C8-ceramide modulates microglia BDNF expression to alleviate postoperative cognition dysfunction via PKCδ/NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is a kind of serious postoperative complication in surgery with general anesthesia and it may affect patients' normal lives. Activated microglia are thought to be one of the key factors in the regulation of POCD process. Once activated, resident microglia change their phenotype and secrete kinds of cytokines to regulate inflammatory response in tissues. Among these secretory factors, brain-derived neurotrophic factor (BDNF) is considered to be able to inhibit inflammation response and protect nervous system. Therefore, the enhancement of BDNF expression derived from resident microglia is suggested to be potential treatment for POCD. In our study, we focused on the role of C8-ceramide (a kind of interventional drug) and assessed its regulatory effect on improving the expression of BDNF secreted from microglia to treat POCD. According to the results of our study, we observed that C8-ceramide stimulated primary microglia to up-regulate the expression of BDNF mRNA after being treated with lipopolysaccharide (LPS) in vitro. We proved that C8-ceramide had ability to effectively improve POCD of mice after being accepted carotid artery exposure and their abnormal behavior recovered better than that of mice from the surgery group. Furthermore, we also demonstrated that C8-ceramide enhanced the cognitive function of mice via the PKCδ/NF-κB signaling pathway. In general, our study has confirmed a potential molecular mechanism that led to the occurrence of POCD caused by surgery and provided a new clinical strategy to treat POCD.

Development and validation of a nomogram for predicting the overall survival in non-small cell lung cancer patients with liver metastasis.

Background: Among all metastatic lesions in non-small cell lung cancer (NSCLC), liver metastasis (LM) is the most lethal site with a median survival of less than 5 months. Few studies exclusively report on prognostic factors for these unique patients. We aimed to construct and validate a practical model to predict the prognosis of NSCLC patients with LM. Methods: Cases of NSCLC with LM diagnosed between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database, and were randomly split into training and validation cohort (7:3). The overall survival (OS) was measured from diagnosis until date of death or last follow-up. Cox regression analyses were performed to identify potential predictors of the model. A nomogram incorporating those independent factors was constructed and validated by the concordance index (C-index) and calibration plots. The decision curve analysis (DCA) and a risk stratification system were used to evaluate its clinical value. Results: A total of 2,367 cases were selected for analysis and randomized to the training cohort (n=1,677) and the validation cohort (n=690). The patients were mainly male (59.3%), married (83.1%) and White (77.3%). Apart from LM, 54.2%, 26.7%, and 36.7% of patients also present with bone, brain, and lung metastases, respectively. The median follow-up was 4.0 months for all patients and 23 months for alive cases. The median OS was 5 months [interquartile range (IQR), 2-11 months]. Sex, age, race, grade, T stage, bone metastasis, brain metastasis, surgery, and chemotherapy were identified as the independent risk factors of the OS and used to develop the nomogram. The calibration curves exhibited excellent agreement between the predicted and actual survival in both the training and validation set, with a C-index of 0.700 [95% confidence interval (CI): 0.684-0.716] and 0.677 (95% CI: 0.653-0.701), respectively. The DCA and the risk classification system further supported that the prediction model was clinically effective. Conclusions: This is the first study to build a prediction model for NSCLC patients with LM. It aids in treatment decisions, focused care, and physician-patient communication. The global prospective data is needed to further improve this model.

Case Report: ICIs-induced Guillain-Barré syndrome recovered from mycophenolate mofetil.

The emergence of immune checkpoint inhibitors (ICIs) has significantly prolonged the survival time of cancer patients. However, it may also lead to various immune-related adverse events (irAEs), including Guillain-Barré syndrome (GBS), a rare type of irAE. Most GBS patients can recover spontaneously due to the self-limited nature of the disease, but severe cases can result in respiratory failure or even death. Here we report a rare case of GBS occurring in a 58-year-old male patient with non-small cell lung cancer (NSCLC) who developed muscle weakness and numbness of the extremities during chemotherapy combined with KN046, a PD-L1/CTLA-4 bispecific antibody. Despite receiving methylprednisolone and γ-globulin, the patient's symptoms did not improve. However, there was significant improvement after treatment with mycophenolate mofetil (MM) capsules, which is not a routine regimen for GBS. To the best of our knowledge, this is the first reported case of ICIs-induced GBS that responded well to mycophenolate mofetil instead of methylprednisolone or γ-globulin. Thus, it provides a new treatment option for patients with ICIs-induced GBS.

