[Effects of simulated gas of thermobaric bomb charge explosion on Tau protein phosphorylation and cognitive function in rats].

Objective: To explore the effect of simulated gas of thermobaric bomb charge explosion on cognitive function and the related mechanism of damage. Methods: In January 2022, thirty-two SPF rats were selected and randomly divided into control group, exposed group 1, 2 and 3 (the exposure time of the simulated gas of the explosion of the thermobaric bomb charge was 5 min, 10 min and 15 min, respectively) according to random number table method, with 8 rats in each group. The simulated gas of the explosion of the thermobaric bomb charge were CO 0.15%, CO(2) 3%, NO 0.1%, O(2) 15%, and the rest were N(2). After 30 days of exposure, water maze was used to detect the learning and memory function of rats. Golgi staining was used to observe the number distribution and morphological structure of hippocampal neurons in rats. Western blot was used to detect the expression of Tau-5, pSer262, pSer396, pThr181 and pThr231 proteins in rats. Repeated measure ANOVA was used to compare the design data of repeated measure, one-way ANOVA was used for multi-group mean comparison, and LSD method was used for pound-wise comparison. Results: There were significant differences in the results of repeated measurement ANOVA of the water maze localization navigation test (F=80.98, P<0.001), and there was an interaction between the group and the training days (F=2.16, P=0.022). There were significant differences in escape latency of rats at the 2nd, 3rd, 4th and 5th days among all groups (P<0.05). The results of spatial exploration showed that the frequency of rats crossing the platform was significantly different among all groups (F=4.49, P=0.011). The frequency of rats crossing the platform in exposed group 2 and exposed group 3 was lower than that in control group, and the frequency of rats crossing the platform in exposed group 3 was lower than that in exposed group 1 (P<0.05). With the increase of exposure time, the number of hippocampal neurons decreased, and the dendrite spine density of neurons in CA1 region decreased (P<0.05). Compared with the control group, there was no significant difference in the relative expression level of Tau-5 protein in all exposed groups (P>0.05), but the expression level of pSer262 protein was significantly increased (P<0.05). Compared with the control group, the protein expressions of pSer396, pThr181 and pThr231 in exposed group 2 and exposed group 3 were significantly increased (P<0.05) . Conclusion: The simulated gas of the explosion of the thermobaric bomb charge may contribute to the development of cognitive dysfunction by damaging hippocampal neurons with aberrant phosphorylation of Tau proteins.

Zinc-finger protein ZFP488 regulates the timing of oligodendrocyte myelination and remyelination.

Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein a H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.Significance statement Precise timing of myelination is essential for efficient neural communication and is linked to the development of cognitive and motor skills as well as myelin repair after injury. ZFP488 is a transcriptional regulator enriched in oligodendrocytes, however its in vivo functions remain unclear. By generating ZFP488 loss-of-function mice, we demonstrated that ZFP488 is critical for the timing of myelination and remyelination and that its loss impaired the initial differentiation of oligodendrocytes but not their precursor formation and proliferation. Transcriptomic profiling showed that ZFP488 functions as a positive regulator of myelination by modulating oligodendrocyte maturation programs. Thus, our findings underscore the important role of ZFP488 in myelination and the potential of ZFP488 augmentation as an avenue to enhance oligodendrocyte regeneration.

[Clinical analysis of dual enhanced antiplatelet therapy after cerebrovascular intervention for reducing the risk of cerebral infarction recurrence].

