Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.

Objective: To provide the mechanism-based pharmacotherapy of the Huatan Qushi formula (HTQS formula), for the health management and treatment of non-alcoholic fatty liver disease (NAFLD). Methods: A rat model of NAFLD was employed to examine the efficacy and safety of the HTQS formula. In vivo active components and potential mechanisms of the HTQS formula were identified using UPLC‒MS/MS combined with network pharmacology. The influence of the HTQS formula on the dominating proteins in PI3K/Akt pathway was validated in vivo using western blot. Finally, 16S rRNA sequencing of the gut microbiome was conducted followed by targeted metabolomics detecting fecal short-chain fatty acids (SCFAs) and bile acids to determine the impact of the HTQS formula on gut microbiota. Results: The HTQS formula reduced weight gain and hepatic steatosis in NAFLD rats and decreased serum total cholesterol (TC), triglycerides, blood glucose, and insulin resistance (IR) without causing liver or kidney injury. We detected 28 components using UPLC‒MS/MS and identified 439 shared targets between NAFLD and the HTQS formula. Primarily, we focused on the PI3K/Akt signaling pathway based on protein‒protein interaction network analysis. We validated that the HTQS formula inhibited liver steatosis and inflammation by increasing the phosphorylation levels of PI3K, AKT, P27, GSK3β in the PI3K/Akt signaling pathway. 16S rRNA sequencing revealed that the HTQS formula reduced the abundance of the genus Family_XIII_AD3011_group, which was positively correlated with IR and taurodeoxycholic acid. In addition, Lachnospiraceae_UCG_010 inversely correlated with TC and five bile acids, which could be essential to the therapeutic effect of the HTQS formula against NAFLD. Conclusions The HTQS formula proved to be an effective pharmacotherapy for NAFLD without causing liver or kidney injury. Multiple potent components of the HTQS formula could alleviate liver steatosis and lipid metabolism disorder by modulating the PI3K/Akt signaling pathway and restoring gut microbiota composition.

Objective:With the in-depth study of complement dysregulation,glomerulonephritis with dominant C3 has received increasing attention,with a variety of pathologic types and large differences in symptoms and prognosis between pathologic types.This study analyzes the clinical,pathological,and prognostic characteristics of different pathological types of glomerulonephritis with dominant C3,aiming to avoid misdiagnosis and missed diagnoses. Methods:The clinical,pathological,and follow-up data of 52 patients diagnosed as glomerulonephritis with dominant C3 by renal biopsy from June 2013 to October 2022 were retrospectively analyzed.According to the clinical feature and results of pathology,15 patients with post-infectious glomerulonephritis(PIGN)and 37 patients with of non-infectious glomerulonephritis(N-PIGN)were classified.N-PIGN subgroup analysis was performed,and 16 patients were assigned into a C3-alone-deposition group and 21 in a C3-dominant-deposition group,or 27 in a C3 glomerulopathy(C3G)group and 10 in a non-C3 nephropathy(N-C3G)group. Results:The PIGN group had lower creatinine values(84.60 μmol/L vs 179.62 μmol/L,P= 0.001),lower complement C3 values(0.36 g/L vs 0.74 g/L,P<0.001)at biopsy,and less severe pathological chronic lesions compared with the N-PIGN group.In the N-PIGN subgroup analysis,the C3-dominant-deposition group had higher creatinine values(235.30 μmol/L vs 106.70 μmol/L,P=0.004)and higher 24-hour urine protein values(4 025.62 mg vs 1 981.11 mg,P=0.037)than the C3-alone-deposition group.The prognosis of kidney in the PIGN group(P=0.049),the C3-alone-deposition group(P=0.017),and the C3G group(P=0.018)was better than that in the N-PIGN group,the C3-dominant-deposition group,and the N-C3G group,respectively. Conclusion:Glomerulonephritis with dominant C3 covers a variety of pathological types,and PIGN needs to be excluded before diagnosing C3G because of considerable overlap with atypical PIGN and C3G;in addition,the deposition of C1q complement under fluorescence microscope may indicate poor renal prognosis,and relevant diagnosis,treatment,and follow-up should be strengthened.

