Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Humans ; Spondylitis, Ankylosing/diagnosis* ; Delayed Diagnosis ; East Asian People ; Asian People

With the population aging, the prevalence of chronic kidney disease(CKD)is increasing.Frailty is a complex syndrome in the elderly.Elderly CKD patients have higher risks of frailty and cognitive impairment than the general elderly population.In recent years, the relationship between frailty and cognition has gradually attracted the attention of researchers at home and abroad.Cognitive frailty is regarded as a subtype of frailty and has become one of the research hotspots in the field of gerontology.However, there are few studies on the relationship between CKD and cognitive frailty in the elderly.This article reviews research progress on the topic, including the epidemiology, evaluation methods and possible pathogenesis of cognitive frailty in elderly CKD patients.

BACKGROUNDFor young patients, the surgical method for lumbar disc herniation remains controversial. The aim of this study was to prospectively determine the short-term clinical outcome after surgery for young patients with lumbar disc herniation.

METHODSIn this prospective comparative study between April 2010 and August 2011, a total of 80 patients underwent primary surgery at a single level for lumbar disc herniation. The patients were divided into two groups: decompression alone and decompression with instrumented fusion. An independent examiner clinically evaluated the patients at preoperation and at 1, 3, 6, and 12 months after surgery. The patients filled out the instruments for back and leg pain using a Visual Analog Scale (VAS), Oswestry Low Back Pain Disability Questionnaire (ODI), and Japanese Orthopaedic Association (JOA) scores. The differences between the two groups were analyzed.

RESULTSThe mean age of all the patients at the time of surgery was 33.7 years. Of the 80 patients, 38 patients underwent decompression alone and 42 patients underwent posterior lumbar interbody fusion. Increasing complexity of surgery was associated with a longer surgery time, greater blood loss, and a longer hospital stay after surgery. Both methods of surgery independently improved outcomes compared with baseline status based on VAS, ODI, and JOA scores (P < 0.05), and no significant differences were found between the two groups at most of the measuring points in time, although patients with decompression alone had a higher JOA score (P = 0.016) and higher JOA recovery rate (P = 0.010) at the 3-month follow-up.

CONCLUSIONSThe short-term results of our study showed that both methods of surgery obtained effective clinical outcomes, but decompression alone had some advantages (shorter surgery time, less blood loss, shorter hospital stay, and lower cost) compared with decompression with instrumented fusion. Young patients with decompression alone could achieve great physical function earlier.

Adult ; Decompression, Surgical ; Female ; Humans ; Intervertebral Disc Displacement ; surgery ; Lumbar Vertebrae ; surgery ; Male ; Prospective Studies ; Spinal Fusion ; Treatment Outcome