Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

Fibromyalgia syndrome （FMS） is a refractory， chronic non-articular rheumatic disease characterized by widespread pain throughout the body， for which there are no satisfactory therapeutic drugs or options. There are rich Chinese medical therapies， and some non-drug therapies， such as acupuncture， Tai Chi， and Ba-Duan-Jin， have shown satisfactory efficacy and safety and definite advantages of simultaneously adjusting mind and body. FMS is taken as a disease responding specifically to traditional Chinese medicine （TCM） by the National Administration of Traditional Chinese Medicine in 2018. In order to clarify the research progress in FMS and the clinical advantages of TCM/integrated Chinese and Western medicine， the China Academy of Chinese Medicine organized a seminar for nearly 20 experts in Chinese and Western medicine， including rheumatology， psychology， acupuncture and moxibustion， and encephalopathy， with the topic of difficulties in clinical diagnosis and treatment of FMS and advantages of TCM and Western medicine. The recommendations were reached on the difficulties in early diagnosis and solutions of FMS， mitigation of common non-specific symptoms， preferential analgesic therapy， TCM pathogenesis and treatment advantages， and direction of treatment with integrated Chinese and Western medicine. FMS is currently facing the triple dilemma of low early correct diagnosis， poor patient participation， and unsatisfactory benefit from pure Western medicine treatment. To solve the above problems， this paper suggests that rheumatologists should serve as the main diagnostic force of this disease， and they should improve patient participation in treatment decision-making， implement exercise therapy， and fully utilize the holistic and multidimensional features of TCM， which is effective in alleviating pain， improving mood， and decreasing adverse events. In addition， it is suggested that FMS treatment should rely on both TCM and Western medicine and adopt multidisciplinary joint treatment， which is expected to improve the standard of diagnosis and treatment of FMS in China.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/ mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

Humans ; Soft Tissue Neoplasms ; Mesenchymoma/diagnostic imaging* ; Paraneoplastic Syndromes/pathology*

The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic. Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022. Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020, BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood. In particular, severe/critical cases of COVID-19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment. Importantly, the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototype-inactivated vaccines, supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records. Furthermore, even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection, vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged ≽ 60 years old. Together, our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.
Humans ; Aged ; Middle Aged ; COVID-19/prevention & control* ; SARS-CoV-2 ; Pandemics/prevention & control* ; China/epidemiology* ; Disease Outbreaks/prevention & control* ; Vaccination

Parkinson's disease is a progressive neurodegenerative disorder often seen in the elderly and seriously affects patients' quality of life.Osteoporosis is also a common systemic metabolic bone disease in the elderly characterized by a predisposition to fractures.Studies have shown that Parkinson's disease is highly correlated with osteoporosis, and patients with Parkinson's disease are at high risk for osteoporosis.Hypoxic environments may aggravate the disease and its complications in patients with Parkinson's disease, and the possible mechanisms may involve inhibition of growth and differentiation of osteoblasts, promotion of the formation of osteoclasts, and thus increased risk of osteoporosis under hypoxic conditions.Recent studies have reported that hypoxia, low air pressure, strong sunlight exposure and diets are associated with Parkinson's disease and osteoporosis at high altitudes.This paper reviews research progress on the relationship between Parkinson's disease and osteoporosis in hypoxic environments.

Objective:To analyze the external root resorption of incisors caused by maxillary canine impaction, and to explore the changes of incisor external root resorption after orthodontic treatment.Methods:Twenty-four patients with impacted maxillary canines leading to external root resorption of incisors treated in Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University from July 2011 to January 2019 were selected. The age ranged from 10 to 14 years [(12.3±1.6) years], including 11 males and 14 females. The maxillary incisors with external root resorption before treatment were included in the resorption group (21 central incisors and 22 lateral incisors), and the maxillary incisors without external root resorption were used as the control group (26 central incisors and 21 lateral incisors). Cone-beam CT was taken before treatment, immediately after treatment and one year after treatment. At the one year follow-up 15 patients were collected (10 central incisors and 12 lateral incisors in the resorption group, while 16 central incisors and 12 lateral incisors in the control group). The root length and tooth volume of maxillary incisors were measured and analyzed before canine traction, after canine traction finished and at the one year follow-up.Results:After the treatment of maxillary impacted canines, the root length and volume of the central and lateral incisors in both resorption group and control group were significantly less than that before treatment ( P<0.05). At the one year follow-up, the root length and volume of the incisors (central incisors in the resorption group and the central and lateral incisors in control group) were significantly less than those immediately after impacted canine traction ( P<0.05). During the canine traction, the difference of the volume change in lateral incisors between the resorption group [(17±6) mm 3] and the control group [(12±5) mm 3] was statistically significant ( t=2.51, P<0.05). During the one year follow-up period, the difference between the changes of the root length in maxillary central incisors in the resorption group [(0.5±0.4) mm] and in the control group [(0.2±0.1) mm] was statistically significant ( t=2.35, P<0.05). Conclusions:For maxillary incisors with external root resorption caused by impacted maxillary canines, the external root resorption could not stop immediately after the treatment of impacted canines. The root resorption in maxillary lateral incisors mainly occured during the traction process, while the root resorption in maxillary central incisors existed during the orthodontic treatment and in the follow-up period.