Corneal stroma is a significant part of the cornea and plays a significant role in the eye's refractive system. Although corneal transplantation is now the most effective treatment for corneal stromal disease, its advancement has been constrained by a shortage of donors, the need for prolonged immunosuppressive medicine to prevent rejection, and low graft survival rates. An alternate strategy is to use the corneal stroma's natural capacity for regeneration to create the ideal conditions for the collagenous extracellular matrix of the stroma to self-renew. However, it is challenging to replicate the intricate ultrastructure of the corneal stroma in vitro. Regenerative medicine has so been used to address these issues. These approaches refer to numerous disciplines, including stem cell-induced differentiation, tissue engineering and gene editing. This article provides potential directions for the future clinical applications of corneal stromal regeneration and repair while summarizing pertinent techniques, research progress, and issues.

BACKGROUND:Stage Ⅲ Kümmell's disease is characterized by a high degree of vertebral compression and posterior wall defects.Most of the patients are elderly people with severe osteoporosis and various medical diseases.Clinically,some surgical methods are often at high risk and are controversial. OBJECTIVE:To investigate the clinical efficacy of screw placement combined with transpedicular impaction bone grafting in the treatment of stage Ⅲ Kümmell's disease. METHODS:The clinical data of injured vertebral screw placement combined with transpedicular impaction bone grafting in treatment of stage Ⅲ Kummell's disease from May 2016 to August 2021 were retrospectively analyzed.Visual analog scale score,Oswestry disability index,anterior vertebral heights,kyphotic Cobb angle and American Spinal Injury Association(ASIA)impairment scale were used to evaluate the effects of surgery.The operation time,intraoperative blood loss and complications were recorded.CT scans were used to evaluate the healing of injured vertebrae at the final follow-up visit. RESULTS AND CONCLUSION:(1)A total of 26 patients were included,with 7 males and 19 females,at the age range of 62-81 years[mean(69.7±4.8)years].The follow-up time was 18-60 months[mean(35.1±8.9)months].The average operative duration was 133.5 minutes(100-165 minutes),and the average intraoperative blood loss was 285.3 mL(210-350 mL).(2)Visual analog scale and Oswestry disability index scores 1 week after surgery were significantly lower than those before surgery.(3)At 1 week after surgery,the anterior vertebral height corrections and the Cobb angle were(9.0±0.7)mm and(16.2±1.0)°,respectively.During the follow-up period,the loss of vertebral height and kyphosis correction were(5.1±0.3)mm and(8.0±0.4)°,respectively.(4)14 patients(54%)had ASIA grade D before operation,which recovered to grade E at the last follow-up.CT scan showed that all patients achieved good osseous union.(5)Complications occurred in seven patients(27%),including hypostatic pneumonia in two cases,postoperative superficial wound tissue liquefaction in two cases,and adjacent vertebral compression fractures in three cases.(6)It is concluded that screw placement of the injured vertebra combined with transpedicular impaction bone grafting can rapidly rebuild spinal stability,effectively relieve pain and improve neurological function in the treatment of stage Ⅲ Kümmell's disease.This technique is an effective and relatively minimally invasive surgical option.

