TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection.

We investigated the role of telomerase and telomere repeat-binding factor 2 (TRF2 or TERF2) in T-cell dysfunction in chronic viral infection. We found that the expression and activity of telomerase in CD4+ T (CD4T) cells from patients with hepatitis C virus (HCV) infections or people living with HIV (PLWH) were intact, but TRF2 expression was significantly inhibited at the post-transcriptional level, suggesting that TRF2 inhibition is responsible for the CD4T cell dysfunction observed during chronic viral infection. Silencing TRF2 expression in CD4T cells derived from healthy subjects induced telomeric DNA damage and CD4T cell dysfunction without affecting telomerase activity or translocation - similar to what we observed in CD4T cells from HCV patients and PLWH. These findings indicate that premature T-cell aging and dysfunction during chronic HCV or HIV infection are primarily caused by chronic immune stimulation and T-cell overactivation and/or proliferation that induce telomeric DNA damage due to TRF2 inhibition, rather than telomerase disruption. This study suggests that restoring TRF2 presents a novel approach to prevent telomeric DNA damage and premature T-cell aging, thus rejuvenating T-cell functions during chronic viral infection.

Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside.

Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + insulin ("high glycolysis group"). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.

Effect of SIRT1 gene single-nucleotide polymorphisms on susceptibility to type 1 diabetes in a Han Chinese population.

AIMS: SIRT1 deficiency has been associated with diabetes, and a variant of the SIRT1 gene has been found to be involved in human autoimmune diabetes; however, it is unclear whether this genetic variation exists in Han Chinese with type 1 diabetes (T1D) and whether it contributes to development of T1D. Therefore, we aimed to explore the association of the SIRT1 gene single-nucleotide polymorphisms (SNPs) rs10997866 and rs3818292 in a Han Chinese population with T1D. METHODS: This study recruited 2653 unrelated Han Chinese individuals, of whom 1289 had T1D and 1364 were healthy controls. Allelic and genotypic distributions of SIRT1 polymorphisms (rs10997866 and rs3818292) were determined by MassARRAY. Basic characteristics, genotype and allele frequencies of selected SNPs were compared between the T1D patients and healthy controls. Further genotype-phenotype association analysis of the SNPs was performed on the T1D patients divided into three groups according to genotype. Statistical analyses included the chi-square test, Mann‒Whitney U test, Kruskal‒Wallis H test and logistic regression. RESULTS: The allelic (G vs. A) and genotypic (GA vs. AA) distributions of SIRT1 rs10997866 were significantly different in T1D patients and healthy controls (P = 0.039, P = 0.027), and rs10997866 was associated with T1D susceptibility under dominant, overdominant and additive models (P = 0.026, P = 0.030 and P = 0.027, respectively). Moreover, genotype-phenotype association analysis showed the GG genotype of rs10997866 and the GG genotype of rs3818292 to be associated with higher titers of IA-2A (P = 0.013 and P = 0.038, respectively). CONCLUSION: SIRT1 rs10997866 is significantly associated with T1D susceptibility, with the minor allele G conferring a higher risk of T1D. Moreover, SIRT1 gene rs10997866 and rs3818292 correlate with the titer of IA-2A in Han Chinese individuals with T1D.

Identification of potential candidate genes for the Huoyan trait in developing Wulong goose embryos by transcriptomic analysis.

1. The Wulong goose is a Chinese breed and a source of high-quality meat and eggs. A characteristic of the Wulong goose is that a proportion of the birds do not have eyelids, known as the Huoyon trait.2. Wulong geese exhibiting the Huoyan trait at embryonic stages of 9 days (E9), 12 days (E12) and 14 days (E14) were selected alongside those with normal eyelids for comprehensive transcriptome sequencing. Differentially expressed gene (DEG) and functional enrichment analyses were performed and finally, eight DEG were chosen to verify the accuracy of qPCR sequencing.3. Overall, 466, 962 and 550 DEG were obtained from the three control groups, D9 vs. N9, D12 vs. N12 and D14 vs. N14, respectively, by differential analysis (p < 0.05). CDKN1C, CRH, CROCC and TYSND1 were significantly expressed in the three groups. Enrichment analysis revealed the enrichment of CROCC and TYSND1 in pathways of cell cycle process, endocytosis, microtubule-based process, microtubule organising centre organisation, protein processing and protein maturation. CDKN1C and CRH were enriched in the cell cycle and cAMP signalling pathway.4. Some collagen family genes were detected among the DEGs, including COL3A1, COL4A5, COL4A2 and COL4A1. FREM1 and FREM2 genes were detected in both Huoyan and normal eyelids. There was a significant difference (p < 0.01) in FREM1 expression between ED9 and ED14 in female embryos, but this difference was not observed in male embryos.