To investigate the clinical assessment of dual-enhanced antiplatelet therapy after cerebrovascular intervention to reduce the risk of cerebral infarction recurrence, and to provide a reference for the prevention and treatment of cerebral infarction recurrence risk. 202 patients with cerebral infarction who underwent cerebrovascular intervention in Tianjin Fifth Central Hospital from January 2018 to October 2022 were selected as study subjects. The patients were divided into a treatment group (n=104) based on randomized controlled single-blind method with 61 males and 43 females with a mean age of (62.33±2.57) years old and a control group (n=98) with 56 males and 42 females with a mean age of (62.49±2.36) years old. The control group was given aspirin mono-antiplatelet therapy, and the treatment group was given clopidogrel doublet augmented antiplatelet therapy on the basis of the control group, and both groups continued the treatment for 2 months. Platelet counts, coagulation indexes and inflammatory factors were compared between the two groups before and after treatment, and the America National Institutes of Health Stroke Scale (NIHSS) score was used to assess the neurological functions of the two groups before and after treatment, and the recurrence of cerebral infarction in the two groups was counted within 6 months after treatment. In addition, the patients in the treatment group were divided into the cerebral infarction recurrence group and the cerebral infarction non-recurrence group according to whether they had cerebral infarction recurrence within 6 months after treatment, and the clinical data of the patients in the treatment group were collected to analyze the influencing factors of the dual-enhancement antiplatelet therapy for the recurrence of cerebral infarction in patients with cerebral infarction after cerebral vascular intervention by multifactorial logistic regression. The results showed that after treatment, patients in the treatment group had an international normalized ratio (INR) of (1.76±0.38), a platelet activation rate of (39.52±4.79)%, a platelet aggregation rate of (48.54±5.21)%, a tumor necrosis factor-alpha (TNF-alpha) of (28.37±4.47)ng/L, an interleukin 6 (IL-6) of (24.77±3.52)ng/L, a high-sensitivity C-reactive protein (hs-CRP) of (7.39±1.53)mg/L and an NIHSS score of (6.11±1.39) were lower than those of the control group (2.32±0.41), (44.81±6.37)%, (51.39±5.58)%, (39.66±4.51) ng/L, (29.25±4.04) ng/L, (9.03±1.78) mg/L and (9.93±1.46) points (all P<0.05). At 6-month follow-up of all patients, cerebral infarction recurred in 16 (15.38%) patients in the treatment group and in 33 (33.67%) patients in the control group (χ2=9.185, P<0.05). Kaplan-Meier results showed a statistically significant difference in the rate of recurrence without cerebral infarction in the treatment group compared with the control group(LogRank χ2=4.595,P<0.05). Logistic regression analysis showed that smoking history, cervical vascular plaque, post-treatment NIHSS score, post-treatment stenosis score, post-treatment INR, post-treatment hs-CRP and CYP2C19 gene polymorphism were independent influences on the recurrence of cerebral infarction in cerebral infarction patients with cerebral vascular interventions followed by doublet augmentation of antiplatelet therapy (all P<0.05). In conclusion, dual-enhanced antiplatelet therapy may be an effective measure to reduce the risk of cerebral infarction recurrence after cerebrovascular intervention in patients with cerebral infarction, but it is still influenced by more factors.

Shared patterns of glial transcriptional dysregulation link Huntington's disease and schizophrenia.

Huntington's disease and juvenile-onset schizophrenia have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between Huntington's disease and schizophrenia hGPCs yet distinct from normal controls that included 174 highly connected genes in the shared disease-associated network, focusing on genes involved in synaptic signalling. These synaptic genes were largely suppressed in both schizophrenia and Huntington's disease hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both schizophrenia and Huntington's disease hGPCs. Chromatin immunoprecipitation sequencing confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signalling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, Huntington's disease and schizophrenia.

Epicardial fat modifies the relationship between coronary calcium score and all-cause mortality: The St. Francis Heart Study.

Objective: Epicardial fat is associated with cardiovascular risk factors and adverse outcomes. However, it is not clear if epicardial fat remains to be a mortality risk when coronary calcium score (CAC) is taken into account. Methods: We studied the 1005 participants from the St. Francis Heart Study who were apparently healthy with CAC scores at 80th percentile or higher for age and gender, randomly assigned to placebo or statin therapy. At baseline, lipid profiles and non-contrast CT images were obtained where the epicardial fat volume was analyzed. Likelihood ratio testing was used to assess the additional prognostic value of epicardial fat to CAC for the risk of all-cause mortality. Results: Increased epicardial fat volume was associated with higher CAC. For each unit increase in lnCAC, the average epicardial fat volume increased by 3.34 mL/m2. After a mean follow-up period of 17 years, 179 (18%) participants died. Increased epicardial fat volume was associated with an adjusted hazard ratio of 1.11 (95% CI: 1.02 to 1.20) predicting all-cause mortality. In the stratified analysis testing strata of epicardial fat and CAC, those with increased epicardial fat and increased CAC had the highest risk of death. Compared with a model containing lnCAC and traditional risk factors, a model additionally containing epicardial fat volume yielded a better model fit (likelihood ratio test p < 0.001). Conclusion: Increased epicardial fat volume is associated with increased all-cause mortality risk. In addition, it portends incremental prognostic value to CAC score in mortality prediction.