Combination of Cefotaxime and Cisplatin Specifically and Selectively Enhances Anticancer Efficacy in Nasopharyngeal Carcinoma.

BACKGROUND: HMOX1 has a dual role in cancers, especially involving chemoresistance. We demonstrate that cephalosporin antibiotics exert strong anticancer activity in nasopharyngeal carcinoma mainly via drastic upregulation of HMOX1. OBJECTIVES: Cephalosporin antibiotics are commonly used for the treatment or prophylaxis of bacterial infectious diseases in cancer patients. It is unknown whether they lead to chemoresistance in cancer patients, especially in nasopharyngeal carcinoma patients, who are being treated or required prophylaxis for an infectious syndrome with cephalosporin antibiotics. METHODS: MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cancer cells. Flow cytometry was used to detect apoptosis. Tumor growth was assessed using a xenograft model. Microarray and RT-qPCR expression analyses investigated differential gene expression. RESULTS: Cefotaxime enhanced anticancer efficacy of cisplatin in nasopharyngeal carcinoma without enhancing the toxic side effects both in vitro and in vivo. However, cefotaxime significantly reduced the cytotoxicity of cisplatin in other cancer cell lines. Cefotaxime and cisplatin co-regulated 5 differential genes in CNE2 cells in a direction supporting the enhancement of anticancer efficacy, of which, THBS1 and LAPTM5 were further upregulated, STAG1, NCOA5, and PPP3CB were further downregulated. Out of the 18 apoptotic pathways significantly enriched in the combination group, THBS1 and HMOX1 overlapped in 14 and 12 pathways, respectively. Extrinsic apoptotic signaling pathway (GO: 2001236) was the only apoptotic pathway commonly enriched in cefotaxime group, cisplatin group and combination group, and THBS1 and HMOX1 were the overlapped genes of this pathway. THBS1 also overlapped in P53 signaling pathway and ECM-receptor interaction signaling pathway enriched by KEGG. CONCLUSION: Cephalosporin antibiotics are chemosensitizers of conventional chemotherapeutic drugs in the chemotherapy of nasopharyngeal carcinoma, but they may lead to chemoresistance by cytoprotection in other cancers. Cefotaxime and cisplatin co-regulate THBS1, LAPTM5, STAG1, NCOA5 and PPP3CB suggesting their involvement in the enhancement of anticancer efficacy in nasopharyngeal carcinoma. Targeting of P53 signaling pathway and ECM-receptor interaction signaling pathway was correlated to the enhancement. With additional benefit for treatment or prophylaxis of an infectious syndrome, cephalosporin antibiotics can benefit the therapy of nasopharyngeal carcinoma either as anticancer agents or as chemosensitizers of chemotherapeutic drugs in combination chemotherapy.

Study on the role of immune­related genes after intracranial subarachnoid hemorrhage.

We aimed to screen the feature genes related to subarachnoid hemorrhage (SAH). The datasets (GSE73378 and GSE36791) were downloaded from National Center for Biotechnology Information database. Limma package in R was used to screen the differentially expressed genes (DEGs). Single sample gene set enrichment analysis algorithm was used to evaluate the type of immune infiltration. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to analyze function of DEGs. The support vector machine (SVM) was used to constructed classifier, which was evaluated using receiver operating characteristic curves. The E­TABM­421 was used to verify the DEGs related to immunity and the classifier. Seven types of immune cells with significant differences were screened, such as activated CD8 T cell and center memory CD4 T cell. We then obtained 408 DEGs related to immune cell. Subsequently, 10 overlapped KEGG pathways related to the DEGs were obtained, such as hematopoietic cell lineage, NOD­like receptor signaling pathway and T cell receptor signaling pathway. Finally, 9 DEGs related to immune cells (CCL5, CD27, CD3D, CREB5, FYN, ITPR3, TAB1, NCR3 and S1PR5) were screened to constructed SVM classifier. The area under the curve was 0.865 in training dataset and the AUC was 0.75 in the validation set. A SVM classifier based on the 9 DEGs (CCL5, CD27, CD3D, CREB5, FYN, ITPR3, TAB1, NCR3 and S1PR5) related to immune cells might effectively identify SAH patients or healthy people.

