[The value of minimal residual disease and IKZF1 deletion for predicting prognosis in adult patients with B-cell acute lymphoblastic leukemia].

Objective: To reassess the prognostic value of minimal residual disease (MRD) and IKZF1 gene deletions in adults with B-cell acute lymphoblastic leukemia (B-ALL) who received pediatric-specific chemotherapy regimens during the Nanfang Hospital PDT-ALL-2016 trial. Methods: We retrospectively analyzed the prognosis of 149 adult patients with B-ALL who were admitted to Nanfang Hospital from January 2016 to September 2020. Prognostic factors were identified using Cox regression models. Results: The complete remission rate was 93.2% in 149 patients, with a 5-year overall survival (OS) rate of (54.3±5.0) % and a cumulative incidence of relapse (CIR) of (47.5±5.2) %. The Cox regression analysis revealed that MRD positivity at day 45 (MRD(3)) after induction therapy was independently associated with relapse risk (HR=2.535, 95%CI 1.122-5.728, P=0.025). Deletion of IKZF1 gene was independently associated with mortality risk (HR=1.869, 95%CI 1.034-3.379, P=0.039). Based on MRD(3) and IKZF1 gene status, we categorized adult patients with B-ALL into the low-risk (MRD(3)-negative and IKZF1 gene deletion-negative) and high-risk (MRD(3)-positive and/or IKZF1 gene wild type) groups. The 5-year OS and CIR rates were (45.5±6.0) % vs (69.4±8.6) % (P<0.001) and (61.6±8.3) % vs (25.5±6.5) % (P<0.001), respectively, in the high-risk and low-risk groups, respectively. The multivariate analysis showed that the high-risk group was an independent risk factor for OS (HR=3.937, 95%CI 1.975-7.850, P<0.001) and CIR (HR=4.037, 95%CI 2.095-7.778, P<0.001) . Conclusion: The combined use of MRD and IKZF1 gene in prognostic stratification can improve clinical outcome prediction in adult patients with B-ALL, helping to guide their treatment.

Liquid nitrogen improves the decellularization effectiveness of whole-ovary.

BACKGROUND: Ovarian tissue cryopreservation for fertility preservation carries a risk of malignant cell re-seeding. Artificial ovary is a promising method to solve such a problem. However, ovary decellularization protocols are limited. Hence, further studies are necessary to get better ovarian decellularization techniques for the construction of artificial ovary scaffolds. OBJECTIVE: To establish an innovative decellularization technique for whole porcine ovaries by integrating liquid nitrogen with chemical agents to reduce the contact time between the scaffolds and chemical reagents. MATERIALS AND METHODS: Porcine ovaries were randomly assigned to three groups: novel decellularized group, conventional decellularized group and fresh group. The ovaries in the novel decellularized group underwent three cycles of freezing by liquid nitrogen and thawing at temperatures around 37 degree C before decellularization. The efficiency of the decellularization procedure was assessed through histological staining and DNA content analysis. The maintenance of ovarian decellularized extracellular matrix(ODECM) constituents was determined by analyzing the content of matrix proteins. Additionally, we evaluated the biocompatibility of the decellularized extracellular matrix(dECM) by observing the growth of granulosa cells on the ODECM scaffold in vitro. RESULTS: Hematoxylin and eosin staining, DAPI staining and DNA quantification techniques collectively confirm the success of the novel decellularization methods in removing cellular and nuclear components from ovarian tissue. Moreover, quantitative assessments of ODECM contents revealed that the novel decellularization technique preserved more collagen and glycosaminoglycan compared to the conventional decellularized group (P<0.05). Additionally, the novel decellularized scaffold exhibited a significantly higher number of granulosa cells than the conventional scaffold during in vitro co-culture (P<0.05). CONCLUSION: The novel decellularized method demonstrated high efficacy in eliminating DNA and cellular structures while effectively preserving the extracellular matrix. As a result, the novel decellularized method holds significant promise as a viable technique for ovarian decellularization in forthcoming studies. Doi.org/10.54680/fr24310110212.

Retraction Note: BNIP1 inhibits cell proliferation, migration and invasion, and promotes apoptosis by mTOR in cervical cancer cells.

