Since the beginning of the new century, advances in understanding the intricate interactions between oncology and the immune system have accelerated the rapid development of immune checkpoint inhibitors for the treatment of non-small cell lung cancer. However, resistance to immunotherapy is inevitable. Therefore, uncovering the mechanisms of immunotherapy resistance, proposing strategies to overcome resistance, and identifying future research directions are imperative. Given the limitations of space in each article, this review will explore the complex mechanisms underlying immunotherapy resistance. These mechanisms involve almost all cell types within the body, excluding foreign cancer cells. Notably, these cells serve as recipients (either inhibitory or stimulatory, or both) and producers of signals, playing different roles in various contexts. At the molecular level, these mechanisms include genetic and epigenetic abnormalities in all cells within the microenvironment, as well as the influence of a variety of protein kinase, growth factors, and cytokines with temporal and spatial heterogeneity. At the macroscopic level, host factors such as nutritional metabolism, comorbidities, and microbiota within the organs, as well as neuro-psychological regulation, influence the efficacy of immunotherapy.

Objective:To study the clustered regularly interspaced short palindromic repeats (CRISPR) genotype of Yersinia pestis and its regional distribution characteristics in natural plague focus of Tibet Autonomous Region. Methods:A total of 125 representative Yersinia pestis strains isolated from natural plague focus in Tibet Autonomous Region at different times, regions, hosts and vectors were selected as experimental strains, and the phenol chloroform mixed extraction method was used to extract Yersinia pestis DNA. Three pairs of CRISPR primers (for YPa, YPb, YPc locus) were used to amplify the DNA of the experimental strains, and the CRISPR genotype of Yersinia pestis was determined by sequencing. Results:All 125 strains of Yersinia pestis had three CRISPR locus: YPa, YPb, and YPc. A total of 18 spacer were found, including 8 in YPa loci, 6 in YPb loci, and 4 in YPc loci. Two new types of spacers had been discovered, namely b52 and c14. CRISPR typing revealed 10 genotypes, including G1, G7, G7-b4''', G7-b52, G7-c2 -, G8, G22, G22-a4 -, G22-b4''', and G22-c14, of which 6 were newly discovered genotypes. Among the 125 experimental strains, G7 was the main genotype, accounting for 65.6% (82/125), which was distributed in 6 prefecture level citys and 1 region of Tibet Autonomous Region. Next were G22 and G7-c2 - genetypes, accounting for 14.4% (18/125) and 11.2% (14/125), respectively. G22 gene type was distributed in Nagqu, Changdu, Lhasa citys, and Ngari Prefecture, while G7-c2 - genetype was distributed in Shigatse and Shannan cities. Conclusion:The CRISPR locus of Yersinia pestis in natural plague focus of Tibet Autonomous Region is highly polymorphic, and the Yersinia pestis strains with different genotypes have obvious regional distribution characteristics.

Ulcerative colitis （UC） is a chronic inflammatory bowel disease with complex etiology. The pathogenesis of this disease， due to a combination of factors， is complex and has not yet been elucidated. Among them， intestinal mucosal barrier damage is the basic pathological change of UC. As a non-destructive response of cells， autophagy regulates intestinal mucosal immunity， inflammation， oxidative stress， and bacterial homeostasis through degradation and reabsorption to actively repair damaged intestinal mucosal barrier， exerting a key role in the occurrence and development of UC. The disease is mainly treated clinically with aminosalicylic acid preparations， glucocorticoids， and immunosuppressants. Western medicine treatment of the disease has a fast onset of effect， and the short-term efficacy is definite， but the long-term application is easy to be accompanied by more adverse reactions. Moreover， some drugs are expensive， bringing great physical and mental pain and economic burden to patients. Therefore， it is urgent to explore new therapies with stable efficacy and mild adverse effects. In recent years， a large number of studies have shown that Chinese medicine can regulate autophagy of the intestinal mucosa with multiple targets and effects and repair the intestinal mucosal barrier function， thereby inhibiting the development of UC. Many experiments have shown that the active ingredient or monomers and compound formulas of Chinese medicine can improve the immunity of the intestinal mucosa， inflammation， oxidative stress， and flora by regulating the level of autophagy to maintain the normal function of the intestinal mucosal barrier to effectively intervene in UC， providing a new measure for the prevention and treatment of UC. However， there is a lack of systematic review of Chinese medicine in regulating the level of autophagy in the intestinal mucosa for the prevention and treatment of UC. Therefore， based on the current research on UC， autophagy process， and Chinese medicine treatment， this article reviewed the relationship of autophagy and its key target proteins with UC to clarify the key role of autophagy in UC production and systematically summarized Chinese medicines targeting the regulation of autophagy to treat UC in recent years to provide new ideas for the treatment and drug development of UC.