Combination of levofloxacin and cisplatin enhances anticancer efficacy via co-regulation of eight cancer-associated genes.

Chemosensitizer or combined chemotherapy can sensitize cancer cells to therapy and minimize drug resistance. We reveal that levofloxacin has broad-spectrum anticancer activity. Here we report that combination of levofloxacin and cisplatin further enhanced cytotoxicity in cancer cells by further promotion of apoptosis. Levofloxacin concentration-dependently promoted the inhibition of clone formation in cancer cells treated by cisplatin, and their combination further suppressed the tumor growth in mice. Levofloxacin and cisplatin co-regulated genes in directions supporting the enhancement of anticancer efficacy, of which, THBS1, TNFAIP3, LAPTM5, PI3 and IL24 were further upregulated, NCOA5, SRSF6 and SFPQ were further downregulated. Out of the 24 apoptotic pathways significantly enriched in the combination group, TNFAIP3, THBS1, SRSF6 and SFPQ overlapped in 14, 13, 3 and 1 pathway respectively. Jak-STAT/Cytokine-cytokine receptor interaction pathway network and extrinsic apoptotic signaling pathway were significantly enriched in levofloxacin group, cisplatin group and combination group. Jak-STAT/Cytokine-cytokine receptor interaction/Focal adhesion/EMC-receptor interaction pathway network was significantly enriched in the combination group, and IL24 and THBS1 were the overlapped genes. In conclusion, enhancement of anticancer efficacy in combination group was associated with the further regulation of THBS1, TNFAIP3, LAPTM5, PI3, IL24 and NCOA5, SFPQ, SRSF6. Targeting of Jak-STAT/Cytokine-cytokine receptor interaction/Focal adhesion/EMC-receptor interaction pathway network was correlated to the enhancement. With additional benefit to cancer patients for treatment or prophylaxis of an infectious syndrome, levofloxacin can benefit cancer chemotherapy no matter it is used independently or used with other chemotherapeutic drugs.

Artificial Intelligence Algorithm-Based Differential Diagnosis of Crohn's Disease and Ulcerative Colitis by CT Image.

The aim of this study was to investigate the effect of low-dose CT enterography (CTE) based on modified guided image filtering (GIF) algorithm in the differential diagnosis of ulcerative colitis (UC) and Crohn's disease (CD). Methods. One hundred and twenty patients with suspected diagnosis of IBD were studied. They were randomly divided into control group (routine CT examination) and observation group (low-dose CTE examination based on improved GIF algorithm), with 60 cases in each group. Comprehensive diagnosis was used as the standard to assess the diagnostic effect. Results. (1) The peak signal-to-noise ratio (PSNR) (26.02 dB) and structural similarity (SSIM) (0.8921) of the algorithm were higher than those of GIF (17.22 dB/0.8491), weighted guided image filtering (WGIF) (23.78 dB/0.8489), and gradient domain guided image filtering (GGIF) (23.77 dB/0.7567) (P < 0.05); (2) the diagnostic sensitivity (91.49%), specificity (92.31%), accuracy (91.67%), positive predictive value (97.73%), and negative predictive value (75%) of the observation group were higher than those of the control group (P < 0.05); the sensitivity and specificity of CTE in the diagnosis of UD and CD were 96.77% and 81.25% and 98.33% and 93.33%, respectively (P < 0.05); there were significant differences in symmetrical intestinal wall thickening and smooth serosal surface between UD and CD (P < 0.05). Conclusion. (1) The improved GIF algorithm has a more effective application value in the denoising processing of low-dose CT images and can better improve the image quality; (2) the accuracy of CTE in the diagnosis of IBD is high, and CTE is of great value in the differential diagnosis of UD and CD.