Objective:To analyze the characteristics of viral isolation and unique recombinant from untreated HIV-1 patients infected through sexual transmission and injection drug use, so as to provide evidence for understanding the biological characteristics and precise prevention and control of HIV-1 infection in different transmission routes.Methods:In view of the different HIV-1 transmission risks, newly diagnosed untreated HIV-1 patients from Beijing, Guangxi and Sichuan were carefully selected. Venous blood was collected to detect the viral load and CD4 + T cell count, and peripheral blood lymphocytes were isolated for virus isolation. Viral RNAs were extracted from the virus supernatant, and the near full-length genome sequences were obtained using in-house method, then the recombination patterns were determined. Results:Among the 65 HIV-1 infection, 32(49.2%), 20(30.8%) and 13(20.0%) were infected via men who have sex with men (MSM), heterosexual and injection drug use (IDU), respectively; genotypes mainly included 26(40.0%) CRF07_ BC, 23(35.4%) CRF01_ AE, and 9(13.8%) unique recombinant types (URFs). A total of 46 HIV-1 clinical strains were isolated. The positive rate of HIV-1 isolation was significantly negatively correlated with CD4 + T cells ( X2=4.22, P=0.04), but positively correlated with viral load ( X2=22.4, P<0.001); the multi-variate generalized estimating equations(GEE) model analysis of HIV-1 P24 antigen content showed similar result. In addition, GEE model showed a positive correlation between viral P24 antigen content and virus-producing culture time (52.14, 95% CI: 9.42~94.87, P=0.017). Viral growth curve analysis showed that the level of viral P24 antigen in MSM Group was significantly higher than that in heterosexual group and IDU group (adjusted P values were p<0.01 and P<0.05, respectively), on the 14th day after culture. The proportion of URFs in MSM Group was higher than that in heterosexual group, and the recombinant breakpoints in MSM Group were more than that in heterosexual group. Conclusions:MSM population was more sensitive to HIV-1 virus isolation; there was unique diversity of recombinant forms of HIV-1 among those with sexually transmitted infections, especially in the MSM population.

The development of information technology in the medical industry is accelerating the construction of 3-level rehabilitation networks centering on community-based rehabilitation, which is based on the Internet and in combination with the Internet of things(IOT). A municipal rehabilitation hospital cooperated with the health centers of sub-district communities in the city to build a remote rehabilitation network based on IOT technology, for rehabilitation training of community stroke patients. The two sides worked out a cooperation scheme on project management, designed and built a remote community rehabilitation management model. Under the remote monitoring and equipment data IOT, the medical team of the municipal rehabilitation hospital could formulate the therapeutic plan according to the immediately obtained relevant functional evaluation data, and the medical team of the community health service center was responsible for the implementation of the plan. Fifty-three patients in the experimental group received the training of remote lower limb intelligent feedback system based on IOT together with routine rehabilitation training. After 8 weeks of treatment, the functional evaluation data of the two groups were improved in varying degrees( P< 0.05), but the improvement of the experimental group was significantly better than that of the control group( P < 0.05). Remote rehabilitation under the construction path of remote rehabilitation network based on IOT technology could significantly promote the improvement of post-functional rehabilitation of community stroke patients. This study can provide reference for the construction of three-level remote rehabilitation networks based on IOT and the implementation of home-based remote rehabilitation therapy in the future.

OBJECTIVE：To analysis the correlation between chrom aticity value and quality index of Atractylodis chinensis decoction piece powder stir-fired with bran ，and to determine its processing time. METHODS ：The processed samples of 16 batches of A. chinensis decoction piece stir-fired with bran （S0-S15，S0 is the raw product of A. chinensis ）were prepared ，and chromaticity values of all samples were determined ，such as lightness value （L*），yellow blue value （b*），red green value （a*）. UPLC fingerprint of sample were analyzed ，and the contents of extract and volatile oil were also determined. Pearson correlation was used to analyze the correlation between the chromaticity value and quality index （relative peak area of each chromatographic peak in UPLC fingerprint ，water-soluble extract content ，alcohol-soluble extract content and volatile oil content ）. Multivariate statistical analysis （principal component analysis ，cluster analysis ，partial least squares discriminant analysis ）was carried out with chromaticity value and quality index ，and the processing time of A. chinensis decoction piece stir-fired with bran was determined by grey correlation method. RESULTS ：In the process of bran frying ，with the extension of processing time ，L* and b* of decoction pieces powder decreased ，and a* increased first and then decreased ；relative areas of peak 1 and peak 2 increased first and then decreased，while relative areas of peak 3（5-hydroxymethyl furfural ）increased，and the areas of the other peaks decreased. The content of the extract did not change significantly with time ，and the content of the volatile oil decreased. The results of correlation analysis showed that the relative peak area of peak 2-27，alcohol-soluble extract content and volatile oil content had a certain correlation with the chromaticity value ，while the relative peak area of peak 1 and water-soluble extract content had no linear correlation with the chromaticity value. Results of multivariate statistical analysis showed that the samples were divided into mild （S0-S5），excessive （S12-S15），moderate （S6-processing time of 18-33 min）. The results of grey correlation method showed that the processing time of A. chinensis decoction piece stir-fired w ith bran should be controlled in the range of 18-24 min，and the optimal processing time was 18 min. CONCLUSIONS ：There is a correlation between chromaticity value of A. chinensis decoction piece powder stir-fired with bran and the relative peak area of 27 chromatographic peaks ，and content of extract and volatile oil. It is suggested that the processing time should be 18 min.