Prediction of Th17/Treg cell balance on length of stay in intensive care units of patients with sepsis.

Background: Prolonged length of stay (LOS) of sepsis can drain a hospital's material and human resources. This study investigated the correlations between T helper type 17 (Th17) and regulatory T (Treg) balance with LOS in sepsis. Methods: A prospective clinical observational study was designed in Changhai Hospital affiliated to Naval Medical University in Shanghai, China, from January to October 2020. The patients diagnosed with sepsis and who met the inclusion and exclusion criteria were recruited and whether the levels of cytokines, procalcitonin, subtypes, and biomarkers of T cells in the peripheral blood were detected. We analyzed the correlation between these and LOS. Results: Sixty septic patients were classified into two groups according to whether their intensive care unit (ICU) stay exceeded 14 days. The patients with LOS ≥14 days were older ([72.6±7.5] years vs. [63.3±10.4] years, P=0.015) and had higher Sequential Organ Failure Assessment (SOFA) (median [interquartile range]: 6.5 [5.0-11.0] vs. 4.0 [3.0-6.0], P=0.001) and higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (16.0 [13.0-21.0] vs. 8.5 [7.0-14.0], P=0.001). There was no difference in other demographic characteristics and cytokines, interleukin-6, tumor necrosis factor-α, and interleukin-10 between the two groups. The Th17/Treg ratio of sepsis with LOS <14 days was considerably lower (0.48 [0.38-0.56] vs. 0.69 [0.51-0.98], P=0.001). For patients with LOS ≥14 days, the area under the receiver operating characteristic curve for the Th17/Treg ratio was 0.766. It improved to 0.840 and 0.850 when combined with the SOFA and APACHE II scores, respectively. Conclusions: The Th17/Treg ratio was proportional to septic severity and can be used as a potential predictor of ICU stay in sepsis, presenting a new option for ICU practitioners to better care for patients with sepsis.

Clinical value of FAT1 mutations to indicate the immune response in colorectal cancer patients.

Immunotherapy is currently approved for CRC whose tumors have high MSI-H. To find additional biomarkers for immunotherapy in CRC, targeted sequencing was performed on tumor tissues from a discovery cohort of 161 CRC patients. Validation cohorts from the cBioPortal were also used for survival and tumor cell infiltration analyses. The FAT1-mutated CRC group often co-occurred with MSI events and displayed a higher tumor mutational burden compared to the FAT1 wild-type CRC. Overall survival was higher in patients with FAT1 mutations than in patients with wild type FAT1. The altered PI3K-AKT pathway and immune pathways were enriched in the FAT1-mutated CRC. A higher infiltration rate of immune cells including CD4+ T cells, CD8+ T cells, macrophages M1 and regulatory T cells were also observed in the colorectal tumors with FAT1 mutation compared to tumors with wild type FAT1. The results showed that CRC patients with FAT1 mutations exhibited an immunotherapy-favorable profile.

Reclassification of RAS/BRAF allele mutations predicts the survival benefit of triplet chemotherapy in metastatic colorectal cancer.

Background: Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Methods: Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. Results: A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12; p = 0.0091). Conclusion: In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

Intestinal Autotransplantation for Locally Advanced or Locally Recurrent Colon Cancer Invading SMA.

OBJECTIVE: To examine the outcomes of intestinal autotransplantation (IATx) in patients with locally advanced or recurrent colon cancer (LACC or LRCC) invading the superior mesenteric artery (SMA). BACKGROUND: SMA Involvement in LACC or LRCC is deemed unresectable and is associated with a poor prognosis. Combined extended resections of multiple organs together with SMA, followed by IATx may offer favorable clinical outcomes. However, data on its safety and efficacy are scarce. DESIGN: This retrospective cohort study included patients undergoing IATx between May 2018 and December 2022 in intestinal transplant programs at two university-affiliated hospitals in China. Patients with LACC or LRCC concomitantly with SMA contact of more than 180° were included. Patients with a locoregional peritoneal, pelvic, or distal metastasis were excluded. RESULTS: Ten patients underwent either IATx combined with pancreaticoduodenectomy (n=8) or IATx alone (n=2). Eight patients (80%) were male, and the median age was 55 years (range, 32 - 71 y). The Kaplan-Meier estimates for recurrence-free survival and overall survival at 3 years after IATx were 68% and 80%, respectively. No perioperative deaths occurred. All ten patients experienced postoperative complications including Clavien-Dindo grade I (n=1), grade II (n=4), grade IIIa (n=1), grade IIIb (n=3) and grade IVa (n=1), which comprised acute venous thromboses, upper gastrointestinal hemorrhage, anastomotic leak, gastropareses and significant pleural effusions. With an average follow-up of 23.9 months, eight patients (80%) were currently alive without evidence of disease. CONCLUSION: Extended resection for LACC or LRCC invading SMA can be performed safely and is associated with prolonged survival.