The article "BNIP1 inhibits cell proliferation, migration and invasion, and promotes apoptosis by mTOR in cervical cancer cells", by F.-H. Li, L. Xiang, L. Ran, S. Zhou, Z. Huang, M. Chen, W.-F. Yu, published in Eur Rev Med Pharmacol Sci 2019; 23 (4): 1397-1407-DOI: 10.26355/eurrev_201902_17096-PMID: 30840260 has been retracted by the Editor in Chief for the following reasons. Following some concerns raised on PubPeer regarding a possible overlap in Figure 2A, the Editor in Chief has started an investigation to assess the validity of the results as well as possible figure manipulation. The journal investigation revealed a duplication in Figure 2A between BNIP1 panels, migration and invasion, respectively and in Control and invasion panels. Consequently, the Editor in Chief mistrusts the results presented and has decided to withdraw the article. The authors have been informed about the journal's investigation but remained unresponsive. https://www.europeanreview.org/article/17096 This article has been retracted. The Publisher apologizes for any inconvenience this may cause.

Orderly specification and precise laminar deployment of cortical glutamatergic projection neuron types through intermediate progenitors.

The cerebral cortex comprises diverse types of glutamatergic projection neurons (PNs) generated from radial glial progenitors (RGs) through either direct neurogenesis or indirect neurogenesis (iNG) via intermediate progenitors (IPs). A foundational concept in corticogenesis is the "inside-out" model whereby successive generations of PNs sequentially migrate to deep then progressively more superficial layers, but its biological significance remains unclear; and the role of iNG in this process is unknown. Using genetic strategies linking PN birth-dating to projection mapping in mice, we found that the laminar deployment of IP-derived PNs substantially deviate from an inside-out rule: PNs destined to non-consecutive layers are generated at the same time, and different PN types of the same layer are generated at non-contiguous times. The overarching scheme of iNG is the sequential specification and precise laminar deployment of projection-defined PN types, which may contribute to the orderly assembly of cortical output channels and processing streams. HIGHLIGHTS: - Each IP is fate-restricted to generate a pair of near-identical PNs - Corticogenesis involves the orderly generation of fate-restricted IP temporal cohorts - IP temporal cohorts sequentially as well as concurrently specify multiple PN types - The deployment of PN types to specific layers does not follow an inside-out order.

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally.

Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels. Teaser: Axon initial segment dynamically responds to changes in local input from chandelier cells to prevent abnormal neuronal functions.

Prognostic significance of serum cystatin C in acute brainstem infarctions patients.

OBJECTIVES: Some studies show that high circulating cystatin C (CysC) may predict cardiovascular events and death after ischemic stroke onset. However, the association between serum CysC and outcome in ischemic stroke patients remains contradictory. We sought to assess the association between a specific stroke subgroup, brainstem infarction (BSI) and serum CysC. MATERIALS AND METHODS: A total of 324 acute BSI patients were included in the study. Serum CysC was used to calculate estimated glomerular filtration rate (eGFRCysC) at baseline. Modified Rankin scale score ((mRS) ≥3) six months after acute BSI indicates poor functional outcome. Patients were categorized into two groups according to mRS and eGFRCysC. Logistic regression analyses were performed to determine independent risk factors. RESULTS: Lower eGFRCysC was associated with hemoglobin A1c (HbA1c). This risk remained statistically significant after controlling for age, hypertension, initial National Institutes of Health Stroke Scale (NIHSS) score, HbA1c, fibrinogen and homocysteine. The serum eGFRCysC levels were significantly lower in the poor functional outcome group than the good functional outcome group (P<0.001). Multivariate logistic regression analyses showed that eGFRCysC level was significantly lower in the poor outcome group after adjusting for age, previous infarctions, initial NIHSS score, and HbA1c. CONCLUSIONS: Lower eGFRCysC levels were strongly associated with poor functional outcome of acute BSI patients with a higher HbA1c level. Lower eGFRCysC may be a more helpful serologic biomarker for the prediction of prognosis in BSI.

[Clinical characteristics of 11 patients with Vibrio vulnificus infection and the establishment of a rapid diagnosis procedure for this disease].

