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Neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio are reported to reflect the inflammation and immune status in critically ill patients, but their role in severe trauma patients with persistent critical illness remains to be elucidated.We aimed to evaluate the relationship of neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio with persistent critical illness in severe trauma patients.In a single-center retrospective cohort study, persistent critical illness was defined as intensive care unit length of stay of more than 10 days. Monocyte-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio were computed individually and categorized into 3 tertiles. Logistic regression analysis was used to assess the relationship of monocyte-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with persistent critical illness. Receiver operating characteristic curves and the Youden index were used to evaluate the discriminatory threshold of persistent critical illness.A total of 851 eligible patients were enrolled in the study: 328 patients with persistent critical illness and 523 without. The median levels of maximum neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio during intensive care unit stay were all higher in patients with persistent critical illness than in those without (11.46 vs. 9.13, p.001 and 0.62 vs. 0.46, p.001). Multivariate analysis revealed that the second (≥0.385,0.693) and third (≥0.693) maximum monocyte-to-lymphocyte ratio tertiles were significantly associated with persistent critical illness after adjusting for confounding factors (odds ratio: 1.89, 95% confidence interval: 1.10-3.26, p = .021 and odds ratio 2.69, 95% confidence interval: 1.44-5.02, p = .002, respectively), whereas maximum neutrophil-to-lymphocyte ratio was not significantly correlated with persistent critical illness. The area under the curve for the maximum monocyte-to-lymphocyte ratio was 0.63 (95% confidence interval: 0.59-0.67), and the optimal cutoff was 0.65 for persistent critical illness.A high maximum monocyte-to-lymphocyte ratio during intensive care unit stay was independently related to persistent critical illness following severe trauma, although with limited sensitivity and specificity.

Background: Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is associated with high mortality and high health care costs, and there is currently no effective target treatment. Mesenchymal stem cells (MSCs) possess multipotent immunomodulatory properties. LPS-preconditioned type 1 MSCs (MSC1s) are potentially beneficial for PIICS treatment because of their proinflammatory, anti-infective, and healing properties. Here, we investigated the therapeutic efficacy and mechanisms of action of MSC1s in PIICS. Methods: We previously optimized a reaggravated PIICS mouse model, which was used in this study. PIICS mice were subjected to cecal ligation and puncture on day 1 and LPS injection on day 11. Subsequently, the mice were treated with or without MSC1s. Animal survival and phenotypes, along with the levels of catabolism, inflammation, and immunosuppression, were evaluated. MSC1s were cocultured with CD8 + T cells in vitro , and inflammatory cytokine levels and CD8 + T-cell function were assessed. Results: MSC1 transplantation alleviated weight loss and muscle wasting, inhibited catabolism and inflammation, and considerably improved the proportion and function of CD8 + T cells in the PIICS mice. After coculture with MSC1s, the expression levels of CD107a and interferon γ increased, whereas the expression level of programmed death 1 decreased significantly in CD8 + T cells. MSC1s also promoted proinflammatory cytokine secretion and reduced the concentration of soluble PD-L1 in vitro . Conclusions: MSC1s can protect mice against critical PIICS, partly by enhancing CD8 + T-cell function. Therefore, MSC1 transplantation is a novel therapeutic candidate for PIICS.

In this study, we used public databases to investigate the prognostic significance of epigenetic regulatory gene expression in patients with non small-cell lung cancer (NSCLC). Oncomine database analysis showed that the mRNA levels of seven epigenetic regulatory genes, UHRF1, EZH2, TTF2, SUV39H2, PCNA, WHSC1 and RAD54L, genes were significantly upregulated in NSCLC patients as compared to normal lung tissues. Functional enrichment analysis of these seven genes showed that the most enriched GO terms were DNA repair and rhythmic process, whereas, the most enriched KEGG pathway was lysine degradation pathway. The mRNA and protein expression levels of UHRF1, EZH2, TTF2, WHSC1 and RAD54L significantly correlated with tumor stage in NSCLC patients. Moreover, NSCLC patients exhibiting higher UHRF1, EZH2, WHSC1 and RAD54L mRNA and protein expression levels had poorer progression-free survival and overall survival. These findings demonstrate that UHRF1, EZH2, WHSC1 and RAD54L are potential prognostic biomarkers to distinguish high-risk from low-risk NSCLC patients.

To evaluate the significance of diaphragm thickness (DT) in assessing the nutritional status and predicting the length of hospital stay (LOS) of patients with COVID-19.The data of 212 patients with severe and critical COVID-19 in Wuhan, China, were retrospectively analyzed. Computed tomography (CT)-obtained DT was measured in cross-sectional images of the mediastinal window at the level of the outlet of the celiac trunk at admission and at 2 weeks, then the rate of change in DT(RCDT) at 2 weeks was calculated. Nutritional risk and malnutrition were evaluated at admission.A total of 91 patients were involved in the study. The mean DT was 3.06±0.58 mm (3.15±0.63 mm in male and 2.93±0.50 mm in female). DT was significantly negatively correlated with malnutrition based on Global Leadership Initiative on Malnutrition (GLIM) criteria (r=-0.324, p=0.002), Nutritional Risk Screening 2002 (NRS-2002) score (r=-0.364, p=0.000) and the Malnutrition Universal Screening Tool (MUST) score (r=-0.326, p=0.002) at admission. For the prediction of LOS ≥4 weeks in patients with COVID-19, the area under the ROC curve (AUC) of the RCDT at 2 weeks was 0.772, while the AUCs of DT, NRS-2002, MUST and Nutrition Risk in Critically Ill scores at admission were 0.751, 0.676, 0.638 and 0.699 respectively. According to the model of multiple linear regression analysis, the DT at admission (β=-0.377, p=0.000), RCDT at 2 weeks (β =-0.323, p=0.001), and mechanical ventilation (β=0.192, p=0.031) were independent risk factors contributed to LOS.CT-obtained DT can be used as a dynamic assessment tool for evaluating the nutritional status of patients in isolation wards for COVID-19.