[Statistical analysis of disability-adjusted life years for stomach and colorectal cancers in Changning District of Shanghai].

Objectives: To analyze the status and temporal changes of disability-adjusted life year (DALY) for stomach and colorectal cancers among registered permanent residents in Changning District of Shanghai Municipality, and provide scientific basis for the prevention and treatment of stomach and colorectal cancers in this district. Methods: Using the cancer registration data of stomach and colorectal cancers from 2002 to 2019, we estimated the indices such as the DALYs, the DALY crude rates, the age-standardized DALY rates, etc. Then we used the Joinpoint regression model to calculate the average annual percent change (AAPC) and annual percent change (APC) to explore the temporal variations in different periods. Results: The DALYs of stomach and colorectal cancers in Changning District from 2002 to 2019 were 55 931 person years and 65 252 person years, respectively. The crude rates of DALY were 512.16/105 and 597.51/105, respectively. We observed a higher disease burden in men than in women, and the peak rate of DALY in stomach cancer was in the 75-79 years age group, while in colorectal cancer the rate was in the 85-years-or-older age group. Joinpoint regression analysis showed that from 2002 to 2019, the age-standardized DALY rate of stomach cancer showed a downward trend (AAPC=-3.86%, P＜0.05), while the trend of colorectal cancer was not statistically significant(AAPC=-0.08%, P＞0.05). However, the trends in the age-standardized DALY rates of colorectal cancer were different between males and females, with males showing an upward trend (AAPC=1.24%, P＜0.05) and females showing a downward trend (AAPC=-1.67%, P＜0.05). Conclusions: The DALY of stomach and colorectal cancers in Changning District of Shanghai showed a decreasing trend. Males and the middle-aged and elderly populations are still the key targets for disease prevention and control in this district.

Effects of Three Different Heating Devices on Patients Undergoing Surgery: A Network Meta-Analysis.

PURPOSE: Perioperative hypothermia is a common anesthesia-related complication that can result in negative outcomes. Intraoperative active heating can positively impact these outcomes. Therefore this study aimed to investigate the effectiveness of three common heating devices for controlling hypothermia, improving thermal comfort, and reducing anesthesia recovery time. DESIGN: Systematic review and meta-analysis. METHODS: Seven electronic literature databases were searched from the inception date of the databases to March 18, 2022. RevMan 5.4 and Stata 15.1 were used to perform meta-analyses on the obtained data, and the Cochrane Evaluation Manual was used for quality risk assessment of the included studies. FINDINGS: A total of 18 studies involving 1,511 patients undergoing surgery using heating devices were included. In this meta-analysis, a ranking method known as the Surface Under the Cumulative Ranking Curve (SUCRA) was used. SUCRA provides a numerical measure of the effectiveness of treatments, with higher values indicating superior efficacy. Findings demonstrated that the concurrent use of three heating devices led to an elevation in core body temperatures (SUCRA = 69.2%) and enhanced delayed recovery (SUCRA = 88.6%) as compared to the application of a single device. Furthermore, for thermal comfort, the employment of heating blankets proved to be the most effective (SUCRA = 87.8%). CONCLUSIONS: This study showed the core body temperatures and reductions in delayed recovery were greater when three heating devices were used together as compared to use one of them alone. Heating blankets was the most effective option for improving the thermal comfort of patients. Thus, clinicians should opt for appropriate heating equipment according to the type of surgery and the characteristics and needs of patients. The choice of appropriate heating equipment will ensure surgical safety, improve patient comfort, and reduce surgical risks.

[Analysis of the effect and safety of lumen reshaping after endovascular repair of Stanford B type aortic dissection at different intervention times].