[MRI manifestations of 40 cases with the hepatic epithelioid hemangioendothelioma classification based on the morphology and size].

Objective: To explore the MRI characteristics of the hepatic epithelioid hemangioendothelioma (HEHE) classification according to morphology and size. Methods: The clinical, pathological, and MRI imaging data of 40 cases with HEHE confirmed pathologically from December 2009 to September 2021 were retrospectively analyzed. A paired sample t-test was used for comparison between the two groups. Results: There were 40 cases (5 solitary, 24 multifocal, 9 local fusion, and 2 diffuse fusion) and 214 lesions (163 nodules, 31 masses, and 20 fusion foci). The most common features of lesions were subcapsular growth and capsular depression. The signal intensity of lesions ≤1cm was usually uniform with whole or ring enhancement. Nodules and mass-like lesions ≥1cm on a T1-weighted image had slightly reduced signal intensity or manifested as a halo sign. Target signs on a T2-weighted image were characterized by: target or centripetal enhancement; fusion-type lesions; irregular growth and hepatic capsular retraction, with ring or target-like enhancement in the early stage of fusion and patchy irregular enhancement in the late stage; blood vessels traversing or accompanied by malformed blood vessels; focal bleeding; an increasing proportion of extrahepatic metastases and abnormal liver function with the type of classified manifestation; primarily portal vein branches traversing; and reduced overall intralesional bleeding rate (17%). Lollipop signs were presented in 19 cases, with a high expression rate in mass-type lesions (42%). The fusion lesions were expressed, but the morphological manifestation was atypical. The diffusion-weighted imaging mostly showed high signal or target-like high signal. An average apparent diffusion coefficient of lesions was (1.56±0.36) ×10(-3)mm(2)/s, which was statistically significantly different compared with that of adjacent normal liver parenchyma (t=8.28, P<0.001). Conclusion: The MRI manifestations for the HEHE classification are closely related to the morphology and size of the lesions and have certain differences and characteristics that are helpful for the diagnosis of the disease when combined with clinical and laboratory examinations.

[Efficacy of alternate mucosa-submucosa clip closure in preventing postoperative complications for patients with gastric mucosal lesions after endoscopic submucosal dissection].

Objective: To analyze the efficacy of alternate titanium clip closure in preventing postoperative complications for patients with gastric mucosal lesions after endoscopic submucosal dissection (ESD). Methods: Clinical data of patients with gastric mucosal lesions who underwent ESD in the Department of Gastroenterology, Zhongda Hospital, Southeast University, were retrospectively collected from January 1, 2013 to August 31, 2023. According to the postoperative wound closure status, the patients were divided into completely closed group (complete closure of ESD wounds using alternate titanium clip closure), partially closed group (partial closure of ESD wounds), and unclosed group (without use of clips for treatment of ESD wounds). The incidence of postoperative complications as well as wound healing at 1 month and 3 months after surgery were compared among three groups, and the factors related to delayed bleeding after ESD for gastric mucosal lesions were analyzed through multiple logistic regression analysis. Results: A total of 846 patients were included, 430 cases in the completely closed group, including 300 males and 130 females, age [M (Q1, Q3)] was 65(56, 72) years old; one hundred and nine cases in unclosed group, including 78 males and 31 females, aged 66 (60, 71) years; and 307 cases in the partially closed group, including 214 males and 93 females, aged 66 (59, 71) years. The difference in the rate of delayed postoperative bleeding between the completely closed group [2.1% (9/430)] and the unclosed group [5.5% (6/109)] was not statistically significant (P=0.072), but both were lower than that of the partially closed group [9.4% (29/307), P<0.05)]. Further stratified analysis showed that, for the lesions located in the lower 1/3 of the stomach, the rate of postoperative bleeding was lower in the completely closed group than in the partially closed and unclosed groups [0.9% (2/222) vs 11.4% (4/35) vs 9.5% (7/74), respectively, P<0.001]. For lesions≥50 mm in length, the rate of postoperative bleeding was lower in the completely closed group than that in the partially closed and unclosed group[0 vs 11.8% (2/17) vs 20.5% (15/73), respectively, P=0.004]. The incidence of postoperative abdominal pain in the completely closed group [84.2% (363/430)] was lower than that in the unclosed group [97.2% (106/109)] and the partially closed group [95.4% (293/307), both P<0.001)]. The score of postoperative abdominal pain in the completely closed group [0 (0, 1)], was lower than that in the unclosed group [3 (2, 3)], and that in the partially closed group [2 (1, 3)] (both P<0.001). The wound healing rate of the completely closed group [80% (176/220)] was higher than that of the unclosed group [52.3% (33/63)] and the partially closed group [52.2% (83/159)] at 1 month postoperatively (both P<0.001); the healing rate of all three groups reached 100% at 3 months postoperatively. Multiple logistic regression analysis showed that the presence of ulcers or scars on the surface of the lesion (OR=2.930, 95%CI:1.503-5.712, P=0.002), and the diameter (OR=1.031, 95%CI:1.015-1.047,P<0.001) were related factors for postoperative bleeding. Conclusions: The alternate titanium clip closure surgery can reduce postoperative abdominal pain and shorten wound healing time in patients with gastric mucosal lesions after ESD surgery. The risk of postoperative bleeding can be reduced for lesions with a diameter≥50 mm and located in the lower 1/3 of the stomach.