Ulcerative colitis （UC） is a chronic， non-specific inflammatory bowel disease. The pathogenesis of this disease is complex and is attributed to multiple factors. Intestinal mucosal barrier damage is the basic pathological change of UC， and intestinal flora disorder is one of the important characteristics of UC. Intestinal flora plays a key role in the pathological process of UC by regulating intestinal mucosal immunity and inflammatory response to repair the damaged intestinal mucosal barrier. At present， western medicine has the advantages of rapid action onset and significant short-term efficacy， but the curative effect of long-term use is not good， accompanied by many adverse reactions， causing great physical and mental pain to patients. Therefore， it is urgent to explore new treatment methods with definite long-term efficacy and mild adverse reactions. A large number of studies have shown that Chinese medicine can regulate intestinal flora through multiple targets in an all-around way， restore the homeostasis of the flora， and repair the damaged intestinal mucosal barrier， thereby inhibiting the progression of UC. Numerous studies have shown that the active components， monomers， and compounds of Chinese medicine can effectively antagonize UC by regulating the intestinal flora to improve the intestinal mucosal immunity， reduce the inflammatory response of the intestinal mucosa， and restore the normal physiological function of the intestinal mucosal barrier， providing a new strategy for UC prevention and treatment. Although there are some studies of the regulation of intestinal flora by Chinese medicine to prevent and treat UC， those studies have the shortcomings of systematic and comprehensive inadequacy. Therefore， based on the research status of UC， intestinal flora， and Chinese medicine treatment， this study reviewed the relationship between intestinal flora and UC and clarified the key role of intestinal flora in the occurrence and development of UC. At the same time， this paper comprehensively summarized the Chinese medicine that targeted the regulation of intestinal flora for the treatment of UC in the past five years to provide new strategies and ideas for UC treatment.

Objective:To evaluate the clinical efficacy and safety of hematoporphyrin monomethyl ether (HMME) -mediated photodynamic therapy (PDT) in the treatment of facial port-wine stains (PWS) in children with Sturge-Weber syndrome (SWS) .Methods:A retrospective analysis was conducted based on the clinical data from SWS children treated with HMME-PDT at the Department of Dermatology, Children's Hospital, Capital Institute of Pediatrics from December 2020 to January 2022. HMME was intravenously injected at a dose of 5 mg/kg, followed by the irradiation of SWS lesions with a 532-nm light-emitting diode light source, and the treatment interval was 8 weeks. The efficacy of HMME-PDT for SWS was evaluated based on the subsidence of erythema and changes in the number and density of blood vessels under a dermoscope before and after treatment; adverse events after treatment were recorded. Fisher's exact test was used to analyze differences in efficacy.Results:A total of 15 children with SWS were included, comprising 7 males and 8 females, with an average age of 4.74 years (range, 1 - 14 years). There were 10 cases of clinical phenotype Ⅰ and 5 cases of type Ⅱ; 10 patients were accompanied by glaucoma, 6 by epilepsy, and 10 showed abnormalities on craniocerebral imaging. After HMME-PDT treatment, 4 out of 15 patients achieved complete remission of SWS lesions, 3 showed marked improvement, and 5 achieved improvement. Among 8 cases receiving 2 sessions of treatment, 1 achieved marked improvement and 4 showed improvement; among 7 cases receiving 3 or more sessions of treatment, 4 achieved complete remission, 2 achieved marked improvement, and 1 showed improvement; the proportions of patients achieving complete remission and marked improvement were significantly higher among those receiving 3 or more sessions of treatment than those receiving 2 sessions (both P < 0.05). Among 7 patients with pink-type PWS, 1 recovered completely, 2 achieved marked improvement, and 4 showed improvement; among 4 patients with purplish-red-type PWS, 3 recovered completely and 1 showed marked improvement; among 4 patients with thickened-type PWS, 1 achieved improvement; there was a significant difference in the proportions of patients achieving marked improvement or improvement among the patients with different types of PWS (both P < 0.05). Among 14 patients with lesions involving the central face region, 4 achieved marked improvement and 2 showed improvement; among 15 with lesions involving the lateral face region, 5 recovered completely, 3 achieved marked improvement, and 4 showed improvement; the recovery rate of lesions was higher in the lateral face region than in the central face region ( P < 0.05). Under a dermoscope, the skin lesions showed 4 vascular patterns: short rod-shaped vessels in 3 cases, linear vessels in 4, reticular vessels in 5, and mixed-type vessels in 3. The 3 patients with short rod-shaped vessels all recovered completely; among the 4 patients with linear vessels, 2 achieved marked improvement, and 2 showed improvement; among the 5 patients with reticular vessels, 1 recovered completely, 1 achieved marked improvement, and 3 showed improvement; the 3 patients with mixed-type vessels all showed poor response to the treatment; the proportions of patients who recovered completely and those who achieved improvement significantly differed among the patients with 4 different vascular patterns (both P < 0.05). All the children experienced varying degrees of pain, swelling, purpura, and crusting after treatment, but none exhibited exacerbation of ocular or neurological complications. Conclusion:HMME-PDT was safe and effective in the treatment of PWS in children with SWS, and its efficacy was related to the number of treatment sessions, lesion types and locations.