Red blood cell distribution width improves the prediction of 28-day mortality for patients with sepsis-induced acute kidney injury: A retrospective analysis from MIMIC-IV database using propensity score matching.

Background: The predictive value of red blood cell distribution width (RDW) for mortality in patients with sepsis-induced acute kidney injury (SI-AKI) remains unclear. The present study aimed to investigate the potential association between RDW at admission and outcomes in patients with SI-AKI. Methods: The Medical Information Mart for Intensive Care (MIMIC)-IV (version 2.0) database, released in June of 2022, provides medical data of SI-AKI patients to conduct our related research. Based on propensity score matching (PSM) method, the main risk factors associated with mortality in SI-AKI were evaluated using Cox proportional hazards regression analysis to construct a predictive nomogram. The concordance index (C-index) and decision curve analysis were used to validate the predictive ability and clinical utility of this model. Patients with SI-AKI were classified into the high- and low-RDW groups according to the best cut-off value obtained by calculating the maximum value of the Youden index. Results: A total of 7574 patients with SI-AKI were identified according to the filter criteria. Compared with the low-RDW group, the high-RDW group had higher 28-day (9.49% vs. 31.40%, respectively, P <0.001) and 7-day (3.96% vs. 13.93%, respectively, P <0.001) mortality rates. Patients in the high-RDW group were more prone to AKI progression than those in the low-RDW group (20.80% vs. 13.60%, respectively, P <0.001). Based on matched patients, we developed a nomogram model that included age, white blood cells, RDW, combined hypertension and presence of a malignant tumor, treatment with vasopressor, dialysis, and invasive ventilation, sequential organ failure assessment, and AKI stages. The C-index for predicting the probability of 28-day survival was 0.799. Decision curve analysis revealed that the model with RDW offered greater net benefit than that without RDW. Conclusion: The present findings demonstrated the importance of RDW, which improved the predictive ability of the nomogram model for the probability of survival in patients with SI-AKI.

Metastatic sites and lesion numbers cooperated to predict efficacy of PD-1 inhibitor-based combination therapy for patients with metastatic colorectal cancer.

BACKGROUND: Limited data have been used to evaluate the efficacy of immunotherapy in metastatic colorectal cancer (mCRC). Furthermore, potential markers that can be used to identify responding patients and to further improve efficacy have not been fully explored. METHODS AND RESULTS: In our study, we included a total of 97 patients with mCRC, who each received programmed death-1 (PD-1) inhibitor-based combination therapy at our center. All 12 hypermutated patients benefited from immunotherapy, with median progression-free survival (mPFS) reaching 28.3 months, regardless of liver metastasis. The objective response rate (ORR) of non-hypermutated patients was 16.5% (14/85), with an mPFS of 4.0 months. For non-hypermutated patients, multivariate analysis revealed that the combination of liver metastasis and baseline lesion number significantly stratified response and survival. The lesion-based analysis indicated that the lymph node was the most responsive, followed by the peritoneum and lung, with liver metastasis being the least responsive. None of the patients (0/7) with negative programmed ligand-1 (PD-L1) expression responded, and positive PD-L1 expression may serve as a biomarker (mPFS 5.7 vs. 2.2 months, p = 0.002) that can be used to further guide treatment in non-hypermutated mCRC with liver metastasis (CRLMs). CONCLUSION: Patients with hypermutated mCRC benefited significantly from immunotherapy, whereas the non-hypermutated cohort with liver metastasis and numerous lesions showed less benefit. The lesion sites reflected varying levels of efficacy, among which PD-L1 potentially cooperated to guide the immunotherapy of CRLMs.