[Retracted] MicroRNA­181 serves an oncogenic role in breast cancer via the inhibition of SPRY4.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the Transwell cell migration assay data shown in Figs. 3B and 9B were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 5603­5613, 2018; DOI: 10.3892/mmr.2018.9572].

Levofloxacin exerts broad-spectrum anticancer activity via regulation of THBS1, LAPTM5, SRD5A3, MFAP5 and P4HA1.

One cost-effective way for identifying novel cancer therapeutics is in the repositioning of available drugs for which current therapies are inadequate. Levofloxacin prevents DNA duplication in bacteria by inhibiting the activity of DNA helicase. As eukaryotic cells have similar intracellular biologic characteristics as prokaryotic cells, we speculate that antibiotics inhibiting DNA duplication in bacteria may also affect the survival of cancer cells. Here we report that levofloxacin significantly inhibited the proliferation and clone formation of cancer cells and xenograft tumor growth through cell cycle arrest at G2/M and by enhancing apoptosis. Levofloxacin significantly altered gene expression in a direction favoring anticancer activity. THBS1 and LAPTM5 were dose-dependently upregulated whereas SRD5A3, MFAP5 and P4HA1 were downregulated. Pathway analysis revealed that levofloxacin significantly regulated canonical oncogenic pathways. Specific network enrichment included a MAPK/apoptosis/cytokine-cytokine receptor interaction pathway network that associates with cell growth, differentiation, cell death, angiogenesis and development and repair processes and a bladder cancer/P53 signaling pathway network mediating the inhibition of angiogenesis and metastasis. THBS1 overlapped in 16 of the 22 enriched apoptotic pathways and the 2 pathways in the bladder cancer/P53 signaling pathway network. P4HA1 enriched in 7 of the top 10 molecular functions regulated by differential downregulated genes. Our results indicate that levofloxacin has broad-spectrum anticancer activity with the potential to benefit cancer patients already treated or requiring prophylaxis for an infectious syndrome. The efficacy we find with levofloxacin may provide insight into the discovery and the design of novel less toxic anticancer drugs.

Tumor regression rate, PD-L1 expression, pembrolizumab/nab-paclitaxel-based regimens, squamous cell carcinoma, and comorbidities were independently associated with efficacy of neoadjuvant chemoimmunotherapy in non-small cell lung cancer.

Background: Neoadjuvant chemoimmunotherapy (NCIO) is more effective than neoadjuvant immunotherapy alone for pathological response in non-small cell lung cancer (NSCLC) patients, but the processes for determining patient suitability for its implementation are not clear. We aimed to identify the most relevant factors and build a convenient model to select NSCLC patients who would benefit most from NCIO. Methods:  We retrospectively collected the clinical data of patients with locally advanced NSCLC who received NCIO followed by surgery at our institution between January 2019 and July 2022. Results: A total of 101 eligible stage IIB-IIIC NSCLC patients were included. After NCIO, all patients successfully underwent surgical resection. A total of 46.53% (47/101) of patients achieved pathological complete response (pCR), and 70.30% (71/101) achieved major pathologic response (MPR). Tumor regression rate (adjusted odds ratio OR = 12.33), PD-L1 expression (adjusted odds ratio (OR) = 9.66), pembrolizumab/nab-paclitaxel-based regimens (adjusted OR = 4.92), and comorbidities (adjusted OR = 0.16) were independently associated with pCR rate (all P < 0.05). Tumor regression rate (adjusted OR = 8.45), PD-L1 expression (adjusted OR = 5.35), and presence of squamous cell carcinoma (adjusted OR = 7.02) were independently associated with MPR rate (all P < 0.05). We established and validated an easy-to-use clinical model to predict pCR (with an area under the curve [AUC] of 0.848) and MPR (with an AUC of 0.847). Of note, the present study showed that CD4+ T-cell count/rate and total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels in the peripheral blood of pre-NCIO patients were also significantly correlated with pathological response in univariate analyses. Conclusions: The tumor regression rate, PD-L1 expression, pembrolizumab/nab-paclitaxel-based regimens, presence of squamous cell carcinoma, and comorbidities were the main influential factors for incidence of pCR/MPR in patients with stage IIB-IIIC NSCLC in the present study. Through predictive models, we can predict who will benefit most from NCIO prior to the emergence of clinical outcomes in locally advanced NSCLC.