Objective: To Compare the effects and safety of lumen reshaping after thoracic endovascular aortic repair (TEVAR) for Stanford B type aortic dissection (AD) at different intervention times. Methods: A retrospective analysis was conducted on the clinical data of 189 patients with Stanford type B aortic dissection treated with TEVAR at the Affiliated Hospital of Chengde Medical College from January 2016 to December 2020.Based on the time from onset to surgery, patients were divided into an early intervention group (≤14 days, n=127) and a delayed intervention group (>14 days, n=62).The diameters of the total aorta, true lumen and false lumen at different times and planes (S1 plane: at the bifurcation of the pulmonary artery; S2 plane: at the lower edge of the left atrium; S3 plane: at the upper edge of the celiac trunk) post-surgery were compared between the two groups, and the rate of change in diameters of true and false lumens across these planes was calculated. The patients were followed until December 1st, 2023, and the median follow-up time was 45(40, 49) months. The postoperative complications and survival of the two groups were compared. Results: The early intervention group comprised 86 men and 41 women, with an average age of (58.3±10.7) years. The delayed intervention group included 41 men and 21 women, with an average age of (58.5±9.2) years. Both groups had an operation success rate of 100%. Six months post-surgery, the early intervention group had an expansion rate of the true lumen diameter at planes S2 and S3 of 40.1%(25.5%, 56.1%) and 5.3%(-2.5%, 15.8%), respectively, which was superior to the delayed intervention group's 18.5%(10.6%, 39.8%) and 1.0%(-8.2%, 9.6%) (both P<0.05).The early intervention group had a reduction rate of the false lumen diameter at planes S1, S2, and S3 of -56.2%(-61.3%, -48.8%), -70.4%(-81.8%, -56.6%), and -5.4%(-17.4%, 0.1%), respectively, better than the delayed intervention group's -44.2%(-53.7%, -38.3%), -49.0%(-57.6%, -35.8%), and -3.1%(-6.7%, 1.8%) (all P<0.05).At plane S1, the true lumen diameter of patients in both groups showed an increasing trend over 36 months post-surgery, while the false lumen diameter showed a decreasing trend (both P<0.05).At plane S2, the true lumen diameter of patients in the early intervention group exhibited an increasing trend over 36 months post-surgery, and the false lumen diameter exhibited a decreasing trend (both P<0.05).At plane S3, the total aortic diameter of patients in the delayed intervention group showed a slight increasing trend over 36 months post-surgery (P<0.05).The overall survival time were 45.0 months (95%CI: 42.9-47.1) for patients in the early intervention group and 46.0 months (95%CI: 43.5-48.5) for those in the delayed intervention group, with no statistically significant difference observed (P>0.05).The incidence rates of complications such as aortic rupture, retrograde Type A dissection, new distal endograft dissection, endoleak, paraplegia, and others showed no statistically significant difference between the two groups (all P>0.05), with no cases of stent migration or deformation observed. Conclusion: Early intervention for Stanford type B aortic dissection provides a better aortic remodeling outcome than delayed intervention, with similar safety.

[Value of peripheral blood rare cell EGFR gene amplification detection in the evaluation of benign and malignant pulmonary nodules].

Objective: To explore the value of detection of epidermal growth factor receptor (EGFR) gene amplification in peripheral blood rare cells in the assessment of benign and malignant pulmonary nodules. Methods: A total of 262 patients with pulmonary nodules were selected as the retrospectively study subjects from the Second Affiliated Hospital of Army Military Medical University and Peking Union Medical College Hospital from July 2022 to August 2023. There were 98 males and 164 females, with the age range from 16 to 79 (52.1±12.1) years. The EGFR gene amplification testing was performed on the rare cells enriched from patients' peripheral blood, and the clinical manifestations, CT imaging features, histopathological and/or pathological cytological confirmed results of patients were collected. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of the method of detection of EGFR gene amplification in peripheral blood rare cells, and its diagnostic efficacy was evaluated. Results: Among the 262 patients, 143 were malignant pulmonary nodules and 119 were benign pulmonary nodules. The differences between malignant pulmonary nodules and benign pulmonary nodules in nodule diameter and nodule density were statistically significant (both P<0.001), while the differences in age, gender and nodule number were not statistically significant (all P>0.05). The number [M (Q1, Q3)] of EGFR gene amplification positive rare cells in patients with malignant pulmonary nodule was 8 (6, 11), which was higher than that in patients with benign pulmonary nodule [2 (1, 4), P<0.001]. The ROC curve results showed that when the optimal cut-off value was 5 (that was, the number of EGFR gene amplification positive rare cells was>5), the area under the curve (AUC) of the detection of EGFR gene amplification in peripheral blood rare cells for discrimination of benign and malignant pulmonary lesions was 0.816 (95%CI: 0.761-0.870), with a sensitivity of 83.2%, a specificity of 80.7%, and an accuracy of 82.1%. Based on the analysis of the diameter of the nodules, the AUC for distinguishing between benign and malignant pulmonary nodules with diameter 5-9 mm and 10-30 mm was 0.797 (95%CI: 0.707-0.887) and 0.809 (95%CI: 0.669-0.949), respectively, with sensitivity, specificity and accuracy reached 75% or above. Based on the analysis of nodule density, the AUC for distinguishing between benign and malignant solid nodule and subsolid nodule was 0.845 (95%CI: 0.751-0.939) and 0.790 (95%CI: 0.701-0.880), respectively, with sensitivity, specificity and accuracy reached 75% or above. Based on the analysis of nodule number, the AUC for distinguishing between benign and malignant solitary pulmonary nodule and multiple pulmonary nodule was 0.830 (95%CI: 0.696-0.965) and 0.817 (95%CI: 0.758-0.877), respectively, with sensitivity, specificity and accuracy reached 80% or above. Conclusion: The detection of EGFR gene amplification in peripheral blood rare cells contributes to the evaluation of benign and malignant pulmonary nodules, and can be used in the auxiliary diagnosis of benign and malignant pulmonary nodules.