Icaritin Derivative IC2 Induces Cytoprotective Autophagy of Breast Cancer Cells via SCD1 Inhibition.

Breast cancer is one of the most prevalent malignancies and the leading cause of cancer-associated mortality in China. Icaritin (ICT), a prenyl flavonoid derived from the Epimedium Genus, has been proven to inhibit the proliferation and stemness of breast cancer cells. Our previous study demonstrated that IC2, a derivative of ICT, could induce breast cancer cell apoptosis by Stearoyl-CoA desaturase 1 (SCD1) inhibition. The present study further investigated the mechanism of the inhibitory effects of IC2 on breast cancer cells in vitro and in vivo. Our results proved that IC2 could stimulate autophagy in breast cancer cells with the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling and mitogen-activated protein kinase (MAPK) signaling. Combination treatment of the AMPK inhibitor decreased IC2-induced autophagy while it markedly enhanced IC2-induced apoptosis. In common with IC2-induced apoptosis, SCD1 overexpression or the addition of exogenous oleic acid (OA) could also alleviate IC2-induced autophagy. In vivo assays additionally demonstrated that IC2 treatment markedly inhibited tumor growth in a mouse breast cancer xenograft model. Overall, our study was the first to demonstrate that IC2 induced cytoprotective autophagy by SCD1 inhibition in breast cancer cells and that the autophagy inhibitor markedly enhanced the anticancer activity of IC2. Therefore, IC2 was a potential candidate compound in combination therapy for breast cancer.

Radical Resection Combined With Intestinal Autotransplantation for Locally Advanced Pancreatic Cancer After Neoadjuvant Therapy: A Report of 36 Consecutive Cases.

OBJECTIVE: To achieve radical resection of locally advanced pancreatic ductal adenocarcinoma (PDAC), and tested the safety and benefits of intestinal autotransplantation in pancreatic surgery. BACKGROUND: PDAC has an extremely dismal prognosis. Radical resection was proved to improve the prognosis of patients with PDAC; however, the locally advanced disease had a very low resection rate currently. We explored and evaluated whether the combination of modern advances in systemic treatment and this macroinvasive surgery was feasible in clinical practice. METHODS: Patients diagnosed as PDAC with superior mesenteric artery involvement and with or without celiac trunk involvement were included. Patients were treated with modified-FOLFIRINOX chemotherapy with or without anti-PD-1 antibodies and were applied to tumor resection combined with intestinal autotransplantation. Data on operative parameters, pathologic results, mortality, morbidity, and survival were analyzed. RESULTS: A total of 36 consecutive cases were applied to this strategy and underwent radical resection combined with intestinal autotransplantation. Among these patients, 24 of them received the Whipple procedure, 11 patients received total pancreatectomy, and the other 1 patient received distal pancreatectomy. The median operation time was 539 minutes. Postoperative pathology showed an R0 resection rate of 94.4%, and tumor invasion of a superior mesenteric artery or superior mesenteric vein was confirmed in 32 patients. The median number of dissected lymph nodes was 43, and 25 patients were positive for lymph node metastasis. The median time of intensive care unit stay was 4 days. Two patients died within 30 days after surgery due to multiorgan failure. The severe postoperative adverse events (equal to or higher than grade 3) were observed in 12 out of 36 patients, and diarrhea, gastroparesis, and abdominal infection were the most frequent adverse events. Postoperative hospital stay was averagely of 34 days. The recurrence-free survival is 13.6 months. The median overall survival of patients after diagnosis and after surgery was 21.4 months and 14.5 months, respectively. CONCLUSIONS: Our attempt suggests the safety of this modality and may be clinically beneficial for highly selected patients with PDAC. However, the experience in multidisciplinary pancreatic cancer care and intestinal transplantation is warranted.

Soluble PD-L1: a potential dynamic predictive biomarker for immunotherapy in patients with proficient mismatch repair colorectal cancer.