Ovarian serous carcinoma (OSC), as a common malignant tumor, poses a serious threat to women's health in that epithelial-mesenchymal transformation (EMT)-related modulation becomes heavily implicated in the invasion and progression of OSC. In this study, two core genes (BUB1B and NDC80) among the 16 hub genes have been identified to be involved in the molecular regulation of EMT and associated with the poor early survival of OSC at stages I+II. Through the Gene Regulatory Networks (GRN) analysis of 15 EMT regulators and core genes, it was revealed that TFAP2A and hsa-miR-655 could elaborately modulate EMT development of OSC. Next genetic variation analysis indicated that EMT regulator ELF3 would also serve as a crucial part in the occurrence and progression of OSC. Eventually, survival investigation suggested that TFAP2A, ELF3 and hsa-miR-655 were significantly associated with the overall survival of progressive OSC patients. Thus, combined with diversified bioinformatic analyses, BUB1B, NDC80, TFAP2A, ELF3 and hsa-miR-655 may act as the key biomarkers for early clinical diagnosis and prognosis evaluation of OSC patients as well as potential therapeutic target-points.

BACKGROUND Massive pulmonary haemorrhage can spoil the entire lung and block the airway in a short period of time due to severe bleeding, which quickly leads to death. Alveolar lavage is an effective method for haemostasis and airway maintenance. However, patients often cannot tolerate alveolar lavage due to severe hypoxia. We used extracorporeal membrane oxygenation (ECMO) to overcome this limitation in a patient with massive pulmonary haemorrhage due to severe trauma and succeeded in saving the life by repeated alveolar lavage. CASE SUMMARY A 22-year-old man sustained multiple injuries in a motor vehicle accident and was transferred to our emergency department. On admission, he had a slight cough and a small amount of bloody sputum; computed tomography revealed multiple fractures and mild pulmonary contusion. At 37 h after admission, he developed severe chest tightness, chest pain, dizziness and haemoptysis. His oxygen saturation was 68%. Emergency endotracheal intubation was performed, and a large amount of bloody sputum was suctioned. After transfer to the intensive care unit, he developed refractory hypoxemia and heparin-free venovenous ECMO was initiated. Fibreoptic bronchoscopy revealed diffuse and profuse blood in all bronchopulmonary segment. Bleeding was observed in the trachea and right bronchus, and repeated alveolar lavage was performed. On day 3, the patient’s haemoptysis ceased, and ECMO support was terminated 10 d later. Tracheostomy was performed on day 15, and the patient was weaned from the ventilator on day 21. CONCLUSION Alveolar lavage combined with ECMO can control bleeding in trauma-induced massive pulmonary haemorrhage, is safe and can be performed bedside.

Although the effect of pseudogene ANXA2P2 on some tumors has been reported in a few literatures, the therapeutic potential and prognostic value of ANXA2P2 in ovarian serous cystadenocarcinoma (OV) have not been elucidated.The correlation for ANXA2P2 expression patterns to prognostic characteristics, tumor immune microenvironment, immune cell infiltration level, tumor mutation burden (TMB), tumor microsatellite instability (MSI), drug sensitivity, and pathway function enrichment were investigated in pan-carcinomaANXA2P2 was frequently overexpressed in a variety of tumors compared with normal tissues. The correlation analysis for prognostic characteristics, tumor immune microenvironment, immune cell infiltration level, TMB, MSI, drug sensitivity, and pathway function enrichment revealed that ANXA2P2 expression patterns might deal a significant impact on the pathogenesis, development, and prognosis of various tumors. Then, GSVA, GSEA, WGCNA, gene mutation, and independent prognostic analysis for OV have indicated that high expression in ANXA2P2 could be mostly enriched in TNF-α signaling-In summary, our findings might provide a helpful foundation for prospective explorative researches, afford new strategies for the clinical treatment, deal prognosis prediction, and give new hope for OV patients.

Purpose Chlamydia psittaci infection in humans can lead to serious clinical manifestations, including severe pneumonia, adult respiratory distress syndrome, and, rarely, death. Implementation of metagenomic next-generation sequencing (mNGS) gives a promising new tool for diagnosis. The clinical spectrum of severe psittacosis pneumonia is described to provide physicians with a better understanding and to highlight the rarity and severity of severe psittacosis pneumonia. Methods Nine cases of severe psittacosis pneumonia were diagnosed using mNGS. Retrospective analysis of the data on disease progression, new diagnosis tool, treatments, and outcomes, and the findings were summarised. Results Frequent symptoms included chills and remittent fever (100%), cough and hypodynamia (100%), and headache and myalgia (77.8%). All patients were severe psittacosis pneumonia developed respiratory failure, accompanied by sepsis in 6/9 patients. mNGS takes 48–72 h to provide the results, and help to identify diagnosis of psittacosis. Laboratory data showed normal or slightly increased leucocytes, neutrophils, and procalcitonin but high C-reactive protein levels. Computed tomography revealed air-space consolidation and ground-glass opacity, which began in the upper lobe of one lung, and spread to both lungs, along with miliary, nodular, or consolidated shadows. One patient died because of secondary infection with Klebsiella pneumoniae, while the other eight patients experienced complete recoveries. Conclusions The use of mNGS can improve accuracy and reduce the delay in diagnosis of psittacosis. Severe psittacosis pneumonia responds well to the timely use of appropriate antibiotics.

Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is a growing challenge in intensive care units (ICUs). PIICS causes a severe illness with high mortality. Currently, treatment is expensive, and the outcomes are dismal. Herein, we established a PIICS model to study the disease pathophysiology and its potential treatment. Using a modified sublethal cecal ligation and puncture (CLP) to induce sepsis (day 1) and the injection of lipopolysaccharide (LPS) to induce an aggravated inflammation response (day 11), CLP + LPS mice recapitulating PIICS features were successfully generated (day 14). Adult male mice were divided into CLP + LPS, CLP + daily chronic stress (DCS), CLP, DCS, LPS, and sham control groups. A survival curve was generated, and phenotypes were analyzed using markers for catabolism, inflammation, and immunosuppression. The CLP + LPS model showed two mortality peaks (after CLP and after LPS), whereas the CLP + DCS and CLP groups showed one peak. Surviving CLP + LPS mice exhibited significantly increased catabolism and inflammatory cytokine levels and aggravated inflammation, including organ inflammation. CLP + LPS mice exhibited strong immune suppression as evidenced by decreased splenic cluster of differentiation (CD)8+ and interferon-γ+CD8+ T cell counts and a concomitant and significant increase in the myeloid-derived suppressor cell population. This CLP+LPS-induced PIICS model differs from acute sepsis models, showing two mortality peaks and a protracted course of 14 days. Compared to previous PIICS models, ours shows a re-aggravated status and higher catabolism, inflammation, and immunosuppression levels. Our aim was to use the PIICS model to simulate PIICS pathophysiology and course in the ICU, enabling investigation of its mechanism and treatment.

Background: Previous studies have demonstrated that engineered 3D stem cells could greatly increase the safety and stability as multifunctional biologics for in vivo inoculation. We designed a kind of novel 3D-pluripotent stem cell biologics which achieved promising results in animal experiments of mice and rhesus monkeys. To evaluate the safety and efficacy of this therapy in clinic, we conducted this phase I study in patients with advanced non-small-cell lung cancer (NSCLC) after standard treatment failure. Methods: Using a dose-escalation strategy, 5*106, 1*107 or 2.5*107 of 3D-pluripotent stem cells are injected subcutaneously every 7 days in a 28-day cycle for a total of 3 cycles until PD or unacceptable toxicity. Assessments includes safety and preliminary anti-tumor effects. Result: With 3 subjects in each dose-escalation, nine patients were available for clinical evaluation. All patients had experienced at least 2 lines of previous treatment (range 2-6 lines, median 3 lines). All treatment-related adverse events (AEs) were Grade 1. No dose-limiting toxicities (DLTs) were observed. The most frequent treatment-related AEs were local injection reactions and itchy skin. Six patients exhibited stable disease (disease control rate 66.7%) and 3 patients had tumor shrinkage. Two of the 9 patients obtained over-long progression-free survival (PFS) of 16.0 months and exceeded 28.3 months, respectively. Three patients are still surviving so far. Their OS time had exceeded 18.4 months (C-02), 28.3 months (A-02) and 29.4 months (A-01), respectively. For the overall, The median PFS was 16.6 weeks (95% confidence interval (95% CI), 7.0-26.2 weeks) and the median overall survival (OS) was 31.6 weeks (95% CI, 26.9-36.3 weeks). Exploratory single-cell RNA-seq analysis revealed the existence of functional NKT cells in these three patients with long-term survival. Functional NKT cells have been demonstrated by CD57/CD8 double-positive co-expression dynamics using cyclical FACS assay, with a co-expression index over 12~13% for A-02 patient lasting to the latest of 28 months after the end of treatment and over 13.8% for C-02 patient for a duration about 12 months and declined shortly before disease progression. Conclusion: Our study proves the clinic safety and preliminary efficacy of 3D-pluripotent stem cell biologics in the clinic. The final dose of 2.5*107 3D stem cells injected every 7 days in a 28-d cycle was well tolerated. This protocol has a promising prospect with the characteristics of low toxicity and exceptional efficacy to convert the utility to long-term survival. Functional NKT cells may play a key role in this therapy by MHC unrestricted immunocompetence. Citation Format: Meijuan Huang, Xiancheng Chen, Yi Qin, Yaling Long, Qian Li, Yanna Zhang, Min Yu, Panyan Hou, Nanxi Liu, Yanying Li, Yang Yu, Xiaojuan Zhou, Youling Gong, Ke Wang, Jiang Zhu, Feng Peng, Yongsheng Wang, You Lu, Yuquan Wei. A phase I clinical trial of 3D-pluripotent stem cell biologics in heavily treated advanced NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT510.