[Clinical and pathological analysis of 345 cases of vulvar lichen sclerosus and a preliminary study on the frequency of maintenance treatment].

Objective: To analyze and summarize the clinical and pathological characteristics, management, and efficacy of patients with vulvar lichen sclerosus (VLS) through a single center large sample study, and preliminarily to explore the frequency of maintenance treatment medication for VLS. Methods: The clinical data of VLS patients in Obstetrics and Gynecology Hospital of Fudan University from 2018 to 2021 were retrospectively collected. The clinicopathological characteristics (patients' age, course of disease, complicated disease history, family history, symptoms, signs and pathology), treatment and effects were retrospectively analyzed. The patients in the maintenance treatment stage were followed up regularly to explore the minimum frequency of individual medication to maintain the stability of the disease. Results: (1) General situation: a total of 345 patients with VLS were included in this study. The average age was (50.4±14.7) years (ranged from 8 to 84 years old), prevalence was highest in the 50-59 years group (30.1%, 104/345). Immune diseases occurred in 18.6% (33/177) of patients, 24.3% (43/177) of patients had allergic skin diseases, and 5.6% (10/177) of the patients' immediate family members had chronic vulvar pruritus or vulvar hypopigmentation. (2) Clinical features: the most common symptom was vulvar pruritus (96.1%, 196/204) among 204 patients with recorded symptoms. The most common sign was hypopigmentation of the vulva (96.3%, 206/214). The most common involved sites were labia minora (70.3%, 142/202), labia majora (67.8%, 137/202), and labial sulcus (59.4%, 120/202). The cumulative number of sites involved in 62 vulvar atrophy patients (2.7±1.1) was significantly higher than that in 152 non-atrophy patients (2.2±1.0; t=3.48, P=0.001). The course of vulvar atrophy was (9.3±8.5) years, which was significantly longer than that of non-atrophy patients [(6.6±5.6) years; t=2.04, P=0.046]. (3) Pathological features: among the 286 patients with electronic pathological sections, the most common pathological feature in the epidermis was epithelial nail process passivation (71.3%, 204/286). The common pathological features in the dermis were interstitial collagenization (84.6%, 242/286), and inflammatory cell infiltration (73.8%, 211/286). (4) Treatment: 177 patients received standardized treatment after diagnosis and were followed up regularly in our hospital. In the initial treatment stage, 26.0% (46/177) of the patients were treated with 0.05% clobetasol propionate cream, and 74.0% (131/177) of the patients were treated with 0.1% mometasone furoate ointment. The complete remission rates of the two methods were respectively 80.4% (37/46) and 74.0% (97/131), and there was no statistically significant difference (χ²=0.76, P=0.385). During maintenance treatment, 27.1% (48/177) of the patients took the medication twice a week, 35.0% (62/177) took the medication once a week, and 37.9% (67/177) took the medication once every 10 days. During follow-up after 6 months of maintenance treatment, there were no patients with recurrence of pruritus or progression of vulvar signs. Conclusions: The majority of VLS patients have itching, hypopigmentation, involvement of labia minora and labia majora, progressive atrophy, and inflammatory infiltration of dermis. Local treatments of mometasone furoate and clobetasol propionate have good initial therapeutic effects. The frequency exploration of individualized maintenance treatment could minimize the occurrence of adverse reactions when ensuring the stability of the patients' condition.