[Association between prenatal exposure to PM2.5 and fetal growth: a prospective cohort study].

Objective: To investigate the association of exposure to PM2.5 and its constituents during pregnancy and fetal growth and to further identify critical windows of exposure for fetal growth. Methods: We included 4 089 mother-child pairs from the Jiangsu Birth Cohort Study between January 2016 and October 2019. Data of general characteristics, clinical information, daily average PM2.5 exposure, and its constituents during pregnancy were collected. Fetal growth parameters, including head circumference (HC), abdominal circumference (AC), and femur length (FL), were measured by ultrasound after 20 weeks of gestation, and then estimated fetal weight (EFW) was calculated. Generalized linear mixed models were adopted to examine the associations of prenatal exposure to PM2.5 and its constituents with fetal growth. Distributed lag nonlinear models were used to identify critical exposure windows for each outcome. Results: A 10 µg/m3 increase in PM2.5 exposure during pregnancy was associated with a decrease of 0.025 (ß=-0.025, 95%CI: -0.048- -0.001) in HC Z-score, 0.026 (ß=-0.026, 95%CI: -0.049- -0.003) in AC Z-score, and 0.028 (ß=-0.028, 95%CI:-0.052--0.004) in EFW Z-score, along with an increased risk of 8.5% (RR=1.085, 95%CI: 1.010-1.165) and 13.5% (RR=1.135, 95%CI: 1.016-1.268) for undergrowth of HC and EFW, respectively. Regarding PM2.5 constituents, prenatal exposure to black carbon, organic matter, nitrate, sulfate (SO42-) and ammonium consistently correlated with decreased HC Z-score. SO42- exposure was also associated with decreased FL Z-scores. In addition, we found that gestational weeks 2-5 were critical windows for HC, weeks 4-13 and 19-40 for AC, weeks 4-13 and 23-37 for FL, and weeks 4-12 and 20-40 for EFW. Conclusions: Our findings demonstrated that exposure to PM2.5 and its constituents during pregnancy could adversely affect fetal growth and the critical windows for different fetal growth parameters are not completely consistent.

Biomolecular condensates: hubs of Hippo-YAP/TAZ signaling in cancer.

Biomolecular condensates, the membraneless cellular compartments formed by liquid-liquid phase separation (LLPS), represent an important mechanism for physiological and tumorigenic processes. Recent studies have advanced our understanding of how these condensates formed in the cytoplasm or nucleus regulate Hippo signaling, a central player in organogenesis and tumorigenesis. Here, we review recent findings on the dynamic formation and function of biomolecular condensates in regulating the Hippo-yes-associated protein (YAP)/transcription coactivator with PDZ-binding motif (TAZ) signaling pathway under physiological and pathological processes. We further discuss how the nuclear condensates of YAP- or TAZ-fusion oncoproteins compartmentalize crucial transcriptional co-activators and alter chromatin architecture to promote oncogenic programs. Finally, we highlight key questions regarding how these findings may pave the way for novel therapeutics to target cancer.