Objective: To analyze the clinical characteristics of patients with Vibrio vulnificus infection, share diagnosis and treatment experience, and establish a rapid diagnosis procedure for this disease. Methods: This study was a retrospective case series study. From January 2009 to November 2022, 11 patients with Vibrio vulnificus infection who met the inclusion criteria were admitted to the Department of Burns and Wound Repair of Guangdong Provincial People's Hospital Affiliated to Southern Medical University. The gender, age, time of onset of illness, time of admission, time of diagnosis, route of infection, underlying diseases, affected limbs, clinical manifestations and signs on admission, white blood cell count, hemoglobin, platelet count, C-reactive protein (CRP), alanine transaminase (ALT), aspartate transaminase (AST), creatinine, procalcitonin, albumin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and blood sodium levels on admission, culture results and metagenomic next-generation sequencing (mNGS) results of pathogenic bacteria and the Vibrio vulnificus drug susceptibility test results during hospitalization, treatment methods, length of hospital stay, and outcomes of all patients were recorded. Comparative analysis was conducted on the admission time and diagnosis time of patients with and without a history of exposure to seawater/marine products, as well as the fatality ratio and amputation of limbs/digits ratio of patients with and without early adequate antibiotic treatment. For the survived patients with hand involvement, the hand function was assessed using Brunnstrom staging at the last follow-up. Based on patients' clinical characteristics and treatment conditions, a rapid diagnosis procedure for Vibrio vulnificus infection was established. Results: There were 7 males and 4 females among the patients, aged (56±17) years. Most of the patients developed symptoms in summer and autumn. The admission time was 3.00 (1.00, 4.00) d after the onset of illness, and the diagnosis time was 4.00 (2.00, 8.00) d after the onset of illness. There were 7 and 4 patients with and without a history of contact with seawater/marine products, respectively, and the admission time of these two types of patients was similar (P>0.05). The diagnosis time of patients with a history of contact with seawater/marine products was 2.00 (2.00, 5.00) d after the onset of illness, which was significantly shorter than 9.00 (4.25, 13.00) d after the onset of illness for patients without a history of contact with seawater/marine products (Z=-2.01, P<0.05). Totally 10 patients had underlying diseases. The affected limbs were right-hand in 8 cases, left-hand in 1 case, and lower limb in 2 cases. On admission, a total of 9 patients had fever; 11 patients had pain at the infected site, and redness and swelling of the affected limb, and 9 patients each had ecchymosis/necrosis and blisters/blood blisters; 6 patients suffered from shock, and 2 patients developed multiple organ dysfunction syndrome. On admission, there were 8 patients with abnormal white blood cell count, hemoglobin, and albumin levels, 10 patients with abnormal CRP, procalcitonin, and NT-proBNP levels, 5 patients with abnormal creatinine and blood sodium levels, and fewer patients with abnormal platelet count, ALT, and AST levels. During hospitalization, 4 of the 11 wound tissue/exudation samples had positive pathogenic bacterial culture results, and the result reporting time was 5.00 (5.00, 5.00) d; 4 of the 9 blood specimens had positive pathogenic bacterial culture results, and the result reporting time was 3.50 (1.25, 5.00) d; the mNGS results of 7 wound tissue/exudation or blood samples were all positive, and the result reporting time was 1.00 (1.00, 2.00) d. The three strains of Vibrio vulnificus detected were sensitive to 10 commonly used clinical antibiotics, including ciprofloxacin, levofloxacin, and amikacin, etc. A total of 10 patients received surgical treatment, 4 of whom had amputation of limbs/digits; all patients received anti-infection treatment. The length of hospital stay of 11 patients was (26±11) d, of whom 9 patients were cured and 2 patients died. Compared with that of the 6 patients who did not receive early adequate antibiotic treatment, the 5 patients who received early adequate antibiotic treatment had no significant changes in the fatality ratio or amputation of limbs/digits ratio (P>0.05). In 3 months to 2 years after surgery, the hand function of 8 patients was assessed, with results showing 4 cases of disabled hands, 2 cases of incompletely disabled hands, and 2 cases of recovered hands. When a patient had clinical symptoms of limb redness and swelling and a history of contact with seawater/marine products or a pre-examination triage RiCH score of Vibrio vulnificus sepsis ≥1, the etiological testing should be initiated immediately to quickly diagnose Vibrio vulnificus infection. Conclusions: Vibrio vulnificus infection occurs most frequently in summer and autumn, with clinical manifestations and laboratory test results showing obvious infection characteristics, and may be accompanied by damage to multiple organ functions. Both the fatality and disability ratios are high and have a great impact on the function of the affected limbs. Early diagnosis is difficult and treatment is easily delayed, but mNGS could facilitate rapid detection. For patients with red and swollen limbs accompanied by a history of contact with seawater/marine products or with a pre-examination triage RiCH score of Vibrio vulnificus sepsis ≥1, the etiological testing should be initiated immediately to quickly diagnose Vibrio vulnificus infection.