[Pseudocarcinomatous hyperplasia of the fallopian tube: a clinicopathological analysis of sixteen cases].

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of pseudocarcinomatous hyperplasia of the fallopian tubes. Methods: Sixteen cases of pseudocarcinomatous hyperplasia of the fallopian tubes diagnosed at Obstetrics and Gynecology Hospital of Fudan University from January 2011 to January 2024 were collected.The pathological sections were reviewed, the clinical and pathological data were consulted, and immunohistochemical examination was conducted along with follow-up. Results: The patients were aged from 19 to 57 years, with an average age of 41 and a median age of 38. Among the 16 cases, 4 were located in the right fallopian tubes, 6 in the left fallopian tubes, while the remaining cases presented bilaterally. The general manifestations were tubal edema, crispness and purulent secretion in the lumen. Morphologically, the fallopian tube mucosa exhibited a significant infiltration of neutrophils, lymphocytes and plasma cells. The epithelial cells of the fallopian tube displayed evident proliferation, stratification and disorganized arrangement leading to formation of small glandular cavity with back-to-back, fissure-like and sieve-like structures. Immunohistochemical analysis revealed positivity for CK7 and WT1, along with wild-type p53 expression, Ki-67 index ranged from 5% to 20%. During the follow-up period ranging from 1 to 156 months, all the patients remained free of disease. Conclusions: Pseudocarcinomatous hyperplasia of the fallopian tube is a rare non-neoplastic lesion, which can lead to epithelial hyperplasia and atypical hyperplasia. The most important significance of recognizing this lesion lies in avoiding misdiagnosis of fallopian tube cancer during intraoperative and postoperative pathological examination. This ensures that clinicians can administer correct clinical interventions.

[Annual review of sleep-disordered breathing in 2023].

Over the past year, significant progress has been made in the field of sleep-disordered breathing, focusing on critical aspects such as the heterogeneity, diagnostic and assessment method, and personalized treatment approaches related to obstructive sleep apnea (OSA). This article summaries of the latest research findings spanning from October 1, 2022, to September 30, 2023. It aims to provide valuable insights into the clinical management of OSA and to outline promising directions for future research.

[Adaptive servo-ventilation in patients with heart failure and sleep apnea: Insights from the ADVENT-HF trial].

Heart failure is strongly associated with obstructive and central sleep apnea. The landmark 2015 SERVE-HF trial showed that using adaptive servo-ventilation (ASV) for central sleep apnea (CSA) management was associated with an increased risk of all-cause and cardiovascular mortality among heart failure patients with reduced ejection fractions. Based on the result, the American Academy of Sleep Medicine and the European Society of Cardiology have recommended against the use of ASV for the treatment of CSA in patients with heart failure with an ejection fraction≤45%. Recently, the results from the ADVENT-HF trial have been formally published, indicating that ASV does not increase adverse outcomes and can improve patients' quality of life. Here, we go over these findings in detail.

[Rigid bronchoscopy combined with flexible bronchoscopy for treatment of central airway stenosis caused by tuberculous tracheobronchial fistula: report of 2 cases].

Tuberculous tracheobronchial fistulas are caused by mediastinal or hilar tuberculous lymph nodes ulcerating into the trachea or bronchus. Patients usually require flexible bronchoscopic interventional procedures in addition to systemic anti-tuberculosis chemotherapy in the ulceration phase. In this paper, we reported 2 cases of central airway stenosis caused by tuberculous tracheobronchial fistula, which had poor treatment results after flexible bronchoscopy. According to the patients' condition, the airway lesions were treated by rigid bronchoscopy combined with flexible bronchoscopy, cryotherapy, argon plasma coagulation, and so on. The central airway stenosis was resolved quickly, and the caseating lymph node tissue was removed as much as possible under the premise of ensuring safety, which shortened the recovery time of tuberculous fistula.

[Impact of COVID-19 on the treatment of sleep medicine].