Objective To investigate the influence factors of lymphovascular space invasion(LVSI)in patients with low-grade endometrioid carcinoma.Methods Clinical data of 167 patients with low-grade(G1,G2)endometrioid carcinoma of uterus diagnosed by surgical pathology from January 2015 to May 2023 were retrospectively analyzed.Univariate analysis of the following 9 indicators was performed:age,postmenopausal status,abnormal vaginal bleeding duration,combined with metabolic syndrome,increased CA125(≥ 35 U/ml),endometrial thickness,uterine occupation,combined with adenomyosis of uterus,stage of the International Federation of Gynecology and Obstetrics(FIGO)2009 standards.The binary logistic refression analysis was made on factors with P＜0.05.Results Among the 167 patients with low-grade endometrioid carcinoma of uterus,24 cases(14.4％)had LVSI.The binary logistic regression analysis was performed for 4 factors(abnormal vaginal bleeding duration ≥ 4 months,increased CA125,combined with adenomyosis of uterus,stage Ⅱ and above)with P＜0.05 in the univariate analysis,and the results showed stage Ⅱ and above(OR=7.357,95％CI:2.140-25.288,P=0.002)and increased CA125(OR=4.883,95％CI:1.612-14.794,P=0.005)were an independent prognostic factor for LVSI in low-grade endometrial carcinoma of uterus.Conclusion Stage Ⅱ(FIGO 2009)and above and CA125≥35 U/ml are associated with LVSI in patients with low-grade endometrioid carcinoma,indirectly suggesting the risk of lymph node metastasis,which should be paid close attention to before surgery in order to develop a more accurate surgical plan.

Objective:To observe the clinical and imaging features of patients with retinal vein occlusion (RVO) complicated with retinal artery occlusion (RAO).Methods:A retrospective clinical study. Fifteen patients with 15 eyes with RVO combined with RAO and macular edema diagnosed by ophthalmology examination in the Department of Ophthalmology, First People's Hospital of Xianyang City during 2 years from February 1, 2022 to January 31, 2024 were included in the study. Branch retinal vein occlusion (BRVO) combined with branch retinal artery occlusion (BRAO) occurred in 3 cases and 3 eyes. Central retinal vein occlusion (CRVO) complicated with central retinal artery occlusion (CRAO) in 12 eyes. Best corrected visual acuity (BCVA), intraocular pressure, scanning laser ophthalmoscope, optical coherence tomography (OCT), fluorescein fundus angiography (FFA) and serum homocysteine were all performed. OCT angiography (OCTA) was performed in 6 eyes. All eyes were treated with intravitreal injection of anti-vascular endothelial growth factor drugs. After the initial 1 treatment, dosage was assessed as needed. Follow-up was performed every month for 12 months after treatment. FFA inspection was performed at 3 months. During follow-up, it was found that there were no perfusion areas of capillaries, and retinal laser photocoagulation therapy was given in time. Fundus manifestations, FFA, OCT, OCTA characteristics and causes of disease were analyzed retrospectively.Results:There were 15 eyes in 15 cases, 9 eyes in 9 males; 6 women with 6 eyes. Age was (61.0±9.7) years. All complained of painless vision loss in one eye. All eyes were positive for relative afferent pupillary disorder. Contralateral congenital optic disc defect was in 1 case; hypertension was in 6 cases; hyperhomocysteinemia was in 2 cases; cerebral infarction was in 3 cases; coronary heart disease was in 1 case. CRVO combined with CRAO was in 12 eyes BCVA light sensitivity-0.25. The BCVA of BRVO combined with BRAO were 0.1, 0.4 and 0.25, respectively. All the patients had retinal edema in the posterior pole of the eye, venous sinuous, dilated, thin arteries and stiff shape. The retina presents with flaky or flame-like bleeding. Posterior polar retinal lint patch was in 13 eyes. In 12 eyes with CRVO combined with CRAO, optic disc edema was observed and the boundary was not clear. In 3 eyes with BRVO combined with BRAO, no obvious abnormality was found in the optic disc, and the boundary was clear. FFA examination showed no or prolonged arterial filling, delayed retinal vein laminar flow, relatively slow or even no capillary filling, macular arteriole atretosis to varying degrees, arch ring structure destruction, optic disc telangiectasia and fluorescein leakage. OCT examination showed that the middle and inner layers of the retina were thickened to varying degrees, the diffuse reflex was enhanced, the interlayer structure was unclear, and the reflex of the lower retinal tissue was weakened. The blood flow density of superficial capillary plexus and deep capillary plexus (DCP) decreased in 6 eyes undergoing OCTA examination. Decreased or interrupted blood flow in the vascular bed of DCP. During the follow-up period, there were 13 eyes with no perfusion area of retinal capillary. The time of occurrence was (1.14±0.95) (0-2) months, and the area was 10-75 disc area. Optic nerve atrophy occurred in 5 eyes. At the last follow-up, visual acuity increased, unchanged and decreased in 12, 2 and 1 eyes, respectively.Conclusions:The pathogenesis of RVO-RAO is complicated. Most RVO and RAO occurred simultaneously, and a few RVO occurred several days after RAO. Although the RAO manifestations are not typical, the radiographic features are both RVO and RAO. Compared with BVRO combined with BRAO, the prognosis of visual acuity in CRAO patients with CRVO is worse.