Sepsis Inflammation Impairs the Generation of Functional Dendritic Cells by Targeting Their Progenitors.

Background: Sepsis is a complex systemic immune dysfunction syndrome induced by infection. Sepsis has a high mortality rate, with most patients dying due to systemic organ failure or secondary infection. Dendritic cells (DCs) are professional antigen-presenting cells. Upon infection with microbes, DCs are activated to induce adaptive immune responses for controlling infection. DC generation and function are impaired during sepsis; however, the underlying mechanisms remain largely unknown. Methods: Peripheral blood samples from sepsis patients were collected to examine DC subsets, DC progenitors, and apoptosis of DCs by flow cytometer. In vitro induction of DCs from hematopoietic stem/progenitor cells were established and a variety of sepsis-associated inflammatory mediators [e.g., interferon-gamma (IFN-γ), interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF)] and Lipopolysaccharide (LPS) were determined for the impact on DC generation and function in vitro. Results: Our results demonstrate that sepsis-induced systemic inflammation impairs the capacity of hematopoietic stem and progenitor cells (HSPCs) to produce DCs, including conventional DCs (cDCs) and plasmacytoid DCs (pDCs). We investigated peripheral blood (PB) samples from 34 pediatric patients on days 1 to 7 following diagnosis. Compared to healthy donors (n = 18), the sepsis patients exhibited a significantly fewer percentage and number of pDCs and cDCs, and a lower expression of antigen presenting molecule HLD-DR and co-stimulatory molecules (e.g., CD86) on the surface of DCs. This sepsis-induced DC impairment was associated with significantly increased apoptotic death of DCs and marked decreases of progenitor cells that give rise to DCs. Furthermore, we observed that among the tested sepsis-associated cytokines (e.g., IFN-γ, IL-1ß, TNF-α, and G-CSF), G-CSF and IFN-γ impaired DC development from cultured HSPCs. G-CSF also markedly decreased the expression of HLA-DR on HSPC-derived DCs and their cytokine production, including IL-12 and IFN-ß. Conclusions: Collectively, these findings indicate that sepsis impairs the survival of functional DCs and their development from HSPCs. Strategies for improving DC reconstitution following sepsis may restore DC progenitors and their associated function.

TERT Promoter Mutations Are Enriched in Oral Cavity Cancers and Associated With Locoregional Recurrence.

Telomerase reverse transcriptase (TERT) promoter mutations are prognostic in many cancers and have been observed in human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). However, the role of TERT promoter mutations in HPV-negative HNSCCs remains poorly understood in these cancers, which have increased risk for locoregional failure (LRF). PATIENTS AND METHODS: We retrospectively identified patients who were diagnosed with HNSCC between July 1, 2004, and October 12, 2017, at Memorial Sloan Kettering Cancer Center and whose tumors underwent next-generation sequencing using the MSK-IMPACT panel. Patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC) were excluded. Cumulative incidence of LRF, patterns of failure, and overall survival were measured. RESULTS: We identified 117 patients with SCC of the oral cavity (OSCC), larynx, hypopharynx, or HPV-negative oropharynx whose tumors underwent next-generation sequencing. Sequencing was performed on 95 tumors that were obtained after recurrence and 22 that were obtained before recurrence. TERT promoter mutations were enriched in OSCC compared with laryngopharyngeal cancers (81.1% v 7.0%; P < .001), which was the largest genetic difference between these anatomic disease subsites. TERT promoter mutations were associated with LRF in OSCCs (Gray's test, P < .001) and in the overall cohort (Gray's test, P < .001). On multivariate analysis, TERT promoter mutations were associated with an increased risk for LRF (subdistribution hazard ratio, 2.82; 95% CI, 1.47 to 5.42; P = .0019), independent of oral cavity primary site and TP53 mutation status. CONCLUSION: TERT promoter status is associated with the cumulative incidence of LRF and patterns of failure. TERT promoter mutations may define a subset of OSCCs with unique pathogenesis that is associated with an increased risk of LRF. Validation in prospective cohorts is warranted.