Effect of NFX-179 MEK inhibitor on cutaneous neurofibromas in persons with neurofibromatosis type 1.

This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle (P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume (P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Comparison of laparoscopic and open inguinal-hernia repair in elderly patients: the experience of two comprehensive medical centers over 10 years.

PURPOSE: The safety of laparoscopic inguinal-hernia repair must be carefully evaluated in elderly patients. Very little is known regarding the safety of the laparoscopic approach in elderly patients under surgical and medical co-management (SMC). Therefore, this study evaluated the safety of the laparoscopic approach in elderly patients, especially patients with multiple comorbidities under SMC. METHODS: From January 2012 to December 2021, patients aged ≥ 65 years who underwent open or laparoscopic inguinal-hernia repair during hospitalization were consecutively enrolled. Postoperative outcomes included major and minor operation-related complications, and other adverse events. To reduce potential selection bias, propensity score matching was performed between open and laparoscopic groups based on patients' demographics and comorbidities. RESULTS: A total of 447 elderly patients who underwent inguinal-hernia repair were enrolled, with 408 (91.3%) underwent open and 39 (8.7%) laparoscopic surgery. All postoperative outcomes were comparable between open and laparoscopic groups after 1:1 propensity score matching (all p > 0.05). Moreover, compared to the traditional care group (n = 360), a higher proportion of the SMC group (n = 87) was treated via the laparoscopic approach (18.4% vs. 6.4%, p = 0.00). In the laparoscopic approach subgroup (n = 39), patients in the SMC group (n = 16) were older with multiple comorbidities but were at higher risks of only minor operation-related complications, compared to those in the traditional care group. CONCLUSIONS: Laparoscopic inguinal-hernia repair surgery is safe for elderly patients, especially those with multiple comorbidities under SMC.

The myelination-associated G protein-coupled receptor 37 is regulated by Zfp488, Nkx2.2, and Sox10 during oligodendrocyte differentiation.

Oligodendrocyte differentiation and myelination in the central nervous system are controlled and coordinated by a complex gene regulatory network that contains several transcription factors, including Zfp488 and Nkx2.2. Despite the proven role in oligodendrocyte differentiation little is known about the exact mode of Zfp488 and Nkx2.2 action, including their target genes. Here, we used overexpression of Zfp488 and Nkx2.2 in differentiating CG4 cells to identify aspects of the oligodendroglial expression profile that depend on these transcription factors. Although both transcription factors are primarily described as repressors, the detected changes argue for an additional function as activators. Among the genes activated by both Zfp488 and Nkx2.2 was the G protein-coupled receptor Gpr37 that is important during myelination. In agreement with a positive effect on Gpr37 expression, downregulation of the G protein-coupled receptor was observed in Zfp488- and in Nkx2.2-deficient oligodendrocytes in the mouse. We also identified several potential regulatory regions of the Gpr37 gene. Although Zfp488 and Nkx2.2 both bind to one of the regulatory regions downstream of the Gpr37 gene in vivo, none of the regulatory regions was activated by either transcription factor alone. Increased activation by Zfp488 or Nkx2.2 was only observed in the presence of Sox10, a transcription factor continuously present in oligodendroglial cells. Our results argue that both Zfp488 and Nkx2.2 also act as transcriptional activators during oligodendrocyte differentiation and cooperate with Sox10 to allow the expression of Gpr37 as a modulator of the myelination process.

[A multicenter study on respiratory pathogen detection with Mycoplasma pneumoniae pneumonia in children].