Inflammatory factors mediated the effect of air pollution on ischemic stroke: a two-step, mediation Mendelian randomization study.

OBJECTIVE: Numerous investigations have indicated a correlation between air pollution (AP) and an elevated ischemic stroke (IS) likelihood. The existing literature does not provide a consensus about the possible link between AP and IS. A two-sample Mendelian randomization (MR) analysis was utilized to systematically measure the causal link between AP and ischemic stroke. Furthermore, the mediating impact of inflammatory factors was also performed by a two-step MR. MATERIALS AND METHODS: A two-sample MR analysis was utilized to examine the AP impact on the incidence of IS. Additionally, a two-step MR approach was carried out to account for possible mediating variables. The indirect impact was determined by employing the product approach, which included multiplying the AP impact on inflammatory factors by the inflammatory factors' impacts on IS. The MR effect was identified through inverse variance-weighted (IVW) meta-analysis of each Wald Ratio. Additionally, complementary studies were conducted using the weighted median and MR-egger approaches. RESULTS: The IVW method with random effects showed that the per unit increase in genetically predicted PM2.5 was linked to the 0.362-fold elevated ischemic stroke risk (OR: 1.362, 95% CI: 1.032-1.796, p=0.029). Furthermore, the IVM technique, incorporating random effects, demonstrated that the per unit increase in genetically predicted PM2.5 was related to an elevated Interleukin (IL)-1ß risk (OR: 1.529, 95% CI: 1.191-1.963, p=0.001), IL-6 (OR: 1.498, 95% CI: 1.094-2.052, p=0.012) and IL-17 (OR: 1.478, 95% CI: 1.021-2.139, p=0.038). IL-1ß, IL-6, and IL-17 modulated the PM2.5 impact on ischemic stroke, while the proportion mediated by them was 59.5%. CONCLUSIONS: A positive correlation between genetically predicted PM2.5 levels and elevated ischemic stroke risk is mediated by IL-1ß, IL-6, and IL-17.

[Prognostic significance of textbook outcome in advanced gastric patients who underwent neoadjuvant chemotherapy followed by surgical resection].

Objective: To investigate the risk factors and prognostic value of the textbook outcome (TO) in patients with advanced gastric cancer (AGC) who underwent neoadjuvant chemotherapy followed by surgical resection. Methods: This is a retrospective cohort study. A total of 253 patients with AGC who underwent neoadjuvant chemotherapy combined with gastrectomy and D2 lymphadenectomy in the Department of Gastric Surgery, Fujian Medical University Union Hospital from January 2010 to December 2019 were retrospectively included. There were 195 males and 58 females, aged (60.3±10.0) years (range: 27 to 75 years). The patients were then divided into the TO group (n=168) and the non-TO group (n=85). Multivariate Logistic regression was used to analyze the independent predictors of TO. Univariate and multivariate Cox analysis were used to analyze independent prognosis factors for overall survival (OS) and disease-free survival (DFS). Propensity score matching was performed to balance the TO and non-TO groups, and the Kaplan-Meier method was used to calculate survival rates and draw survival curves. Results: Among the 253 patients, 168 patients (66.4%) achieved TO. The Eastern Cooperative Oncology Group score (OR=0.488, 95%CI: 0.278 to 0.856, P=0.012) and ypN stage (OR=0.626, 95%CI:0.488 to 0.805, P<0.01) were independently predictive of TO. Multivariate analysis revealed that TO was an independent risk factor for both OS (HR=0.662, 95%CI: 0.457 to 0.959,P=0.029) and DFS (HR=0.687, 95%CI: 0.483 to 0.976, P=0.036). After matching, the 5-year OS rate (42.2% vs. 27.8%) and the 5-year DFS rate (37.5% vs. 27.8%) were significantly higher in the TO group than in the non-TO group (both P<0.05). Furthermore, patients in the non-TO group benefited significantly from postoperative chemotherapy (both P<0.05), but those in the TO group did not (both P>0.05). Conclusion: TO is an independent prognosis factor in patients undergoing neoadjuvant chemotherapy and surgery for AGC and is associated with postoperative chemotherapy benefits.

[Thoughts and suggestions on digital services to enhance the level of vaccination management].