Background Epileptic seizures are common symptoms in brain arteriovenous malformation patients and seizure control was an important issue in the treatments. This retrospective study attempted to define the risk factors of seizure presentation and to evaluate the effects of treatment modalities on seizure outcomes. Methods Patients receiving single treatment modality during 2013-2016 years, followed up more than 2 years were recruited. Logistic regression analysis was used to detect independent predictors. The factors associated with seizure control were analyzed in patients with pre-treatment seizures, and the factors associated with de novo seizures were analyzed in patents without pre-treatment seizures. Results Multivariate analysis identified that the independent predictors of seizure presentation were unruptured (ruptured vs. unruptured, OR =0.314), and in the frontal (frontal vs. parietal, OR =3.982) or temporal lobe (temporal vs parietal, OR =3.313). In 47 patients with seizure presentation, good seizure outcomes were achieved in 26 cases. Partial obliteration of nidus (partial vs complete, OR =32.301) and headache presentation were independent predictors of poor outcome. In 169 patients without seizure presentation, de novo seizures occurred in 22 cases. Treatments of microsurgery or radiosurgery led to a higher incidence of de novo seizures than intravascular embolization. Conclusions Patients with unruptured and frontal/temporal lobe located nidus were more likely to manifest seizure presentation. Incomplete nidus obliteration was an independent risk factor of poor outcomes in patients with pre-existing seizures. However, compared to microsurgery or radiosurgery, endovascular embolization was less likely to cause de novo seizures in patients without pre-existing seizures.

AIM To investigate whether conicity index, abdominal volume index, body adiposity index, body roundness index, cardiometabolic index and lipid accumulation product compared with waist circumference could predict future diabetes in a 15-year prospective study. METHODS The data were collected in 1992 and recollected in 2007 from the same group of 687 individuals. Anthropometric indices and biochemical data were obtained. Cox's proportional hazards regression models were used to estimate the hazard ratios of anthropometric measures. The discriminatory power of anthropometric measures for incident diabetes were assessed by Harrell's C-statistic. RESULTS During follow-up, 74 participants were newly diagnosed with diabetes. In multivariable Cox regression analysis after adjusting potential for confounders, log10 -conicity index [HR: 1.67 (95% CI: 1.31-2.11) per sd; P < 0.0001], log10 -abdominal volume index [HR: 1.95 (95% CI: 1.50-2.55) per sd; P < 0.0001], log10 -body adiposity index [HR: 1.82 (95% CI: 1.33-2.50) per sd; P < 0.0001], log10 -body roundness index [HR: 2.16 (95% CI: 1.63-2.88) per sd; P < 0.0001], log10 -cardiometabolic index [HR: 1.70 (95% CI: 1.39-2.09) per sd; P < 0.0001], log10 -lipid accumulation product [HR: 2.06 (95% CI: 1.56-2.73) per sd; P < 0.0001] and log10 -waist circumference [HR: 1.99 (95% CI: 1.51-2.46) per sd; P < 0.0001] were significantly associated with incident diabetes. Additionally, lipid accumulation product had the highest Harrell's C-statistic at 0.715 (95% CI: 0.656-0.775), followed by body roundness index at 0.714 (95% CI: 0.658-0.770) and cardiometabolic index at 0.704 (95% CI: 0.643-0.764) then by waist circumference at 0.701 (95% CI: 0.644-0.759). CONCLUSIONS Conicity index, abdominal volume index, body adiposity index, body roundness index, cardiometabolic index and lipid accumulation product were independent predictors of future diabetes. The discriminatory power of body roundness index, cardiometabolic index and lipid accumulation product for diabetes prediction were higher than that of waist circumference.

Cancer-initiating/sustaining stem cell subsets (CSCs) have the potential to regenerate cancer cell populations and are resistant to routine therapeutic strategies, thus attracting much attention in anticancer research. In this study, an innovative framework of endogenous microenvironment-renewal for addressing such a dilemma has been just developed. CSCs in three-dimensional multipotent spheroid-engineered biologics were prepared with 150 Gy radiation and inoculated into 15-mo-old BALB/c and C57BL/6 mice bearing diverse advanced tumors covering Mammary 4T1, liver Hepa, lung LL/2, and colon C26 tumors and distant metastases. Subsequently, the systematic microenvironment of tumor-bearing hosts was rapidly remodeled to resettle thymic cortex and medulla rudiment as an endogenous foxn1-thymosin reprogramming TCR-repertoire for resetting MHC-unrestricted multifunction renewal. Postrenewal Vγ4γδT-subsets would bind and lead migrating CSCs into apoptosis. Moreover, TCR repertoire multifunction renewal could reverse tumor metastases from tumoricidal resistance into eventual regression as a blockade of cancer-sustaining Bmi-1/Nanog-Oct4-Sox2 renewal loop with sequent multivalent depletion of both migrating/in situ CSCs and non–stem terminal cancer cell subsets. This study represents a promising start to set up a generalizable strategy of three-dimensional biologics evoking an endogenous integral microenvironment into pluripotent renewal versus advanced cancer.