Objective: To analyze the status of respiratory pathogen detection and the clinical features in children with Mycoplasma pneumoniae pneumonia (MPP). Methods: A prospective, multicenter study was conducted to collect clinical data, including medical history, laboratory examinations and multiplex PCR tests of children diagnosed with MPP from 4 hospitals in China between November 15th and December 20th, 2023. The multiplex PCR results and clinical characteristics of MPP children in different regions were analyzed. The children were divided into severe and mild groups according to the severity of the disease. Patients in the severe group were further divided into Mycoplasma pneumoniae (MP) alone and Multi-pathogen co-detection groups based on whether other pathogens were detected besides MP, to analyze the influence of respiratory pathogen co-detection rate on the severity of the disease. Mann-Whitney rank sum test and Chi-square test were used to compare data between independent groups. Results: A total of 298 children, 136 males and 162 females, were enrolled in this study, including 204 children in the severe group with an onset age of 7.0 (6.0, 8.0) years, and 94 children in the mild group with an onset age of 6.5 (4.0, 7.8) years. The level of C-reactive protein, D-dimer, lactic dehydrogenase (LDH) were significantly higher (10.0 (5.0, 18.0) vs. 5.0 (5.0, 7.5) mg/L, 0.6 (0.4, 1.1) vs. 0.5 (0.3, 0.6) mg/L, 337 (286, 431) vs. 314 (271, 393) U/L, Z=2.02, 2.50, 3.05, all P<0.05), and the length of hospitalization was significantly longer in the severe group compared with those in mild group (6.0 (6.0, 7.0) vs. 5.0 (4.0, 6.0) d, Z=4.37, P<0.05). The time from onset to admission in severe MPP children was significantly shorter than that in mild MPP children (6.0 (5.0, 9.5) vs. 9.0 (7.0, 13.0) d, Z=2.23, P=0.026). All patients completed the multiplex PCR test, with 142 cases (47.7%) MPP children detected with 21 pathogens including adenovirus 25 cases (8.4%), human coronavirus 23 cases (7.7%), rhinovirus 21 cases (7.0%), Streptococcus pneumoniae 21 cases (7.0%), influenza A virus 18 cases (6.0%). The pathogens with the highest detection rates in Tianjin, Shanghai, Wenzhou and Chengdu were Staphylococcus aureus at 10.7% (8/75), adenovirus at 13.0% (10/77), adenovirus at 15.3% (9/59), and both rhinovirus and Haemophilus influenzae at 11.5% (10/87) each. The multi-pathogen co-detection rate in severe MPP children was significantly higher than that in mild MPP group (52.9% (108/204) vs. 36.2% (34/94), χ²=10.62,P=0.005). Among severe MPP children, there are 89 cases in the multi-pathogen co-detection group and 73 cases in the simple MPP group. The levels of LDH, D-dimer and neutrophil counts in the multi-pathogen co-detection group were significantly higher than those in the simple MPP group (348 (284, 422) vs. 307 (270, 358) U/L, 0.8 (0.5, 1.5) vs. 0.6 (0.4, 1.0) mg/L, 4.99 (3.66, 6.89)×109 vs. 4.06 (2.91, 5.65)×109/L, Z=5.17, 4.99, 6.11, all P<0.05). Conclusions: The co-detection rate of respiratory pathogens, LDH and D-dimer in children with severe MPP were higher than those with mild MPP. Among severe MPP children the stress response of children in co-detection group was more serious than that of children with simple MPP.

Comprehensive genomic profiling to identify actionable alterations for breast cancer brain metastases in the Chinese population.

BACKGROUND: Breast cancer brain metastasis (BCBM) is a crucial issue in the treatment of breast cancer and is associated with poor prognosis. Therefore, novel therapeutic targets are urgently needed in clinical practice. In this study, we aimed to identify potential actionable targets in brain metastases (BMs) utilising the FoundationOne® CDx (F1CDx). PATIENTS AND METHODS: Formalin-fixed paraffin-embedded archived specimens including 16 primary breast tumours (PTs), 49 BCBMs and 7 extracranial metastases (ECMs) from 54 patients who underwent surgery for BCBM were tested using F1CDx. Tumour-infiltrated lymphocytes (TILs) of BMs were also tested using haematoxylin-eosin staining. RESULTS: The median tumour mutational burden (TMB) and TILs in BMs were 5.0 (range 0-29) mut/Mb and 1.0% (range 0%-5.0%), respectively. High TMB (≥10 mut/Mb) was detected in four cases (8%). Genomic alterations (GAs) were detected in all samples. The top-ranked somatic mutations in BMs were TP53 (82%), PIK3CA (35%), MLL2 (22%), BRCA2 (14%) and ATM (14%) and the most prevalent copy number alterations were ERBB2 (64%), RAD21 (36%), CCND1 (32%), FGF19 (30%) and FGF3 (30%). The most prevalent GAs were relatively consistent between paired PTs and BMs. Actionable GAs were detected in 94% of all BMs. Consistent rate in actionable GAs was 38% (6/16) between paired PTs/ECMs and BMs. Compared to matched PTs/ECMs, additional actionable GAs (BRAF, FGFR1, PTEN, KIT and CCND1) were discovered in 31% (5/16) of the BMs. CONCLUSIONS: TMB and TILs were relatively low in BCBMs. Comparable consistency in actionable GAs was identified between BCBMs and matched PTs/ECMs. It was, therefore, logical to carry out genomic testing for BCBMs to identify potential new therapeutic targets when BCBM specimens were available, as ∼31% of samples carried additional actionable GAs.