With the development of information technology and the increasing demand for vaccination services among the people, it is a definite trend to enhance the quality of vaccination services through digitization. This article starts with a clear concept of digital services for vaccination, introduces the current development status in China and abroad, analyzes the advantages and disadvantages of existing models in leading regions, takes a glean from the summation, and proposes targeted solutions. This study suggests establishing a departmental coordination mechanism for data interconnection and sharing, formulating data standards and functional specifications, enhancing the functionalities of the immunization planning information system, strengthening data collection and analytical usage, and intensifying appointment management and science and health education to provide expert guidance for the construction of digital vaccination services across the country in the future.

[Mediating effect of hypertension on risk of stroke associated with hyperuricemia].

Objective: To investigate the association between hyperuricemia and the risk for stroke occurrence, as well as the mediating effect of hypertension on this association. Methods: In this study, the China Chronic Diseases and Nutrition Surveillance system in 2015 was used as baseline data. We identified hospital admissions for stroke using the electronic homepage of inpatient medical records from 2013-2020, and death data were obtained from the 2015-2020 National Mortality Surveillance System. A retrospective cohort was established after matching and linking the database. The Cox proportional hazard regression model was used to analyze the relationship between hyperuricemia and the risk of stroke and its subtypes. Restricted cubic spline analysis was conducted to examine the dose-response relationship between serum uric acid levels and the risk for stroke. Mediation analysis was performed to investigate the mediating effect of hypertension on the association between hyperuricemia and the risk for stroke and its subtypes. Subgroup analyses were conducted based on gender and age groups. Results: A total of 124 352 study subjects were included, with an accumulative follow-up time of 612 911.36 person-years. During the follow-up period, 4 638 cases of stroke were found, including 3 919 cases of ischemic stroke and 689 cases of hemorrhagic stroke. The incidence density of stroke was 756.72 per 100 000 person-years, 641.37 per 100 000 person-years for ischemic stroke, and 114.60 per 100 000 person-years for hemorrhagic stroke. Multivariable Cox proportional hazards regression models showed that after adjusting for covariates, compared to those without hyperuricemia, individuals with hyperuricemia had a 16% higher risk for stroke [hazard ratio (HR)=1.16, 95%CI: 1.06-1.27], a 12% higher risk of ischemic stroke (HR=1.12, 95%CI: 1.01-1.24), and a 39% higher risk of hemorrhagic stroke (HR=1.39, 95%CI: 1.11-1.75). Mediation analysis showed that hypertension partially mediated the associations between hyperuricemia and the risk for stroke, ischemic stroke, and hemorrhagic stroke, with mediation proportions of 36.07%, 39.98%, and 25.34%, respectively. The mediating effect is pronounced in the male population and individuals below 65. Conclusion: Hyperuricemia is a risk factor for stroke, and hypertension partially mediates the effect of hyperuricemia on stroke.

Comparison of cryobiopsy and forceps biopsy for the diagnosis of mediastinal lesions: A randomised clinical trial.

INTRODUCTION: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the standard approach for lung cancer staging. However, its diagnostic utility for other mediastinal diseases might be hampered by the limited tissue retrieved. Recent evidence suggests the novel sampling strategies of forceps biopsy and cryobiopsy as auxiliary techniques to EBUS-TBNA, considering their capacity for larger diagnostic samples. METHODS: This study determined the added value of forceps biopsy and cryobiopsy for the diagnosis of mediastinal diseases. Consecutive patients with mediastinal lesions of 1 cm or more in the short axis were enrolled. Following completion of needle aspiration, three forceps biopsies and one cryobiopsy were performed in a randomised pattern. Primary endpoints included diagnostic yield defined as the percentage of patients for whom mediastinal biopsy led to a definite diagnosis, and procedure-related complications. RESULTS: In total, 155 patients were recruited and randomly assigned. Supplementing EBUS-TBNA with either forceps biopsy or cryobiopsy increased diagnostic yield, with no significant difference between EBUS-TBNA plus forceps biopsy and EBUS-TBNA plus cryobiopsy (85.7 % versus 91.6 %, P = 0.106). Yet, samples obtained by additional cryobiopsies were more qualified for lung cancer molecular testing than those from forceps biopsies (100.0 % versus 89.5 %, P = 0.036). When compared directly, the overall diagnostic yield of cryobiopsy was superior to forceps biopsy (85.7 % versus 70.8 %, P = 0.001). Cryobiopsies produced greater samples in shorter procedural time than forceps biopsies. Two (1.3 %) cases of postprocedural pneumothorax were detected. CONCLUSIONS: Transbronchial mediastinal cryobiopsy might be a promising complementary tool to supplement traditional needle biopsy for increased diagnostic yield and tissue harvesting. TRIAL REGISTRATION: ChiCTR2000030373.