Endoplasmic reticulum stress (ERS) plays a vital role in mediating apoptosis in the brain following cardiac arrest (CA). Studies have shown that therapeutic hypothermia (TH) provides neuroprotection through anti-apoptosis; however, the effects of temperature variability in TH on the brain remain unclear. In this study, we investigated the different effects of temperature variability through extracorporeal membrane oxygenation on apoptosis and ERS in the brain following CA. Eighteen male domestic pigs underwent 6-min duration of no-flow induced by ventricular fibrillation. Extracorporeal cardiopulmonary resuscitation was then performed, and the return of spontaneous circulation (ROSC) was achieved. The animals were randomly assigned to the following groups: normothermia, non-temperature variability, and temperature variability. TH (core temperature, 33–35 °C) was maintained for 24 h post-ROSC, and the animals were rewarmed for 8 h. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry for Bax and Bcl-2 transcripts and proteins, respectively, were used to investigate apoptosis in the cerebral cortex. Expression levels of the ERS molecules, GRP78 and CHOP, were also detected by qRT-PCR, and cellular morphology was evaluated using transmission electron microscopy. qRT-PCR and immunohistochemistry results revealed that TH significantly increased the expression levels of Bcl-2 and GRP78 and decreased that of Bax and CHOP than under normothermia conditions. Compared to the non-temperature variability group, temperature variability did not decrease the expression levels of Bcl-2 and GRP78 and not increase the levels of Bax and CHOP. Endoplasmic reticulum ultrastructural changes were significantly improved under TH. No statistical difference was observed between the temperature variability and non-temperature variability groups. TH can reduce neuronal apoptosis by ERS, while temperature variability does not attenuate this beneficial effect.

So far, thymus involution in adults is believed to be irreversible, and endogenous innovation for thymus‐related immunodeficiency remains to be an intractable puzzle. With the expectation of addressing this dilemma, human ovarian surface epithelium (OSE) has been reengineered as epithelial‐mesenchymal transition (EMT)‐tridimensional‐spheroid biologics (ETSB) using a dynamic EMT‐3D‐floating system along with 160 Gy X‐ray‐amelioration, which inoculates subcutaneously into aging rhesus and athymic Balb/cnu/nu mice. Herein, it is bioinformatically validated that ETSB can reset Clock/Arntl‐Per3/Tim molecule rhythm dynamics to re‐prime thymus residual (parathyroid or fatty‐like invalid vesicles yet no thymic architecture) to evolutionary transcription with overall cortex‐medulla endogenized by TECs undergoing MET/EMT reversion. Rhythm dynamics immediately resettles the bHLH‐LTβR‐NFκB‐RelA/B loop as a cascade to provoke the core immune microenvironment for multifunctional innovation of dynamic TCR orchestration, with harmonious naïve T‐subsets and TRECs renewals (P < 0.005). Subsequently, peripheral biological burden and tumor metastasis dynamics are addressed by innovative TCR‐defense/attack dynamics quickly (P < 0.005 vs Control), yet without autoimmune indication to hosts. Moreover, a functional blockade of core‐rhythm dynamics deeply impedes the endogenous innovation of invalid thymus residual. Thus this study may help pioneer a prospective strategy to innovate panoramic central‐peripheral immune microenvironments and defense dynamics for immune‐deficient/aging victims., Epithelial‐mesenchymal transition (EMT)‐tridimensional‐spheroid biologics (ETSB) could reset Clock/Arntl‐Per3/Tim molecule rhythm dynamics to reprime thymus residual (parathyroid or fatty‐like invalid vesicles yet no thymic architecture) to evolutionary transcription with overall cortex‐medulla endogenized by thymic epithelial cells (TECs) undergoing MET/EMT reversion. Rhythm dynamics immediately resettles bHLH‐LTβR‐NFκB‐RelA/B loop as cascade to provoke core immune microenvironment for multifunctional innovation of dynamic TCR orchestration, with harmonious naïve T‐subsets and T cell receptor excision circles (TRECs) renewals.

Multidrug-resistant (MDR) bacterial infection is a common complication of severe acute pancreatitis (SAP). This study aimed to explore the association between human leukocyte antigen-antigen D-related (HLA-DR) expression and multidrug-resistant infection in patients with SAP. A total of 24 SAP patients who were admitted to Nanjing Drum Tower Hospital between May 2015 and December 2016 were enrolled in the study. The percentages of CD4+, CD8+, natural killer (NK), and HLA-DR (CD14+) cells and the CD4+/CD8+ cell ratio on days 1,7,14, and 28 after admission were determined by flow cytometry. Eighteen patients presented with the symptoms of infection. Among them, 55.6% patients (10/18) developed MDR infection. The most common causative MDR organisms were Enterobacter cloacae and Acinetobacter baumannii. The CD4+/CD8+ cell ratio and the percentage of NK cells were similar between patients with non-MDR and patients with MDR infections. In patients without infection, the HLA-DR percentage was maintained at a high level throughout the 28 days. Compared to the patients without any infection, the HLA-DR percentage in patients with non-MDR infection was reduced on day 1 but increased and reached similar levels on day 28. In patients with MDR infection, the HLA-DR percentage remained below normal levels at all-time points. It was concluded that persistent down-regulation of HLA-DR expression is associated with MDR bacterial infection in patients with SAP.