BACKGROUND: Circulating soluble programmed death ligand 1 (sPD-L1) can negatively regulate T-cell function and serve as a prognostic or predictive marker in a variety of cancers. However, rare studies have evaluated the potential roles of sPD-L1, and no study has estimated its predictive value for the efficacy of immune treatment in colorectal cancer (CRC). METHODS: Plasma samples from 192 CRC patients were used to estimate correlations between clinicopathological features and sPD-L1, secreted PD-L1 (secPD-L1) and exosomal PD-L1 (exoPD-L1). Baseline and posttreatment sPD-L1 levels were also investigated in 55 patients with metastatic CRC (mCRC) treated with chemotherapy ± targeted therapy and 40 patients with proficient mismatch repair (pMMR) mCRC treated with combination immunotherapy. Both sPD-L1 and secPD-L1 were quantified by enzyme-linked immunosorbent assay, while exoPD-L1 was analyzed using flow cytometry. RESULTS: secPD-L1 was the major component and positively correlated with sPD-L1 in CRC, while exoPD-L1 was almost undetectable. Higher levels of sPD-L1 were detected in patients with distant metastasis, especially those with distant lymph node metastasis and tissue combined positive score (CPS) instead of tumor proportion score (TPS). Chemotherapy or targeted therapy did not significantly impact sPD-L1 concentration. Progressive disease on combination immunotherapy was associated with an increase in sPD-L1 level, whereas no significant change was observed in patients with durable clinical benefit. CONCLUSION: sPD-L1 mainly consisted of secPD-L1, and its level was higher in patients with distant metastasis, especially distant lymph node metastasis and positive CPS. sPD-L1 is a potential dynamic marker to identify rapid progression on combination immunotherapy and avoid ineffective treatment for pMMR CRC.

Short- and long-term complications after living donor ileal resection.

Intestinal transplantation from deceased donors is the established procedure for patients with irreversible intestinal failure. However, a living-donor intestinal transplant has not been routinely performed yet because of undefined surgical risks to the donor. In this report, we reviewed our experience with living-donor ileal resection from May 1999 to December 2021. A total of 40 living-donor ileal resections were performed for 40 intestinal transplant recipients. Clinical data were prospectively collected and analyzed for postoperative complications after ileal procurement. None of the donors experienced life-threatening complications or mortality. Six (15%) of 40 donors experienced minor operative complications. Transit intestinal graft inadequacy including weight loss, diarrhea, and vitamin B12 deficiency was common early following surgery, but was manageable and disappeared in most cases within a year. All donors had significant reductions in total plasma cholesterol and low-density lipoprotein cholesterol concentrations after donation as compared with the baseline levels. With an average follow-up of 67.8 months, bilateral kidney stones occurred in one donor and gallstones in the other. All the donors have regained their normal capacity for work. Living-donor ileal resection is associated with minimal short- and long-term morbidity and remains an attractive alternative for potential recipients when suitable deceased donors are unavailable.

Living Donor Intestinal Transplantation: Recipient Outcomes.

OBJECTIVE: To examine outcomes of living-donor intestinal transplant (LDITx) recipients. BACKGROUND: LDITx is not routinely performed because of surgical risks to the donor and the potential inferior physiologic performance of the segmental graft. However, data on the effectiveness of LDITx are scarce. DESIGN: This retrospective cohort study included patients undergoing LDITx between May 1999 and December 2021 in intestinal transplant programs in 2 university-affiliated hospitals in China. RESULTS: Actuarial survival rates were 80%, 72.7%, 66.7% for patient and 72.4%, 63.6%, 60% for graft at 1, 3, and 5 years, respectively. Recipients with >3/6 HLA-matched grafts had superior patient and graft survival rates than those with ≤3/6 HLA-matched grafts ( P <0.05). There were 12 deaths among the recipients, with infection being the leading cause (41.7%), followed by rejection (33.3%), surgical complications (16.7%), and others (8.3%). There were 16 graft losses among the recipients, with acute cellular rejection being the predominant cause (37.5%), followed by infection (25%), technical failure (12.5%), chronic rejection (12.5%), and others (12.5%). With an average follow-up of 3.7 (range, 0.6-23) years, the rates of acute and chronic rejection were 35% and 5%, and the rate of cytomegalovirus disease and post-transplant lymphoproliferative disease were 5% and 2.5%, respectively. Of the 40 patients, 28 (70%) are currently alive and have achieved enteral autonomy. CONCLUSIONS: LDITx is a valuable treatment option for patients with end-stage intestinal failure. Improved immunosuppression, better HLA matching, and shorter cold ischemia times were associated with reduced rates of rejection, viral-mediated infection and improved graft survival.