The prevalence of high myopia is increasing year by year and leads to a variety of ocular complications,of which pathological myopia has become a major cause of irreversible blindness worldwide.Patients with high myopia often suffer from reduced retinal perfusion and varying degrees of visual field defects.High myopia can cause irreversible damage to the fundus,leading to increased susceptibility to glaucoma and myopic maculopathy.Therefore,it is of great clinical sig-nificance to understand the characteristics of the fundus and complications of high myopia to slow the myopia progression and prevent complications.This article introduces the dangers of high myopia in details from the aspects of fundus perfu-sion,visual field defects and complications,aimed at guiding clinicians in early detection,diagnosis and intervention of high myopia and its complications to reduce the prevalence of high myopia and blindness and improve the vision and life quality of the general public.

Objective:To investigate the expression of circ_0063865 in esophageal squamous cell carcinoma(ESCC)tissues and cells and its effect on the biological properties of the cells.Methods:The loop structure and stability of circ_0063865 were identified by Sanger sequencing, back-to-back primer validation and the ribonuclease R(Rnase R)tolerance assay.The expression of circ_0063865 was detected by RNA fluorescence in situ hybridization in an ESCC tissue microarray and its clinical relevance was analyzed.The expression levels of circ_0063865 in a normal esophageal epithelial cell line and ESCC cell lines were measured by real-time quantitative polymerase chain reaction(RT-qPCR). Cell counting Kit-8, the colony formation assay, the scratch assay, the transwell invasion assay and flow cytometry were used to detect the effects of circ_0063865 on cell proliferation, migration, invasion abilities and apoptosis, respectively.Results:The loop formation of circ_0063865 was verified by Sanger sequencing, back-to-back primer and Rnase R tolerance assays.The results of RNA fluorescence in situ hybridization showed that the mean fluorescence intensity of circ_0063865 expressed in ESCC tissues was significantly higher than in its paired paracancerous normal tissues( t=2.267, P<0.05). The expression of circ_0063865 was significantly associated with lymph node metastasis( χ2=4.356, P<0.05). The average overall survival time of patients with high circ_0063865 expression ESCC was lower than that of patients with low circ_0063865 expression ESCC.RT-qPCR results demonstrated that, compared with HEEC, circ_0063865 expression was elevated in ESCC cell lines( F=18.413, P<0.05). In addition, after circ_0063865 knockdown, the proliferation, migration and invasion abilities of KYSE-30 and KYSE-150 cells were significantly decreased, and the level of apoptosis was significantly increased(both P<0.05). Conclusions:The expression of circ_0063865 in ESCC is high, and changes in its expression are significantly correlated with lymph node metastasis.Additionally, circ_0063865 can promote the proliferation, migration and invasion of ESCC cells.