OBJECTIVEMalignant meningioma is rare and classified as Grade III in the WHO classification of CNS tumors. However, the presence of estrogen receptor (ER) in WHO Grade III meningiomas and its correlation with patients’ outcomes are still unclear. In this single-center cohort study, the authors analyzed clinical features, treatment, and prognosis of these malignant tumors in patients with long-term follow-up.METHODSA total of 87 patients who were pathologically diagnosed with WHO Grade III meningiomas between 2003 and 2008 were enrolled in this study and followed for at least 7 years. Clinical information was collected to analyze the factors determining the prognosis.RESULTSTwelve patients with rhabdoid, 12 with papillary, and 63 with anaplastic meningioma were included. The mean progression-free survival (PFS) and overall survival (OS) were 56.2 ± 49.8 months and 68.7 ± 47.4 months, respectively. No significant differences were observed among the 3 histological subtypes in either PFS (p = 0.929) or OS (p = 0.688). Patients who received gross-total resection had a longer PFS (p = 0.001) and OS (p = 0.027) than those who received subtotal resection. Adjuvant radiotherapy was associated with OS (p = 0.034) but not PFS (p = 0.433). Compared with primary meningiomas, patients with recurrent disease had worse PFS (p < 0.001). For patients who had malignant transformations, the prognosis was poorer than for patients without malignant transformations for both PFS (p = 0.002) and OS (p = 0.019). ER-positive patients had a significantly worse prognosis than ER-negative patients regarding both PFS (p = 0.003) and OS (p < 0.001), whereas no association between progesterone receptor and patients’ outcomes was observed. Multivariate analysis demonstrated that ER expression was an independent prognostic factor for both PFS (p = 0.008) and OS (p < 0.001).CONCLUSIONSThis retrospective study showed that patients with meningioma with ER-positive expression had a much worse prognosis than those with ER weak–positive or ER-negative status. The results demonstrated that ER is an independent prognostic factor for both PFS and OS of patients with WHO Grade III meningioma. The authors also found that more radical resection of the tumor, as well as postoperative radiotherapy, may prolong patients’ survival time.

Objectives To explore the endocrine profiles during the development from endometrial hyperplasitic disease to endometrial cancer (EC). Methods A prospective study in the Obstetrics and Gynecology Hospital of Fudan University from September 2011 to Nov 2018 was conducted. A total of 1874 cases were enrolled, including 764 cases of healthy women, 145 cases diagnosed with disordered proliferative endometrium (DPE), 250 cases with simple hyperplasia (SH), 200 cases with complex hyperplasia (CH), 259 cases with endometrial atypical hyperplasia (EAH), 256 cases of EC. Profiles of BMI and sex hormone levels (Estrodiol, P, T, FSH, LH, SHBG and E2/SHBG) were analyzed and compared in different groups. Multiple linear regression analysis was done to control for the counfounding factor, age. Results Physiologically, text-book hormonal profiles were confirmed with our study in control group as shown below. Estradiol elevation only took place in pre-cancerous stage. However, progesterone trend is a bit delayed, the significant difference totally vanished until the stage EEC G2, which stage is also a contraindication for conservative treatment with high potency progestins. No significant difference was found for free estrogen level (FEI) in different groups compared with the control. BMI gradually increases and peaks at EEC (G1, G2), and this group of patients was the only group with both median and mean BMI> 25kg/m2, aka, overweight. Conclusions “Guider Effect Model” was hypothesized that E2 in here is as a guider in theater, once cancer cells gain carnogenic mutation,(seated in cancer), the guider just left immediately, while other hormones will be interpreted in presentation d/t word limit

Objective The aim of this study was to investigate delayed complications in patients with brain arteriovenous malformation (BAVM) after Gamma Knife stereotactic radiosurgery and to present the salvage therapy experiences of patients with BAVM with radiation-induced changes (RICs) or intracranial hemorrhage (ICH). Methods This cohort consisted of 44 patients with BAVM who underwent failed GKRS between 2000 and 2015. These patients were further divided into an RIC group (23 patients) and an ICH group (21 patients) based on their post-GKRS complications. The patients' characteristics, treatment strategies, and long-term outcomes were analyzed. The modified Rankin Scale was used to assess the neurologic status of each patient. Results In our study, the marginal dose and radiosurgery-based arteriovenous malformation score were not significantly different between the 2 groups. Craniotomy was performed in 26 patients (9 patients with ICH and 17 patients with RICs), and histologic examination showed cavernous angioma changes in 6 patients. In addition, 6 patients underwent repeat radiosurgery in the ICH group, and 7 patients used bevacizumab in the RIC group. Thirty patients showed good outcomes at the last follow-up (modified Rankin Scale score Conclusions Salvage therapy for patients with BAVM should be performed based on the latency period and lesion characteristics of each individual. Prompt treatment and a longer follow-up are recommended to achieve good clinical outcomes.

Background Intraoperative ultrasonography is widely used in neurosurgery for the management of intracerebral hematoma and brain tumor. However, the clinical value of this method in the surgery of cerebral arteriovenous malformations (AVMs) has not been reported. In this study, the application of intraoperative ultrasonography for AVM surgery was evaluated prospectively. Methods This prospective clinical study comprised 41 patients who underwent microsurgical resection of cerebral AVMs at our institute. After routine craniotomy, ultrasonographic imaging with color Doppler ultrasonography and real-time contrast-enhanced ultrasonographic angiography if necessary were applied as navigated images on the monitor during the operation. Results Ultrasonographic imaging made it easier to understand the vascular architecture during the operation. Color Doppler flow imaging clearly delineated the shape and margin of the AVMs. Intraoperative real-time contrast-enhanced ultrasonographic angiography enabled the surgeons to categorically identify AVM feeders both on the surface and deep in the tissue. Conclusions Microneurosurgery with intraoperative ultrasonographic image guidance was a safe, effective, and reliable method for identifying the afferent and efferent vessels and for confirming the complete resection of AVMs. These benefits of image-guided microsurgery were mostly apparent for deep-seated AVMs that were not visible on the surface of the brain.