Identification of icaritin derivative IC2 as an SCD-1 inhibitor with anti-breast cancer properties through induction of cell apoptosis.

BACKGROUND: Breast cancer is the most common malignancy affecting women, yet effective targets and related candidate compounds for breast cancer treatment are still lacking. The lipogenic enzyme, stearoyl-CoA desaturase-1 (SCD1), has been considered a potential target for breast cancer treatment. Icaritin (ICT), a prenylflavonoid derivative from the Traditional Chinese Medicine Epimedii Herba, has been reported to exert anticancer effects in various types of cancer. The purpose of the present study was to explore the effect of the new ICT derivative, IC2, targeting SCD1 on breast cancer cells and to explore the specific mechanism. METHODS: Immunohistochemistry and semiquantitative evaluation were performed to detect the expression level of SCD1 in normal and tumor samples. Computer-aided drug design (CADD) technology was used to target SCD1 by molecular docking simulation, and several new ICT derivatives were prepared by conventional chemical synthesis. Cell viability was evaluated by an MTT assay and dead cell staining. SCD1 expression in cancer cells was determined by Western blot and qRT-PCR analyses. The enzymatic activity of SCD1 was evaluated by detecting the conversion rate of [d31] palmitic acid (PA) using Gas chromatography-mass spectrometry (GC-MS). DAPI staining, flow cytometry and Western blot were used to detect cell apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) assays were used to determine cell mitochondrial function. Lentiviral transduction was utilized to generate SCD1-overexpressing cell lines. RESULTS: We found that SCD1 was overexpressed and correlated with poor prognosis in breast cancer patients. Among a series of ICT derivatives, in vitro data showed that IC2 potentially inhibited the viability of breast cancer cells, and the mechanistic study revealed that IC2 treatment resulted in ROS activation and cellular apoptosis. We demonstrated that IC2 inhibited SCD1 activity and expression in breast cancer cells in a dose-dependent manner. Moreover, SCD1 overexpression alleviated IC2-induced cytotoxicity and apoptosis in breast cancer cells. CONCLUSIONS: The new ICT derivative, IC2, was developed to induce breast cancer cell apoptosis by inhibiting SCD1, which provides a basis for the development of IC2 as a potential clinical compound for breast cancer treatment.

[Corrigendum] miR­647 and miR­1914 promote cancer progression equivalently by downregulating nuclear factor IX in colorectal cancer.

Subsequently to the publication of this paper, an interested reader drew to the authors' attention that, in the scratch­wound assays shown in Fig. 3A on p. 8195, the data shown for the '0 h/NC' and '0 h/miR­1914 antagomir' data panels appeared to be strikingly similar, such that they may have been derived from the same original source. The authors have consulted their original data, and realize that the '0 h/miR­1914 antagomir' data panel was inadvertently selected incorrectly for Fig. 3A. The corrected version of Fig. 3, now showing the correct data for the '0 h/miR­1914 antagomir' data panel in Fig. 3A, is shown on the next page. Note that the errors in Fig. 3 did not significantly affect the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 16, 8189­8199, 2017; DOI: 10.3892/mmr.2017.7675].

Aspartate transaminase/alanine transaminase (De Ritis ratio) predicts survival in major burn patients.