OBJECTIVES: Tubulointerstitial diseases is one of the common causes of renal dysfunction. Some rare pathological types are easy to be misdiagnosed and missedly diagnosed because of their low prevalence and relatively insufficient understanding, which affects the treatment and prognosis of patients. This study aims to explore clinical manifestations and pathological characteristics of several rare tubulointerstitial diseases, and therefore to improve their diagnosis and treatment. METHODS: A total of 9 363 patients diagnosed by renal biopsy in the Department of Nephrology, Second Xiangya Hospital, Central South University from November 2011 to September 2021 were selected. Six cases of light chain cast nephropathy (LCCN), 2 cases of light chain proximal tubulopathy (LCPT), 1 case of LCCN with LCPT, 4 cases of genetic tubulointerstitial disease, and 6 cases of non-genetic related tubulointerstitial lesion were screened out, and their clinical manifestations and renal biopsy pathological results were collected, compared, and analyzed. RESULTS: Patients with LCCN presented with mild to moderate anemia, microscopic hematuria, and mild to moderate proteinuria. Compared with patients with LCPT, proteinuria and anemia were more prominent in patients with LCCN. Five patients with LCCN and 2 patients with LCPT had elevated serum free kappa light chain. Five patients with LCCN presented clinically with acute kidney injury (AKI). Two patients with LCPT and 1 patient with LCCN and LCPT showed CKD combined with AKI, and 1 LCPT patient presented with typical Fanconi syndrome (FS). Five patients with LCCN, 2 patients with LCPT, and 1 patient with LCCN and LCPT were diagnosed with multiple myeloma. Five patients with LCCN had kappa light chain restriction in tubules on immunofluorescence and a "fractured" protein casts with pale periodic acid-Schiff (PAS) staining on light microscopy. Immunohistochemical staining of 2 LCPT patients showed strongly positive kappa light chain staining in the proximal tubular epithelial cells. And monoclonal light chain crystals in crystalline LCPT and abnormal lysosomes and different morphological inclusion bodies in noncrystalline LCPT were observed under the electron microscope. Six patients with LCCN were mainly treated by chemotherapy. Renal function was deteriorated in 1 patient, was stable in 4 patients, and was improved in 1 patient. Two patients with LCPT improved their renal function after chemotherapy. Four patients with genetic tubulointerstitial disease were clinically presented as CKD, mostly mild proteinuria, with or without microscopic hematuria, and also presented with hyperuricemia, urine glucose under normal blood glucose, anemia, polycystic kidneys. Only 1 case had a clear family history, and the diagnosis was mainly based on renal pathological characteristics and genetic testing. Compared with patients with non-genetic related tubulointerstitial lesion, patients with genetic tubulointerstitial disease had an earlier age of onset, higher blood uric acid, lower Hb and estiated glomemlar fitration (eGFR), and less edema and hypertension. Renal pathology of genetic tubulointerstitial disease presented tubular atrophy and interstitial fibrosis, abnormal tubular dilation, glomerular capsuledilation, and glomerular capillary loop shrinkage. Glomerular dysplasia and varying degrees of glomerular sclerosis were observed. Genetic tubulointerstitial disease patients were mainly treated with enteral dialysis, hypouricemic and hypoglycemic treatment. Two genetic tubulointerstitial disease patients had significantly deteriorated renal function, and 2 patients had stable renal function. CONCLUSIONS Patients with AKI or FS, who present serum immunofixation electrophoresis and/or serum free kappa light chain abnormalities, should be alert to LCCN or LCPT. Renal biopsy is a critical detection for diagnosis of LCCN and LCPT. Chemotherapy and stem cell transplantation could delay progression of renal function in patients with LCCN and LCPT. If the non-atrophic area of the renal interstitium presents glomerular capsule dilatation, glomerular capillary loop shrinkage, and abnormal tubular dilatation under the light microscopy, genetic tubulointerstitial disease might be considered, which should be traced to family history and can be diagnosed by genetic testing.
Humans ; Hematuria ; Immunoglobulin Light Chains/analysis* ; Multiple Myeloma ; Proteinuria ; Nephritis, Interstitial ; Acute Kidney Injury ; Anemia ; Renal Insufficiency, Chronic