Severe pneumonia caused by influenza virus infection can be secondary to invasive pulmonary fungal (IPF) infection. This study aimed to summarize the incidence of IPF infection secondary to influenza virus infection and further explore its etiologic mechanism and high-risk factors. All adult patients with confirmed influenza A (H1N1) virus infection admitted to the intensive care units (ICUs) of Nanjing Drum Hospital from November 2017 to March 2018 were retrospectively selected. The differences in baseline factors, risk factors, immune function and outcome parameters were studied between patients with and without IPF. Of the 19 critically ill patients with H1N1 infection, 11 (57.9%) developed IPF infection after 7 days of ICU admission. Two patients had proven and nine probable IPF infection. A difference in human leukocyte antigen–DR isotype (△HLA-DR; day 7–day 1) was found between the two groups. △HLA-DR (day 7–day 1) was higher in patients with no IPF infection than in those with IPF infection [(14.52 ± 14.21)% vs ( − 11.74 ± 20.22)%, P = 0.019]. The decline in HLA-DR indicated impaired immune function secondary to fungal infection in patients with H1N1 infection. IPF infection was diagnosed in 57.9% of critically ill patients with H1N1 virus infection after a median of 7 days following ICU admission. A continuous decline in immune function could lead to the development of IPF infections. Dynamic monitoring of immune function may help in the early detection of IPF infection.

Yan-na Zhang, Xiao-gang Duan, Wen-hui Zhang, Ai-ling Wu, Huan-Huan Yang, Dong-ming Wu, Yu-Quan Wei, Xian-cheng Chen State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China Abstract: Cancer stem cells (CSCs) are critical for tumor initiation/maintenance and recurrence or metastasis, so they may serve as a potential therapeutic target. However, CSC-established multitherapy resistance and immune tolerance render tumors resistant to current tumor-targeted strategies. To address this, renewable multiepitope-integrated spheroids based on placenta-derived mesenchymal stem cells (pMSCs) were X-ray-modified, at four different irradiation levels, including 80, 160, 240, and 320Gy, as pluripotent biologics, to inoculate hosts bearing Lewis lung carcinoma (LL2) and compared with X-ray-modified common LL2 cells as control. We show that the vaccines at the 160/240Gy irradiation levels could rapidly trigger tumor cells into the apoptosis loop and evidently prolong the tumor-bearing host’s survival cycle, in contrast to vaccines irradiated at other levels (P

Aim: To analyze the clinicopathological features of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 RCC) in our institution. Materials & methods: We screened 983 RCC specimens. TFE3 immunohistochemical staining and FISH assay confirmed 22 Xp11.2 RCCs out of 65 suspicious cases. Clinicopathological and treatment outcomes of 22 patients were retrospectively analyzed. Results: In total, 22 patients included 13 females and nine males with a mean age of 27 years. Ten patients showed gross hematuria. Treatments included surgeries, immunotherapy and molecular-targeted therapy. Seven cases were at stage III/IV and four cases had tumor thrombosis or distant metastasis. During a median follow-up of 34 months, 19 patients were alive while three died of distant metastasis. Conclusion: Xp11.2 RCC is rare and FISH proved a useful diagnostic tool. Surgical resection achieved favorable outcome for early disease. Adult patients at advanced stage had poorer outcomes even with postoperative adjuvant therapy.

CSCs are able to survive routine anticancer procedures and peripheral-immune attack. Here we develop and detail a framework of CSC elimination governed by 3D-biologics. Pluripotent cells-engineered 3D-biologics (PMSB) and control non-3D-biologics were prepared from placenta-based somatic stem cells (PSCs) and inoculated respectively into senile hosts bearing progressive mammary, lung, colon carcinomas and melanoma. We demonstrate that PMSB evokes in vivo central-immune microenvironment with subsequent re-expression of thymosin-α1 ~ β4 in thymic cortex-medulla borderline for rapid MHC-unrestricted renewal of γδT-dominated immunocompetence. The post-renewal γδT-subsets could accurately bind and drive CSCs into apoptosis. Finally, with central/peripheral integral microenvironment renewal and TERT/Wnt/β-catenin pathway blockade, the CSC-subsets are fully depleted, leading to substantial cure of diverse tumors by PMSB inoculation (P < 0.01), yet not by non-3D-biologics. Thus, our study may contribute to open up a new avenue for tumor remission via pluripotent cells-engineered 3D-biologics addressing quick renewal of central-thymus and peripheral immune-microenvironment.

Introduction Severe fever with thrombocytopenia syndrome (SFTS) has been prevalent in parts of Asia during recent years. However, SFTS with invasive pulmonary aspergillosis (IPA) is rare, and it is important to understand its clinical features. Materials and methods Total four cases of SFTS with IPA are reviewed and detailing the disease progression, treatment options, and prognosis were summarized and analyzed. Results The patients with SFTS-associated IPA first presented with fever, gastrointestinal symptoms, thrombocytopenia, leukopenia, and multiple organ failure. After 1–2 weeks, the patients developed mild polypnea and wheezing rales, and quickly developed dyspnea and respiratory failure. Tracheal intubation was usually performed, but did not relieve the intractable airway spasm and pulmonary ventilation failure. Bronchoscopy confirmed that the antifungal treatment was ineffective and the aspergillosis had worsened. All patients died of type 2 respiratory failure caused by continued airway obstruction and spasticity. Conclusions Given the high mortality rate in this series, there is a need for increased awareness of SFTS-associated IPA. Additional examinations should be performed in these cases, and early-stage antifungal treatment with organ support may be helpful.