BACKGROUND: Although treatment of burn patients has significantly improved in recent decades, major burns remain fatal. Therefore, the evaluation of the death risk of the patients with extensive burns is very important. The ratio between the serum levels of aspartate transaminase and alanine transaminase (De Ritis ratio) was an independent predictor of poor outcomes in patients with acute ischemic stroke, cardiac surgery, non-metastatic renal cell carcinoma, and upper urinary tract urothelial carcinoma. Our aim was to determine whether the ratio between the serum levels of AST and ALT (De Ritis ratio) was useful to assess prognosis in extensively burned patients. METHODS: We conducted a single-center cohort study at the Burns Department of Changhai Hospital. This retrospective observational analysis was performed based on the clinical data of major burn patients admitted between May 1, 2005 and April 30, 2018. Univariate and multivariate logistic regression analyses were performed on variables such as age, sex, total body surface area (TBSA), De Ritis ratio, and serum albumin level, which may affect mortality in major burn patients. We assessed their diagnostic value and found the cut-off value by receiver operative characteristic (ROC) curve analysis. We used the Kaplan-Meier curve to display the impact of the De Ritis ratio and serum albumin level on survival in burn patients. RESULTS: A total of 351 patients with extensive burns were included in the study. The cohort predominantly consisted of males (74.64%), and most of the patients (78.35%) had been burned by a flame. Age, TBSA, inhalation, and the De Ritis ratio were found to be independent risk factors for the 30-days mortality of major burn patients, while age, TBSA, inhalation, and the De Ritis ratio were independent risk factors for 90-day mortality. Further, the De Ritis ratio was a better mortality predictor than serum albumin in severely burned patients, whose area under ROC for 30-day and 90-day mortality was 0.771 (95% confidence intervals [CI], 0.708-0.835) and 0.750 (95% CI, 0.683, 0.818). CONCLUSIONS: The De Ritis ratio was useful as a prognostic indicator for major burn patients, which can be conveniently obtained through blood examination. Regardless of whether the prediction was for 30-day or 90-day mortality, the accuracy remained high. Moreover, compared to serum albumin level, the De Ritis ratio was superior in assessing the prognosis of extensively burned patients.

Combination of transcriptional biomarkers and clinical parameters for early prediction of sepsis indued acute respiratory distress syndrome.

Objective: As a common yet intractable complication of severe sepsis, acute respiratory distress syndrome (ARDS) is closely associated with poor clinical outcomes and elevated medical expenses. The aim of the current study is to generate a model combining transcriptional biomarkers and clinical parameters to alarm the development of ARDS in septic patients. Methods: Gene expression profile (GSE66890) was downloaded from the Gene Expression Omnibus database and clinical data were extracted. Differentially expressed genes (DEGs) from whole blood leukocytes were identified between patients with sepsis alone and septic patients who develop ARDS. ARDS prediction model was constructed using backward stepwise regression and Akaike Information Criterion (AIC). Meanwhile, a nomogram based on this model was established, with subsequent internal validation. Results: A total of 57 severe septic patients were enrolled in this study, and 28 (49.1%) developed ARDS. Based on the differential expression analysis, six DEGs (BPI, OLFM4, LCN2, CD24, MMP8 and MME) were screened. According to the outcome prediction model, six valuable risk factors (direct lung injury, shock, tumor, BPI, MME and MMP8) were incorporated into a nomogram, which was used to predict the onset of ARDS in septic patients. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. The area under the receiver operating characteristic (AUROC) for the prediction of ARDS occurrence in septic patients by the nomogram was 0.86 (95% CI = 0.767-0.952). A sensitivity analysis showed that the AUROC for the prediction of ARDS development in septic patients without direct lung injury was 0.967 (95% CI = 0.896-1.0). Conclusions: The nomogram based on transcriptional biomarkers and clinical parameters showed a good performance for the prediction of ARDS occurrence in septic patients.

Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy.

Introduction: Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study. Methods: Among 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively. Results: BRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p<0.05). Subsequently, transcriptomic study analysis further revealed MSI-H altered CRC patients were linked to an immune-active tumor microenvironment with higher levels of Teff IFN-gamma, CYT, and MERCK 18 signatures, and lower levels of the IPRES gene signature, EMT and TGF Beta signatures. In addition, case study supported MSI-H CRC patient harboring targetable alterations might also achieved a long-term disease-free survival benefit from immunotherapy. Discussion: Our study preliminary revealed MSI-H altered as a novel subtype of MSI-H CRC patients with unique molecular signatures and immune-active tumor microenvironment. Given the accessibility of immune checkpoint inhibitors (ICIs) treatment, our results might provide clinical evidence for immunotherapy in MSI-H CRC patients with targetable alterations.