[Clinical Efficacy of Autologous Hematopoietic Stem Cell Transplantation for Patients with Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To compare the clinical efficacy of first-line and salvage autologous hematopoietic stem cell transplantation (auto-HSCT) in the treatment of patients with diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 30 patients with DLBCL aged≤60 years old were retrospectively analyzed, and the patients were divided into first-line auto-HSCT group (15 cases) and salvage auto-HSCT group (refractory relapsed patients, 15 cases) according to the timing of transplantation, and the efficacy was analyzed. Anyone of the factors must be followed in patients receiving first-line HSCT: aaIPI score≥2 points, Ann-Arbor stage III-IV, large mass (diameter≥10 cm) or double expression of c-myc/BCL-2. RESULTS: The median follow-up time for all patients after transplantation was 26 (3-103) months. Until the end of follow-up, 23 patients survived and 7 patients died. All the 7 dead patients with multiple organ failure due to the relapse and disease progression. The median survival time of 7 dead patients from transplantation to death was 6 (3-11) months. Among the 15 patients in the first-line auto-HSCT group, there were 2 patients relapsed (13.3%), 1 dead (6.7%), 14 patients survived [overall survival (OS) rate was 93.3%]. Among the 15 patients treated with salvage auto-HSCT, 6 patients died due to disease progression or relapse (40%), 9 cases survived (OS rate was 60%). There was a statistically significant difference in the mortality of patients between the two groups (6.7% vs 40%, P=0.006). The 3-year PFS and OS rates of patients in first-line auto-HSCT group were both 93.3%. The 3-year PFS and OS of patients in salvage auto-HSCT group were 58.7% and 59.2%. The 3-year OS and PFS of patients in the first-line auto-HSCT group were significantly higher than those in the salvage auto-HSCT group (P=0.03, P=0.04). The bone marrow suppression was the most common adverse complication and all patients showed grade III-IV granulocytopenia. Non-hematological adverse reactions were mainly gastrointestinal adverse reactions and oral mucositis. There was no statistically significant difference in adverse reactions between the two groups. CONCLUSION: First-line auto-HSCT can be used as a consolidation treatment for DLBCL patients with poor prognostic factors. Auto-HSCT can further improve the prognosis of salvage chemotherapy-sensitive patients with refractory relapsed DLBCL.

Long-Term High-Altitude Exposure Does Not Increase the Incidence of Atrial Fibrillation Associated with Organic Heart Diseases.

Wang, Man, Mengxue Liu, Jia Huang, Dan Fan, Shengzhong Liu, Tao Yu, Keli Huang, Xinchuan Wei, and Qian Lei. Long-term high-altitude exposure does not increase the incidence of atrial fibrillation associated with organic heart diseases. High Alt Med Biol. 22:285-292, 2021. Background: Atrial fibrillation (AF) is one of the most common arrhythmias and is associated with several complications following cardiac surgery. However, the differences in the incidence of AF associated with organic heart diseases between highland and lowland populations have not been comprehensively studied. Methods: In this retrospective study, a total of 2,316 highland and lowland patients who underwent cardiac surgery between January 2013 and December 2018 in a single center were enrolled. According to the altitude of residence, patients were divided into high-altitude (>1,500 m) and low-altitude (<1,500 m) groups. A propensity score matching analysis was performed to estimate the association of lifetime high-altitude exposure with AF. Results: Among the enrolled patients, 239 (10.9%) were from a high-altitude plateau, while 1,946 (89.1%) were from a low-altitude area. There were statistical differences in age, gender, European System for Cardiac Operative Risk Evaluation, and other factors, between the two groups (p < 0.05). According to the propensity score, 237 patients in the high-altitude group were successfully matched to 237 patients in the low-altitude group without significant difference in baseline data (p > 0.05). Among the matched patients, 125 patients (26.4%) suffered from AF, with 66 (27.8%) in the high-altitude group and 59 (24.9%) in the low-altitude group. The incidence of AF was statistically similar between the two groups and not significantly influenced by long-term high-altitude exposure (odds ratio 1.07; 95% confidence interval 0.71-1.60, p > 0.05). Conclusion: Long-term high-altitude exposure did not significantly increase the occurrence of AF in patients with organic heart diseases. Clinical Trial No. ChiCTR1900028612.

