient factors， etc. At present， drugs for treating TIPN mainly include those that inhibit axonal degeneration （such as dosazosin， tamsulosin）， prevent mitochondrial dysfunction （such as glutathione trisulfides， antioxidants α -lipoic acid）， improve calcium imbalance in the internal environment （Shaoyao gancao decoction， N-type voltage-gated calcium channel inhibitor IPPQ）， and inhibit neuroinflammation （such as chemokine inhibitors and selective interleukin-8 receptor inhibitors DF2726A）. Further exploration of drug treatment strategies targeting different induction mechanisms is expected to become a new direction for precise clinical prevention and personalized treatment of TIPN.

Humans ; SARS-CoV-2 ; COVID-19 ; Antibodies ; Antibodies, Viral/therapeutic use* ; Antibodies, Neutralizing/therapeutic use*

OBJECTIVE: To review the studies about the tibial-graft fixation methods on anterior cruciate ligament (ACL) reconstruction, in order to provide clinical reference. METHODS: The literature about the tibial-graft fixation methods on ACL reconstruction at home and abroad was extensively reviewed, and the factors that affect the selection of fixation methods were summarized. RESULTS: The knee flexion angle, graft tension, and graft fixation device are mainly considered when the tibial-graft was fixed on ACL reconstruction. At present, the graft is mainly fixed at 0°/30° of knee flexion. The study shows that the knee joint is more stable after fixed at 30°, while the incidence of knee extension limitation decrease after fixed at 0°. In terms of graft tension, a good effectiveness can be obtained when the tension level is close to 90 N or the knee flexion is 30° to recover the affected knee over-restrained 2 mm relative to the healthy knee. In terms of the graft device, the interference screw is still the most commonly used method of tibial-graft fixation, with the development of all-inside ACL reconstruction in recent years, the cortical button fixation may become the mainstream. CONCLUSION Arthroscopic reconstruction is the main treatment of ACL rupture at present. However, there is no optimal fixation method for the tibial-graft, the advantages and disadvantages of each fixation methods need to be further studied.
Humans ; Tibia/surgery* ; Anterior Cruciate Ligament Reconstruction ; Knee Joint/surgery* ; Anterior Cruciate Ligament Injuries/surgery* ; Bone Screws

Objective:To construct a traditional Chinese medicine syndrome differentiation model for tinnitus using automatic machine learning technology, and to explore the key factors that affect the results of tinnitus syndrome differentiation.Methods:The clinical characteristics of 594 patients with subjective tinnitus in seven medical units in Shanghai from January 2021 to January 2022 were retrospectively analyzed. The Auto-sklearn automatic machine learning method was used to compare 15 algorithms, and the model with the best classification effect was selected to analyze the key factors affecting tinnitus.Results:The results showed that the optimal algorithm for classification results was the random forest, its accuracy, precision, sensitivity, specificity, F1-score, AUC and kappa coefficient were 87.37%, 88.34%, 89.06%, 96.63%, 88.38%, 97.50%, and 83.37%, respectively. It is concluded that the key factors affecting the classification of the pattern of kidney yin deficiency and fire effulgence, the pattern of liver fire disturbing upward, the pattern of stagnation and binding of phlegm and fire, the pattern of spleen and stomach deficiency, the pattern of wind and heat attacking the external are smooth pulse, string pulse, smooth pulse, weak tongue, and floating pulse respectively.Conclusions:Random forest can provide a good classification prediction function for structured clinical data, suggesting that machine learning technology has clinical application value in assisting the diagnosis of subjective tinnitus.

There are few reports on the use of Allium stents in the treatment of membranous urethral stricture in China. Its safety and effectiveness need to be observed. This study retrospectively analyzed the data of 5 patients admitted to our hospital for the treatment of membranous urethral stricture using Allium-covered metal urethral stents in the past 5 years. The preoperative International Prostatic Symptom Score (IPSS) score was 8.80±1.30, quality of life(QOL)score was 4.20 ±0.84, and the International Index of Erectile Function-5(IIEF-5) score was 20.20 ± 1.92, respectively. Six months after the operation, the IPSS score was 3.60±1.52, the QOL score was 1, and the IIEF-5 score was 19.80±1.48. This operation is easy with little invasion. It can alleviate the dysuria of patients with membranous urethral stricture and has little impact on the sexual function of patients. It is generally safe and controllable, but the appropriate time for implantation still needs to be explored.