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.

Stem cell modeling of nervous system tumors.

Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations associated with nervous system cancers can be introduced. These stem cells can be used to create self-assembling three-dimensional cerebral organoids that preserve key features of the developing human brain. Moreover, stem cell-engineered lines are amenable to xenotransplantation into mice as a platform to investigate the tumor cell of origin, discover cancer evolutionary trajectories and identify therapeutic vulnerabilities. In this article, we review the current state of human stem cell models of nervous system tumors, discuss their advantages and disadvantages, and provide consensus recommendations for future research.

[Analysis of the incidence and symptomatology of low anterior resection syndrome after laparoscopic anterior resection for rectal cancer].

Objective: This study aims to explore the temporal trend of Low Anterior Resection Syndrome (LARS) and its symptoms after laparoscopic anterior resection for rectal cancer. Methods: A retrospective cohort study design was employed. The study included primary rectal (adenocarcinoma) cancer patients who underwent laparoscopic anterior resection at Tongji Hospital, Huazhong University of Science and Technology, between January 1, 2010, and December 31, 2020. Complete medical records and follow-up data at 3, 6, 9, 12, and 18 months postoperatively were available for all patients. A total of 1454 patients were included, of whom 1094 (75.2%) were aged ≤65 years, and 597 (41.1%) were females. Among them, 1040 cases (71.5%) had an anastomosis-to-anus distance of 0-5cm, and 86 cases (5.9%) received neoadjuvant treatment. All patients completed the Chinese version of the LARS questionnaire and their LARS occurrence and specific symptom information were recorded at 3, 6, 9, 12, and 18 months postoperatively. Considering past literature and clinical experience, further subgroup analyses were performed to explore the potential impact factors on severe LARS, including anastomosis level, preoperative neoadjuvant therapy, postoperative adjuvant therapy, and the presence of preventive stoma. Results: The occurrence rates of LARS at 3, 6, 9, 12, and 18 months postoperatively were 78.5% (1142/1454), 71.4% (1038/1454), 55.0% (799/1454), 45.7% (664/1454), and 45.7% (664/1454), respectively (χ2=546.180, P<0.001). No statistically significant difference was observed between the 12-month and 18-month time points (P>0.05). When compared with the symptoms at 3 months, the occurrence rates of gas incontinence [1.7% (24/1454) vs. 33.9% (493/1454)], liquid stool incontinence [3.9% (56/1454) vs. 41.9% (609/1454)], increased stool frequency [79.6% (1158/1454) vs. 95.9% (1395/1454)], stool clustering [74.3% (1081/1454) vs. 92.9% (1351/1454)], and stool urgency [46.5% (676/1454) vs. 78.7% (1144/1454)] in the LARS symptom spectrum were significantly alleviated at 12 months (all P<0.05) and remained stable beyond 12 months (all P>0.05). With the extension of postoperative time, the incidence rates of severe LARS exhibited a decreasing trend in different subgroups, of anastomosis level, preoperative neoadjuvant therapy, postoperative adjuvant therapy, and the presence of preventive stoma, and reached stability at 12 months postoperatively (all P>0.05). Conclusion: LARS and its specific symptom profile showed a trend of gradual improvement over time up to 1 year postoperatively, and stabilized after more than 1 year. Increased stool frequency and stool clustering are the most common features of abnormal bowel dys function, which improve slowly after surgery.