Ischemic diseases represent a challenging worldwide health burden. The current study investigated the therapeutic potential of genetically modified human placenta-derived mesenchymal stem cells (hPDMSCs) with basic fibroblast growth factor (FGF2) and platelet-derived growth factor-BB (PDGF-BB) genes in hindlimb ischemia. Mesenchymal stem cells obtained from human term placenta were transfected ex vivo with adenoviral bicistronic vectors carrying the FGF2 and PDGF-BB genes (Ad-F-P). Unilateral hindlimb ischemia was surgically induced by excision of the right femoral artery in New Zealand White rabbits. Ad-F-P genetically modified hPDMSCs, Ad-null (control vector)-modified hPDMSCs, unmodified hPDMSCs or media were intramuscularly implanted into the ischemic limbs 7 days subsequent to the induction of ischemia. Four weeks after cell therapy, angiographic analysis revealed significantly increased collateral vessel formation in the Ad-F-P-hPDMSC group compared with the control group. Histological examination revealed markedly increased capillary and arteriole density in the Ad-F-P-hPDMSC group. The xenografted hPDMSCs survived in the ischemic tissue for at least 4 weeks subsequent to cell therapy. The current study demonstrated that the combination of hPDMSC therapy with FGF2 and PDGF-BB gene therapy effectively induced collateral vessel formation and angiogenesis, suggesting a novel strategy for therapeutic angiogenesis.

Angiomatous meningioma (AM) is a rare subtype of meningioma characterized by highly vascular tumor tissue comprising predominantly variable sized hyalinized blood vessels. The aim of this study is to evaluate the clinical radiologic features of AM and the long-term prognosis in a single neurosurgical center.A total of 93 patients who underwent surgical resection of AMs between 2003 and 2008 were enrolled for analysis. Clinical information, treatment, and radiologic images were collected and analyzed; follow-up was carried out as well. Expression of estrogen receptor, progesterone receptor, and vascular endothelial growth factor was analyzed by immunohistochemistry.Forty-eight females and 45 males were identified. Forty-four patients (47.31%) manifested as hypersignal in T1-weighted imaging sequences and 68 (73.12%) as hypersignal in T2-weighted imaging, and a characteristic ringlike signal was observed in 28 patients (30.11%). Eighty-one cases (87.10%) showed different degrees of peritumor brain edema and it was significantly correlated with the vascular endothelial growth factor expression (P 0.001). Simpson I resection was achieved in 63 patients (67.74%), grade II in 27 patients (29.03%), and grade III in 3 patients (3.23%). The extent of resection was not associated with the postoperative neurologic function (P = 0.546). Only 4 patients experienced recurrences during the follow-up and these 4 patients were stable until the last follow-up.AMs were a special subtype of meningioma with distinctive radiologic features. AMs manifest benign behavior with a satisfying outcome, which makes Simpson grade II resection an option.

Meningiomas are the most common primary tumors in central nervous system. While recent studies have revealed genetic clues to lower grade human meningiomas, the molecular determinants driving the progression and recurrence of anaplastic meningioma, the most malignant subtype with a low prevalence but high morbidity, are still poorly understood. It has been proposed that high recurrence rates of malignant meningiomas are linked to cancer stem cells. Indeed, tumor stem-like cells have been isolated from various meningioma subtypes, but never been obtained from anaplastic meningioma. In this study, we successfully isolated stem-like cells from human anaplastic meningioma. These cells are capable of forming spheres and initiating xenograft tumors that recapitulate anaplastic meningioma phenotypes, and thus could serve as an in vitro model for malignant meningiomas. KLF4, a transcription factor known for its role in stemness maintenance, was identified as one of the most frequently mutated genes in the benign secretory meningioma. Interestingly, we found that KLF4 is downregulated in anaplastic meningioma compared with low-grade meningioma subtypes. By manipulating KLF4 expression in anaplastic meningioma stem-like cells, we demonstrated that KLF4 acts as a tumor suppressor during malignant progression in meningioma, affecting apoptosis, proliferation, invasion, and cell cycle. These results suggest a potential therapeutic value of KLF4 for clinical intervention of anaplastic meningioma.

Despite of the immense breakthroughs of induced pluripotent stem cells (iPSCs), clinical application of iPSCs and their derivates remains hampered by a lack of definitive in vivo studies. Here, we attempted to track iPSCs-derived neural stem cells (NSCs) in the rodent and primate central nervous system (CNS) and explore their therapeutic viability for stem cell replacement in traumatic brain injury (TBI) rats and monkeys with spinal cord injury (SCI). Superparamagnetic iron oxide (SPIO) particles were used to label iPSCs-derived NSCs in vitro. Labeled NSCs were implanted into TBI rats and SCI monkeys 1 week after injury, and then imaged using gradient reflection echo (GRE) sequence by 3.0T magnetic resonance imaging (MRI) scanner. MRI analysis was performed at 1, 7, 14, 21, and 30 days, respectively, following cell transplantation. Pronounced hypointense signals were initially detected at the cell injection sites in rats and monkeys and were later found to extend progressively to the lesion regions, demonstrating that iPSCs-derived NSCs could migrate to the lesion area from the primary sites. The therapeutic efficacy of iPSCs-derived NSCs was examined concomitantly through functional recovery tests of the animals. In this study, we tracked iPSCs-derived NSCs migration in the CNS of TBI rats and SCI monkeys in vivo for the first time. Functional recovery tests showed obvious motor function improvement in transplanted animals. These data provide the necessary foundation for future clinical application of iPSCs for CNS injury.