Objective:To learn about the single nucleotide polymorphism (SNP) population structure and regional distribution characteristics of Yersinia pestis in the natural focus of plague in Qinghai-Tibet Plateau. Methods:A total of 319 representative strains of Yersinia pestis isolated from natural focus of plague in Qinghai-Tibet Plateau from 1954 to 2020 were selected, and 2 298 SNP loci included in the global Yersinia pestis phylogenetic tree were compared by whole genome sequencing technology. MEGA 6.0 software was used to construct phylogenetic trees of 319 strains of Yersinia pestis from Qinghai-Tibet Plateau, determine the SNP population structure of Yersinia pestis in the focus, and describe its regional distribution characteristics. Results:The 319 strains of Yersinia pestis isolated from Qinghai-Tibet Plateau natural plague foci were distributed in 5 clades, namely 1.IN, 2.ANT, 3.ANT, 0.PE and 2.MED. The 1.IN clade contained 209 strains (65.52%, 209/319), which was the dominant population of strains in Qinghai Province, accounting for 90.51% (143/158). The 2.ANT clade contained 83 strains (26.02%, 83/319), which was the dominant population in Tibet Autonomous Region, accounting for 67.24% (78/116). The 3.ANT, 0.PE, and 2.MED clades contained 12 (3.76%, 12/319), 9 (2.82%, 9/319) and 6 strains (1.88%, 6/319), respectively, which were scattered in Qinghai Province, Gansu Province, Sichuan Province, Tibet Autonomous Region, and Xinjiang Uygur Autonomous Region under the jurisdiction of Qinghai-Tibet Plateau. Conclusion:The SNP population structure of Yersinia pestis in natural focus of plague in Qinghai-Tibet Plateau is relatively rich, and the strains are distributed in 5 clades: 1.IN, 2.ANT, 3.ANT, 0.PE and 2.MED, showing the distribution characteristics of specific regions.

Abstract: Objective To understand the phenotypic and genetic characteristics of Yersinia pestis strains isolated from Himalayan marmot natural focus area and domestic rat plague focus area in southern China, and provide reference for mastering the pathogenic characteristics of Yersinia pestis of two plague foci. Methods A total of 412 of Yersinia pestis strains isolated from Himalayan marmot plague focus and domestic rat plague focus of southern China were subjected to to sorbitol fermentation assays, virulence factor, different region (DFR) typing, and clustered regularly interspaced palindromic repeats (CRISPR) typing. Results The biochemical types of Y. pestis from the two plague foci showed distinct regional distribution features. Five biochemical phenotypes were identified in Yersinia pestis isolated from Himalayan marmot natural focus area, while only one biochemical phenotype was identified in strains isolated from the domestic rat plague focus of Southern China. Most of the Yersinia pestis isolated from the two plague foci were capable of producing the virulence factors of Fl and PstI. Among the strains from Himalayan marmot focus, 70.53% (201/285) were VW-positive, 75.09% (214/285) were Pgm-positive, 20.00% (57/285) of the strains were Pgm-negative, and 5.26% (15/285) were Pgm mixed-type strains. Among strains from domestic rat plague focus of southern China, 37.80% (48/127) were VW-positive, 29.13% (37/127) were Pgm-positive, 58.27% (74/127) were Pgm-negative, and 12.60% (16/127) were Pgm mixed-type strains. DFR typing revealed 22 genotypes of Y. pestis from the Himalayan marmot plague focus, with the main genotypes being type 5, 7, 8, 10, 19, 32 and 49. All strains from domestic rat plague focus area in southern China belonged to type 9. CRISPR typing revealed that all strains from the Himalayan marmot natural focus were classified into 7 CRISPR gene clusters and 14 CRISPR genotypes, with the main genotypes being G7, G22, G26-a1'and G22-A1'. All strains from domestic rat plague focus area in southern China belonged to CRISPR genotype G30, with the gene cluster being Ca8. Conclusions The phenotypes and genotypes of the Yersinia pestis of Himalayan marmot plague focus are diverse, with an obvious characteristics of geographical distribution. The phenotype and genotype of the Yersinia pestis of domestic rat plague focus of Southern China are single. DFR and CRISPR genotyping methods with phenotypic characteristics can effectively identify the Yersinia pestis isolated from the two plague foci, thereby meeting the needs of identification and traceability research.