The outbreak of coronavirus disease 2019 (COVID-19) has become a major threat to the global healthcare system. As an airborne disease, COVID-19 posed a great challenge to the management of sleep medicine. Given the increased risk of adverse events in obstructive sleep apnea patients infected with COVID-19, strategies have been proposed worldwide. These include standard treatment procedure, use of self-protect equipment, telemedicine services, development of machine learning and portable monitoring, and in-home sleep monitoring and titration. This review aims to introduce the impact of COVID-19 on the operation of sleep medicine landscape and provide advice on public health care emergency.

[Effect of glucocorticoids on the efficacy of non-small cell lung cancer patients treated with immune-checkpoint inhibitors].

Lung cancer is a highly lethal malignant tumor worldwide and in China, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases globally. In recent years, immune checkpoint inhibitor (ICI) had changed the paradigm of lung cancer treatment, either alone or in combination with chemotherapy and recomended as the first-line treatment for NSCLC. NSCLC patients often required glucocorticoid(GC) due to the cancer itself, tumor complications, or immune-related adverse event (irAE). GC had sparked debates on their impact on the therapeutic effectiveness of ICI in NSCLC patients as a substance with immunomodulatory effects. While some studies suggested that GC use did not influence patients survival, others argued the opposite. Understanding the effects of GC on immunotherapy is crucial for managing complaications in cancer patients and addressing irAE. This review explores the impact of GC on the efficacy of ICI in NSCLC patients, aiming to provide insights for clinical treatment.

[New insights into the role of macrophages in tumor immunotherapy].

Macrophages are the main components of the innate immunity system, derived mainly from blood monocytes, and help the host to defend itself against many pathogens and cancers. Most established tumors can educate macrophages into tumor-associated macrophages (TAMs), which contribute to tumor growth, invasion and metastasis, as well as resistance to chemotherapeutic agents and immune checkpoint inhibitors. However, when appropriately activated, macrophages can also exert anti-tumor effects through enhanced phagocytosis and cytotoxicity against tumor cells. In addition, TAMs are associated with poor prognosis and drug resistance, including immunotherapies, suggesting that macrophages are attractive targets as part of combination therapy in cancer treatment. Herein, we review the recent findings on the role of macrophages in tumor development, metastasis and immunotherapy. We focus mainly on macrophage-centered therapy, including strategies to reduce and reshape TAMs, to represent potential targets for tumor immunotherapy.

[Application of interventional respiratory techniques in the treatment of pulmonary bullae:an update].

Pulmonary bullae is a common complication of chronic obstructive pulmonary disease(COPD), causing the deterioration in lung function, leading to aggravated dyspnea and poor quality of life for patients. The traditional therapeutic approach for pulmonary bullae is bullectomy using surgical thoracoscopy. The disadvantage of this approach is the postoperative complications and high risk of recurrence in many patients. In addition, for some patients, due to the patient's physical conditions, such as poor lung function and other diseases, bullectomy could not be used. Therefore, new alternative approaches were urgently needed. In recent years, interventional respiratory technology has been trialed to treat pulmonary bulla all around the world and has achieved great success. In this paper, we reviewed the relevant clinical research progress of interventional respiratory medicine techniques in the treatment of pulmonary bullae.

Synthetic gRNA/Cas9 ribonucleoprotein targeting HBV DNA inhibits viral replication.

The presence of hepatitis B virus (HBV) covalently closed circular (ccc) DNA (cccDNA), which serves as a template for viral replication and integration of HBV DNA into the host cell genome, sustains liver pathogenesis and constitutes an intractable barrier to the eradication of chronic HBV infection. The current antiviral therapy for HBV infection, using nucleos(t)ide analogues (NAs), can suppress HBV replication but cannot eliminate integrated HBV DNA and episomal cccDNA. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 is a powerful genetic tool that can edit integrated HBV DNA and minichromosomal cccDNA for gene therapy, but its expression and delivery require a viral vector, which poses safety concerns for therapeutic applications in humans. In the present study, we used synthetic guide RNA (gRNA)/Cas9-ribonucleoprotein (RNP) as a nonviral formulation to develop a novel CRISPR/Cas9-mediated gene therapy for eradicating HBV infection. We designed a series of gRNAs targeting multiple specific HBV genes and tested their antiviral efficacy and cytotoxicity in different HBV cellular models. Transfection of stably HBV-infected human hepatoma cell line HepG2.2.15 with HBV-specific gRNA/Cas9 RNPs resulted in a substantial reduction in HBV transcripts. Specifically, gRNA5 and/or gRNA9 RNPs significantly reduced HBV cccDNA, total HBV DNA, pregenomic RNA, and HBV antigen (HBsAg, HBeAg) levels. T7 endonuclease 1 (T7E1) cleavage assay and DNA sequencing confirmed specific HBV gene cleavage and mutations at or around the gRNA target sites. Notably, this gene-editing system did not alter cellular viability or proliferation in the treated cells. Because of their rapid DNA cleavage capability, low off-target effects, low risk of insertional mutagenesis, and readiness for use in clinical application, these results suggest that synthetic gRNA/Cas9 RNP-based gene-editing can be utilized as a promising therapeutic drug for eradicating chronic HBV infection.