[The efficacy and safety analysis of endoscopic resection for infratemporal fossa benign mass].

Objective: To investigate the efficacy and safety of endoscopic resection of infratemporal fossa mass and to determine the indications for surgery. Methods: A retrospective case series study was conducted, including a total of 29 patients who underwent endoscopic surgery to treat infratemporal fossa mass in the Department of Rhinology of Beijing Tongren Hospital, Capital Medical University, from April 2008 to December 2021. Ten males and 19 females were included in the study, with age of (46.5±13.7) years. Pre-and post-operative sinus CT, sinus or nasopharyngeal enhanced MRI were evaluated, respectively. The main outcome measurements were the total resection of mass and the incidence of surgery-related complications. Results: Among the 29 cases of infratemporal fossa mass, 22 were schwannomas, 3 were cysts, 2 were neurofibromas, 1 was pleomorphic adenoma and 1 was basal cell adenoma. Preoperative imaging showed well-defined lesion boundaries, and postoperative pathology confirmed the benign nature of all cases. The endoscopic transnasal approach was used in 28 patients, while the combination of the transnasal approach and the transoral approach was used in 1 patient. Complete tumor removal was achieved in all cases with a 100% resection rate. The average follow-up time was 38 months (7-168 months), and no tumor recurrence was observed. Conclusions: The Endoscopic transnasal approach is a safe and effective surgical approach for the treatment of benign tumors or masses in the infratemporal fossa.

[Comparison of efficacy and safety between domestic immune checkpoint inhibitors and pembrolizumab in the treatment of driver gene-negative advanced non-small cell lung cancer].

Objective: To compare the efficacy and safety of domestic immune checkpoint inhibitors and pembrolizumab in the treatment of driver gene-negative advanced non-small cell lung cancer. Methods: A retrospective analysis was conducted on the data of 1 241 patients with driver gene-negative, unresectable stage ⅢB to Ⅳ non-small cell lung cancer who were treated at the Hunan Cancer Hospital from January 1, 2017 to October 1, 2022. All patients received monotherapy or combination therapy with domestic immune checkpoint inhibitors or pembrolizumab. Among the 1 241 patients, there were 1 066 males and 175 females, with an age range of 14 to 84 years and a median age of 62 years. Among them, 67 patients received monotherapy with domestic immune checkpoint inhibitors, 695 patients received combination therapy with domestic immune checkpoint inhibitors, 102 patients received monotherapy with pembrolizumab, and 377 patients received combination therapy with pembrolizumab. The efficacy and safety of domestic immune checkpoint inhibitors and pembrolizumab monotherapy or combination therapy were compared. Results: In the immune checkpoint inhibitor monotherapy group, the objective response rate (ORR) using domestic immune checkpoint inhibitors and pembrolizumab was 43.3%(29/67) and 44.1%(45/102), respectively, and the disease control rate (DCR) was 79.1%(53/67) and 84.3%(86/102), respectively, with no statistically significant differences (both P>0.05). In the immune combination therapy group, the ORR using domestic immune checkpoint inhibitors and pembrolizumab was 60.9%(423/695) and 62.9%(237/377), respectively, and the DCR was 92.9%(646/695) and 91.0%(343/377), respectively, with no statistically significant differences (both P>0.05). In the immune checkpoint inhibitor monotherapy group, the median progression-free survival (PFS) using domestic immune checkpoint inhibitors and pembrolizumab was 9.0 (95%CI: 3.0-15.0) months and 7.4 (95%CI: 4.8-9.8) months, respectively, with no statistically significant differences (P=0.660). The median overall survival (OS) was 27.0 (95%CI: 25.0-29.0) months and 22.0 (95%CI: 17.1-26.9) months, respectively, with no statistically significant differences (P=0.673). In the immune combination therapy group, the median PFS using domestic immune checkpoint inhibitors and pembrolizumab was 9.0 (95%CI: 8.2-9.8) months and 10.5 (95%CI: 9.0-12.0) months, respectively, with no statistically significant differences (P=0.186). The median OS was 24.0 (95%CI: 19.1-28.9) months and 26.0 (95%CI: 21.3-30.7) months, respectively, with no statistically significant differences (P=0.359). The incidence of grade 1-2 reactive capillary proliferation of the skin in the domestic immune checkpoint inhibitor group and pembrolizumab group was 14.0% (107/762) and 0, respectively. The incidence of grade≥3 reactive capillary proliferation of the skin was 1.0% (7/762) and 0, respectively, with statistically significant differences (both P<0.05). No statistically significant differences were observed in other adverse reactions (all P>0.05). Conclusions: The efficacy of domestically produced immune checkpoint inhibitors is comparable to that of pembrolizumab in the treatment of driver gene-negative advanced non-small cell lung cancer. There is little difference in safety, except for the specific difference in domestically produced immune checkpoint inhibitor, which has a unique risk of reactive cutaneous capillary endothelial proliferation.