Dexmedetomidine post-conditioning attenuates cerebral ischemia following asphyxia cardiac arrest through down-regulation of apoptosis and neuroinflammation in rats.

BACKGROUND: Neuroprotection strategies after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) remain key areas of basic and clinical research. This study was designed to investigate the neuroprotective effects of dexmedetomidine following resuscitation and potential mechanisms. METHODS: Anesthetized rats underwent 6-min asphyxia-based cardiac arrest and resuscitation, after which the experimental group received a single intravenous dose of dexmedetomidine (25 µg/kg). Neurological outcomes and ataxia were assessed after the return of spontaneous circulation. The serum levels and brain expression of inflammation markers was examined, and apoptotic cells were quantified by TUNEL staining. RESULTS: Neuroprotection was enhanced by dexmedetomidine post-conditioning after the return of spontaneous circulation. This enhancement was characterized by the promotion of neurological function scores and coordination. In addition, dexmedetomidine post-conditioning attenuated the serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α at 2 h, as well as interleukin IL-1ß at 2, 24, and 48 h. TUNEL staining showed that the number of apoptotic cells in the dexmedetomidine post-conditioning group was significantly reduced compared with the control group. Further western blot analysis indicated that dexmedetomidine markedly reduced the levels of caspase-3 and nuclear factor-kappa B (NF-κB) in the brain. CONCLUSIONS: Dexmedetomidine post-conditioning had a neuroprotective effect against cerebral injury following asphyxia-induced cardiac arrest. The mechanism was associated with the downregulation of apoptosis and neuroinflammation.

Preoperative carbohydrate loading and intraoperative goal-directed fluid therapy for elderly patients undergoing open gastrointestinal surgery: a prospective randomized controlled trial.

BACKGROUND: The effect of a combination of a goal-directed fluid protocol and preoperative carbohydrate loading on postoperative complications in elderly patients still remains unknown. Therefore, we designed this trial to evaluate the relative impact of preoperative carbohydrate loading and intraoperative goal-directed fluid therapy versus conventional fluid therapy (CFT) on clinical outcomes in elderly patients following gastrointestinal surgery. METHODS: This prospective randomized controlled trial with 120 patients over 65 years undergoing gastrointestinal surgery were randomized into a CFT group (n = 60) with traditional methods of fasting and water-deprivation, and a GDFT group (n = 60) with carbohydrate (200 ml) loading 2 h before surgery. The CFT group underwent routine monitoring during surgery, however, the GDFT group was conducted by a Vigileo/FloTrac monitor with cardiac index (CI), stroke volume variation (SVV), and mean arterial pressure (MAP). For all patients, demographic data, intraoperative parameters and postoperative outcomes were recorded. RESULTS: Patients in the GDFT group received significantly less crystalloids fluid (1111 ± 442.9 ml vs 1411 ± 412.6 ml; p < 0.001) and produced significantly less urine output (200 ml [150-300] vs 400 ml [290-500]; p < 0.001) as compared to the CFT group. Moreover, GDFT was associated with a shorter average time to first flatus (56 ± 14.1 h vs 64 ± 22.3 h; p = 0.002) and oral intake (72 ± 16.9 h vs 85 ± 26.8 h; p = 0.011), as well as a reduction in the rate of postoperative complications (15 (25.0%) vs 29 (48.3%) patients; p = 0.013). However, postoperative hospitalization or hospitalization expenses were similar between groups (p > 0.05). CONCLUSIONS: Focused on elderly patients undergoing open gastrointestinal surgery, we found perioperative fluid optimisation may be associated with improvement of bowel function and a lower incidence of postoperative complications. TRIAL REGISTRATION: ChiCTR, ChiCTR1800018227 . Registered 6 September 2018 - Retrospectively registered.