【Objective】 To report the early clinical effects and surgical complications of endoscopic spinal fusion technology （Endo-LIF） in the treatment of degenerative lumbar disease. 【Methods】 The clinical data of 31 patients with degenerative lumbar spine disease treated with Endo-LIF from June 2019 to May 2021 were retrospectively analyzed. All the 31 patients underwent endoscopic spinal fusion therapy. We recorded the operation time， hospital stay duration， postoperative complications， visual analogue scale for pain （VAS）， oswestry dysfunction Index （ODI） and low back pain in the Chinese Orthopaedic Association Spine Group Surgery scoring standards before operation， immediately after operation， and the last follow-up to evaluate clinical efficacy. 【Results】 The operation time of the 31 patients was （134.80±34.98） min， the intraoperative blood loss was （100.13±18.49） mL， the hospital stay was （6.65±0.17） days， and the follow-up time was 6 to 18 （14±2.3） months. One patient had hematoma compression after surgery； he had incision made immediately to clear the hematoma and healed after bed rest. Two patients developed spinal hypertension and healed after bed rest. All the patients had no symptoms of nerve injury after operation， and the clinical symptoms were significantly relieved. We compared the perioperative VAS score and ODI index of all the patients， which were lower immediately after operation and at the last follow-up than those before the operation （P<0.05）， and the difference was statistically significant. 【Conclusion】 Endo-LIF technology has good short-term clinical effects and the advantages of milder trauma， less blood loss， and quick recovery after surgery. It is a safe and minimally invasive lumbar fusion surgery.

One hundred eighty-four cases of awake craniotomy in Xijing Hospital from September 2010 to June 2019 were retrospectively included in the study.Patients were divided into Asleep-Awake-Asleep (AAA) group and monitored anesthesia care (MAC) group.In AAA group, general anesthesia was used in the early arousal period, sedatives and analgesics were stopped during the arousal period, and the bispectral index (BIS) value was maintained at 60-80 in the late arousal period.In MAC group, dexmedetomidine and remifentanil were intravenously infused in the early arousal period, and the BIS value was maintained at 60-80 in the late arousal pericd.Dexmedetomidine and remifentanil infused were reduced or stopped according to the Observer′s Assessment of Altertness/Sedation score during the arousal period, so that the patient could be awakened at any time, and the BIS value was maintained at 60-80 in the late arousal period.Compared with AAA group, the consumption of local anesthetic and remifentanil was significantly decreased, the operation and anesthesia time was shortened, the requirement for rescue analgesia was decreased, mean arterial pressure, end-tidal pressure of carbon dioxide (P ETCO 2) and partial pressure of arterial carbon dioxide (PaCO 2) were increased and partial pressure of arterial oxygen (PaO 2) was decreased after laryngeal mask insertion or sedation, and heart rate and PaO 2 were decreased, P ETCO 2 and PaCO 2 were increased after awakening in group MAC ( P<0.05). There were no significant differences in anesthesia failure rate in the awake craniotomy, incidence of adverse events during the arousal period, intraoperative incidence of tachycardia/bradycardia and hypertension/hypotension, Observer′s Assessment of Alertness/Sedation score during the arousal period, rate of postoperative visual analogue scale score>5 after surgery, postoperative requirement for rescue analgesia, neurological deficit rate and rehabilitation discharge rate between the two groups ( P>0.05). Compared with those after laryngeal mask insertion or after sedation, mean arterial pressure, heart rate, P ETCO 2 and PaCO 2 were significantly increased, and PaO 2 was decreased after awakening in AAA group ( P<0.05), and no statistically significant change was found in the parameters mentioned above after awakening in MAC group ( P>0.05). In summary, MAC shortens the operation and anesthesia time, no artificial airway is required, and it is suitable for the short time and minor operation.AAA has a better hemodynamics and oxygenation in the early arousal period, but the patient′s stress is more obvious after awakening, and effective prevention and intervention are needed.