Intestinal Translocation of Live Porphyromonas gingivalis Drives Insulin Resistance.

Periodontitis has been emphasized as a risk factor of insulin resistance-related systemic diseases. Accumulating evidence has suggested a possible "oral-gut axis" linking oral infection and extraoral diseases, but it remains unclear whether periodontal pathogens can survive the barriers of the digestive tract and how they play their pathogenic roles. The present study established a periodontitis mouse model through oral ligature plus Porphyromonas gingivalis inoculation and demonstrated that periodontitis aggravated diet-induced obesity and insulin resistance, while also causing P. gingivalis enrichment in the intestine. Metabolic labeling strategy validated that P. gingivalis could translocate to the gastrointestinal tract in a viable state. Oral administration of living P. gingivalis elicited insulin resistance, while administration of pasteurized P. gingivalis had no such effect. Combination analysis of metagenome sequencing and nontargeted metabolomics suggested that the tryptophan metabolism pathway, specifically indole and its derivatives, was involved in the pathogenesis of insulin resistance caused by oral administration of living P. gingivalis. Moreover, liquid chromatography-high-resolution mass spectrometry analysis confirmed that the aryl hydrocarbon receptor (AhR) ligands, mainly indole acetic acid, tryptamine, and indole-3-aldehyde, were reduced in diet-induced obese mice with periodontitis, leading to inactivation of AhR signaling. Supplementation with Ficz (6-formylindolo (3,2-b) carbazole), an AhR agonist, alleviated periodontitis-associated insulin resistance, in which the restoration of gut barrier function might play an important role. Collectively, these findings reveal that the oral-gut translocation of viable P. gingivalis works as a fuel linking periodontitis and insulin resistance, in which reduction of AhR ligands and inactivation of AhR signaling are involved. This study provides novel insight into the role of the oral-gut axis in the pathogenesis of periodontitis-associated comorbidities.

Review of three-dimensional spheroid culture models of gynecological cancers for photodynamic therapy research.

Photodynamic therapy (PDT) is a specific cancer treatment with minimal side effects. However, it remains challenging to apply PDT clinically, partially due to the difficulty of translating research findings to clinical settings as the conventional 2D cell models used for in vitro research are accepted as less physiologically relevant to a solid tumour. 3D spheroids offer a better model for testing PDT mechanisms and efficacy, particularly on photosensitizer uptake, cellular and subcellular distribution and interaction with cellular oxygen consumption. 3D spheroids are usually generated by scaffold-free and scaffold-based methods and are accepted as physiologically relevant models for PDT anticancer research. Scaffold-free methods offer researchers advantages including high efficiency, reproducible, and controlled microenvironment. While the scaffold-based methods offer an extracellular matrix-like 3D scaffold with the necessary architecture and chemical mediators to support the spheroid formation, the natural scaffold used may limit its usage because of low reproducibility due to patch-to-patch variation. Many studies show that the 3D spheroids do offer advantages to gynceologcial cancer PDT investigation. This article will provide a review of the applications of 3D spheroid culture models for the PDT research of gynaecological cancers.

Peritumoural MRI radiomics signature of brain metastases can predict epidermal growth factor receptor mutation status in lung adenocarcinoma.