Cephalosporin antibiotics specifically and selectively target nasopharyngeal carcinoma through HMOX1-induced ferroptosis.

AIMS: Many antibiotics derived from mold metabolites have been found to possess anticarcinogenic properties. We aimed to investigate whether they may elicit anticancer activity, especially against nasopharyngeal carcinoma. MAIN METHODS: The response of nasopharyngeal and other carcinoma cell lines to cephalosporin antibiotics was evaluated in vitro and in vivo. MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cells. Flow cytometry was used to assess cell cycle parameters and apoptotic markers. Tumor growth was determined using a xenograft model in vivo. Microarray and RT-qPCR expression analyses investigate differential gene expression. Mechanistic assessment of HMOX1 in cefotaxime-mediated ferroptosis was tested with Protoporphyrin IX zinc. KEY FINDINGS: Cephalosporin antibiotics showed highly specific and selective anticancer activity on nasopharyngeal carcinoma CNE2 cells both in vitro and vivo with minimal toxicity. Cefotaxime sodium significantly regulated 11 anticancer relevant genes in CNE2 cells in a concentration-dependent manner. Pathway analyses indicate apoptotic and the ErbB-MAPK-p53 signaling pathways are significantly enriched. HMOX1 represents the top one ranked upregulated gene by COS and overlaps with 16 of 42 enriched apoptotic signaling pathways. Inhibition of HMOX1 significantly reduced the anticancer efficacy of cefotaxime in CNE2 cells. SIGNIFICANCE: Our discovery is the first to highlight the off-label potential of cephalosporin antibiotics as a specific and selective anticancer drug for nasopharyngeal carcinoma. We mechanistically show that induction of ferroptosis through HMOX1 induction mediates cefotaxime anticancer activity. Our findings provide an alternative treatment for nasopharyngeal carcinoma by showing that existing cephalosporin antibiotics are specific and selective anticancer drugs.

[Comparison of Frontline Haploidentical Hematopoietic Stem Cell Transplantation and Salvage Haploidentical Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia].

OBJECTIVE: To compare the clinical efficacy between frontline haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) and salvage haplo-HSCT for patients with severe aplastic anemia (SAA). METHODS: A total of 39 patients with severe aplastic anemia or very severe aplastic anemia from May 1st, 2013 to December 31st, 2018 were analyzed retrospectively. All of them underwent bone marrow + peripheral blood hemopoietic stem cell transplantation. There were 20 cases who accepted frontline haplo-HSCT for a median course of 1 (1-3) month, and 19 cases who accepted salvage haplo-HSCT for a median course of 72 (6-168) months. Conditioning regimen: 22 cases received Flu/Cy+ATG, and 17 cases received Bu/Cy+ATG. RESULTS: The time of hematopoietic reconstitution, infection rate, and grade I-Ⅱ and Ⅲ-Ⅳ acute/chronic graft versus host disease showed no statistically significance between the frontline haplo-HSCT group and the salvage haplo-HSCT group. In the frontline haplo-HSCT group, 1 case (5%) failed in second engraftment, in the salvage haplo-HSCT group 2 cases (10.5%) failed in primary engraftment and 4 cases (21.1%) in second engraftment. The incidence of engraftment failure was higher in the salvage haplo-HSCT group than that in the frontline haplo-HSCT group (P=0.04). The median time of follow-up after allo-HSCT was 45 months (ranging from 3 to 92). The mortality was 10% (2/20) in the frontline haplo-HSCT group, and 42.1% (8/19) in the salvage haplo-HSCT group. The estimated 5-year failure-free survival rate (FFS) of the frontline haplo-HSCT group was higher than that of the salvage haplo-HSCT group (90% vs 57.4%) (P=0.02). CONCLUSION: The frontline haplo-HSCT is an effective and safe approach for the patients with severe aplastic anemia who lack a HLA-matched sibling donor.