Objective:To analyze skin manifestations associated with coronavirus disease 19 (COVID-19) in children.Methods:Children diagnosed with COVID-19 accompanied by skin manifestations were retrospectively collected from outpatient clinics or teleclinics at the Department of Dermatology, Children′s Hospital, Capital Institute of Pediatrics from November 1st, 2022 to December 10th, 2022, and their clinical characteristics were analyzed. Analysis of variance was used for comparing measurement data, and Fisher′s exact test for comparing enumeration data.Results:A total of 61 children with COVID-19 accompanied by skin lesions were included, they were aged from 22 days to 17 years (2.83 ± 2.47 years, and their course of disease ranged from 2 to 14 days. Skin lesions manifested as acute urticaria in 25 cases (41.0%), eruptive/maculopapular lesions in 10 cases (16.4%), facial vascular edema in 6 cases (9.8%), urticarial vasculitis in 5 cases (8.2%), pityriasis rosea and erythema multiforme each in 4 cases (6.6%), purpura in 2 cases (3.3%), mixed skin lesions in 2 cases (3.3%), and folliculitis, erythema nodosum, as well as angioedema of the limbs each in 1 case (1.6%). The age of children with different skin manifestations significantly differed ( F = 4.67, P < 0.001). Forty-eight patients (78.69%) presented with generalized skin lesions, while 13 (21.31%) with localized skin lesions; 10 (16.4%) had itching, 3 (4.9%) had a burning sensation, while 48 (78.7%) showed no symptoms. Skin lesions persisted for ≤ 3 days in 36 cases (59.0%) and for > 3 days in 25 cases (41.0%), and all lesions persisted for less than 2 weeks. All 61 patients had fever up to 38.5 ℃; 1 (1.6%) developed skin lesions before the fever, 41 (67.2%) developed lesions during the fever, and 19 (31.2%) developed lesions after the fever. The skin manifestations significantly differed among various groups divided by patients with different lesion distribution, self-reported symptoms, duration of lesions, and sequence between fever and lesion onset (all P < 0.05). No recurrence was observed after recovery, and skin lesions subsided without pigment changes or scaring. Conclusion:COVID-19 was often accompanied by various skin lesions in children, which mainly manifested as urticaria and eruptive/maculopapular lesions.

OBJECTIVE: To explore the genetic basis for a patient with Dilated cardiomyopathy. METHODS: A patient admitted to Beijing Anzhen Hospital Affiliated to Capital Medical University in April 2022 was selected as the study subject. Clinical data and family history of the patient was collected. Targeted exome sequencing was carried out. Candidate variant was verified by Sanger sequencing and bioinformatic analysis based on guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS: DNA sequencing revealed that the patient has harbored a heterozygous c.5044dupG frameshift variant of the FLNC gene. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PVS1+PM2_Supporting+PP4). CONCLUSION The heterozygous c.5044dupG variant of the FLNC gene probably underlay the pathogenesis in this patient, which has provided a basis for the genetic counseling for his family.
Humans ; Cardiomyopathy, Dilated/genetics* ; Genetic Testing ; Genetic Counseling ; Computational Biology ; Frameshift Mutation ; Mutation ; Filamins

Objective:To investigate the clinical features and risk factors of infection in patients with heat stroke (HS).Methods:The patients with HS who were admitted to the emergency departments of seven hospitals, including West China Hospital of Sichuan University, the Second Affiliated Hospital of Chengdu Medical College and so on, between July 01, 2020 and September 30, 2022 were retrospectively analyzed. The basic characteristics and laboratory test results of the patients were collected. The patients were divided into infected group and non-infected group according to the etiological results, and the differences in clinical characteristics between the different groups were compared. Multivariate logistic regression was used to screen variables, and the predictive model was established and ROC curve was performed to compare the predictive efficiency with SOFA score.Results:During the study period, a total of 183 patients with HS were included, and 156 patients were finally included for analysis according to the inclusion and exclusion criteria. Among them, 58 cases (37.2%) were in the infected group. The mortality of infected group was significantly higher than that of non-infected group (41.4% vs. 25.5%, P < 0.05). Compared with the patients in non-infected group, the infected gourp serum procalcitonin, direct bilirubin, alanine transaminase (ALT), creatinine, lactate dehydrogenase (LDH), creatine kinase isoenzymes, myoglobin, activated partial thromboplastin time (APTT) and respiratory support ratio at admission were significantly higher and albumin level was lower in infected group (all P < 0.05). Multivariate logistic regression analysis showed that myoglobin, ALT, APTT and respiratory support required at admission were independent risk factors for HS co-infection. A prediction model was constructed based on these four indicators, and the area under ROC curve of the prediction model was 0.846, which was better than SOFA score (0.732, P < 0.05). Conclusions:The prognosis of patients with heat stroke complicated with infection were obviously poor. Myoglobin, ALT, APTT and need for respiratory support at admission are risk factors for HS complicated with infection. The prediction model based on these four indicators is better than SOFA score for the early identification of the HS patients with infection.