AIM: To investigate whether magnetic resonance imaging (MRI) radiomics features of brain metastases (BMs) can predict epidermal growth factor receptor (EGFR) mutation status in lung adenocarcinoma. MATERIALS AND METHODS: Between June 2014 and December 2022, 58 histopathologically confirmed lung adenocarcinoma patients (27 with EGFR wild-type, 31 with EGFR mutation) who underwent gadobenate dimeglumine-enhanced brain MRI were recruited retrospectively. A total of 123 metastatic brain lesions were allocated randomly into the training cohort (n=86) and test cohort (n=37) at a ratio of 7:3. Radiomics models based on multi-sequence MRI images in different regions such as volume of interest (VOI)enhancing tumour, VOIwholetumour, VOIperitumour 1mm, VOIperitumour 3mm, and VOIperitumour 5mm were built. The optimal radiomics model was integrated into the clinical or radiological indicators to construct a fusion model through multivariable logistic regression analysis. RESULTS: The optimal radiomics model based on the VOIperitumour 1mm, a combination of nine features selected from the fluid-attenuated inversion recovery (FLAIR) sequence, yielded areas under the curves (AUCs) of >0.75 in the training and test cohorts. The prediction of the fusion model with integration of clinical factors (age) and radiomics score (the optimal radiomics model) was not better than that of the optimal radiomics model alone in the test cohort (AUC: 0.808 and 0.785, respectively, p=0.525). CONCLUSION: The FLAIR radiomics model based on VOIperitumour 1mm as an effective biomarker helps predict EGFR mutation status in lung adenocarcinoma patients with BMs and then assists clinicians in selecting optimal treatment strategies.

Age-specific characteristics of head and neck second primary malignancies in patients treated for nasopharyngeal carcinoma: a retrospective study.

This study was performed to analyse the age-specific characteristics of head and neck second primary malignancies (SPMs) in patients treated for nasopharyngeal carcinoma (NPC). The medical records of 56 NPC patients diagnosed with head and neck SPMs were reviewed retrospectively. Patients < 45 years old at NPC diagnosis were assigned to the younger group and those ≥ 45 years of age were assigned to the older group. The treatment of the index NPC, latency period, pathological TNM stage, survival status, and SPM subsite were analysed. Patients in the older group were found to have a shorter median latency period than those in the younger group: 8.5 years (range 3-20 years) versus 11 years (range 1-30 years) (P = 0.015). The proportion of SPMs in the jaw was significantly higher in the younger group (P = 0.002). Patients in the younger group receiving radiotherapy with chemotherapy had a shorter latency period (P = 0.003) and higher risk of developing SPMs in the jaw (P = 0.036) than those receiving radiotherapy alone. A long-term and age-dependent regular customised follow-up strategy for NPC is necessary for the prevention and early detection of head and neck second primary malignancies.

Clinicopathological and prognostic significance of PD-L1 and TIM-3 expression in medullary thyroid carcinoma: a retrospective immunohistochemistry study.

PURPOSE: Expression of the programmed death-ligand 1 (PD-L1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) in medullary thyroid carcinoma (MTC) has been controversial and rarely reported. METHODS: Surgical specimens of 190 MTC patients who had initial curative-intent surgery were collected. Immunohistochemistry of PD-L1 and TIM-3 was performed using 22C3 pharmDx (Dako, Carpinteria, CA) and anti-TIM-3 (1:500, ab241332, Abcam). Stained slides were scored using a combined positive score (CPS) with a cutoff of ≥ 1. We established correlations between PD-L1 expression, TIM-3 expression, clinicopathological, and survival data. RESULTS: 13 cases (13/190, 6.84%) were positive for PD-L1 expression, and 42 cases (42/154, 27.27%) for TIM-3 expression. PD-L1 expression was correlated to TIM-3 expression (P = 0.002), but was not related to overall survival (OS) or progression-free survival (PFS). TIM-3 expression was correlated to perineural invasion (P = 0.040). Multivariate Cox analysis showed that lymphovascular invasion (LVI) was independently associated with OS. And tumor size, LVI, and lymph node metastases were significantly associated with PFS. Furthermore, the multivariate logistic analysis showed multifocal status, LVI, pathological T stage and lymph node metastasis were independent risk factors for biochemical recurrence/persistent disease. CONCLUSIONS: We demonstrated that PD-L1 and TIM-3 expression were not frequent in MTC and were not associated with survival prognosis. Our results should be considered when clinical trials of PD-L1 or TIM-3 blockades are implemented.