Dysregulated energy metabolism impairs chondrocyte function in osteoarthritis.

OBJECTIVES: Metabolic pathways are a series of chemical reactions by which cells take in nutrient substrates for energy and building blocks needed to maintain critical cellular processes. Details of chondrocyte metabolism and how it rewires during the progression of osteoarthritis (OA) are unknown. This research aims to identify what changes in the energy metabolic state occur in OA cartilage. METHODS: Patient matched OA and non-OA cartilage specimens were harvested from total knee replacement patients. Cartilage was first collected for metabolomics, proteomics, and transcriptomics analyses to study global alterations in OA metabolism. We then determined the metabolic routes by tracking [U-13C] isotope with liquid chromatography-mass spectrometry (LC-MS). We further evaluated cellular bioenergetic profiles by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and investigated the effects of low-dose and short-term effects of 2-deoxyglucose (2DG) on chondrocytes. RESULTS: OA chondrocytes showed increased basal ECAR and more lactate production compared to non-OA chondrocytes. [U-13C] glucose labelling revealed that less glucose-derived carbon entered the tricarboxylic acid (TCA) cycle. On the other hand, mitochondrial respiratory rates were markedly decreased in the OA chondrocytes compared to non-OA chondrocytes. These changes were accompanied by decreased cellular ATP production, mitochondrial membrane potential and disrupted mitochondrial morphology. We further demonstrated in vitro that short-term inhibition of glycolysis suppressed matrix degeneration gene expression in chondrocytes and bovine cartilage explants cultured under inflammatory conditions. CONCLUSION: This study represents the first comprehensive comparative analysis of metabolism in OA chondrocytes and lays the groundwork for therapeutic targeting of metabolism in OA.

Long Noncoding RNA RUNXOR Promotes Myeloid-Derived Suppressor Cell Expansion and Functions via Enhancing Immunosuppressive Molecule Expressions during Latent HIV Infection.

RUNX1 overlapping RNA (RUNXOR) is a long noncoding RNA and a key regulator of myeloid-derived suppressor cells (MDSCs) via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported MDSC expansion and inhibition of host immune responses during viral infections; however, the mechanisms regulating MDSC differentiation and suppressive functions, especially the role of RUNXOR-RUNX1 in the regulation of MDSCs in people living with HIV (PLHIV), remain unknown. In this study, we demonstrate that RUNXOR and RUNX1 expressions are upregulated in MDSCs that expand and accumulate in human PBMCs derived from PLHIV. We found that the upregulation of RUNXOR and RUNX1 is associated with the expressions of several key immunosuppressive molecules, including arginase 1, inducible NO synthase, STAT3, IL-6, and reactive oxygen species. RUNXOR and RUNX1 could positively regulate each other's expression and control the expressions of these suppressive mediators. Specifically, silencing RUNXOR or RUNX1 expression in MDSCs from PLHIV attenuated MDSC expansion and immunosuppressive mediator expressions, whereas overexpressing RUNXOR in CD33+ myeloid precursors from healthy subjects promoted their differentiation into MDSCs and enhanced the expression of these mediators. Moreover, loss of RUNXOR-RUNX1 function in MDSCs improved IFN-γ production from cocultured autologous CD4 T cells derived from PLHIV. These results suggest that the RUNXOR-RUNX1 axis promotes the differentiation and suppressive functions of MDSCs via regulating multiple immunosuppressive signaling molecules and may represent a potential target for immunotherapy in conjunction with antiviral therapy in PLHIV.