Elevated serum procalcitonin early after extensive burn: influencing factors and clinical significance.

The study was carried out to analyze the factors influencing the elevated serum procalcitonin (PCT) levels during the early phase of extensive burn, and to investigate its potential for sepsis prediction and prognosis. Clinical data of 324 patients with extensive burns treated at our department from July 2014 to December 2019 were retrospectively analyzed. Approximately half of the patients (50.93%) exhibited elevated serum PCT concentrations during the early phase, and elevated PCT levels may not be caused by infections. Early-phase PCT level was an independent risk factor for sepsis occurrence in extensive-burn patients within 60 days of injury. Burn index, degree of inhalation injury, and APACHE-II score influenced PCT level elevation during the early phase. Patient age, burn index, APACHE-II score at admission, early-phase PCT level, and sepsis occurrence were risk factors for mortality in extensive-burn patients. During the early phase, approximately 50.93% of the extensive-burn patients exhibited elevated PCT levels, which were associated with non-infectious factors. As elevated PCT level during the early phase predicted sepsis occurrence within 60 days of injury and was significantly associated with patient mortality, it might be a potential burn severity indicator during the early phase of burn injury.

Risk Factors for Transfusion-Related Acute Lung Injury.

BACKGROUND: Until now, transfusion-related acute lung injury (TRALI) has been considered the leading cause of blood transfusion-related diseases and death. In addition, there is no clinically effective treatment plan for TRALI. The aim of this study was to systematically summarize the literature on risk factors for TRALI in critical patients. METHODS: Electronic searches (up to March 2020) were performed in the Cochrane Library, Web of Knowledge, Embase, and PubMed databases. We included studies reporting on the risk factors of TRALI for critical patients and extracted risk factors. A total of 13 studies met the inclusion criteria. RESULTS: We summarized and analyzed the potential risk factors of TRALI for critical patients in 13 existing studies. Host-related factors were age (odds ratio [OR] 1.16 [95% CI 1.08-1.24]), female sex (OR 1.26 [95% CI 1.16-1.38]), tobacco use status (OR 3.82 [95% CI 1.91-7.65]), chronic alcohol abuse (OR 3.82 [95% CI 2.97-26.83]), positive fluid balance (OR 1.24 [95% CI 1.08-1.42]), shock before transfusion (OR 4.41 [95% CI 2.38-8.20]), and American Society of Anesthesiologists (ASA) score of the recipients (OR 2.72 [95% CI 1.43-5.16]). The transfusion-related factors were the number of transfusions (OR 1.40 [95% CI 1.14-1.72]) and units of fresh frozen plasma (OR 1.21 [95% CI 1.01-1.46]). The device-related factor was mechanical ventilation (OR 4.13 [95% CI 2.20-7.76]). CONCLUSIONS: The risk factors that were positively correlated with TRALI in this study included number of transfusions and units of fresh frozen plasma. Age, female sex, tobacco use, chronic alcohol abuse, positive fluid balance, shock before transfusion, ASA score, and mechanical ventilation may be potential risk factors for TRALI. Our results suggest that host-related risk factors may play a more important role in the occurrence and development of TRALI than risk factors related to blood transfusions.

Intestinal ischemic reperfusion injury: Recommended rats model and comprehensive review for protective strategies.

Intestinal ischemic reperfusion injury (IIRI) is a life-threatening condition with high morbidity and mortality in the clinic. IIRI was induced by intestinal ischemic diseases such as, small bowel transplantation, aortic aneurysm surgery, and strangulated hernias. Although related mechanisms have not been fully elucidated, during the last decade, researches have demonstrated that many factors are crucial in the pathological process, including oxidative stress (OS), epithelial barrier function disorder, and so on. Rats model, as the most applied animal IIRI model, provides specific targets for researches and therapeutic strategies. Moreover, various treatment strategies such as, anti-oxidative stress, anti-apoptosis, and anti-inflammation, have shown promising effects in alleviating IIRI. However, current researches cannot solve the clinical problems of IIRI, and specific treatment strategies are still needed to be exploited. This review focuses on a recommended experimental IIRI rat model and understanding of the involved mechanisms such as, OS, gut bacteria translocation, apoptosis, and necroptosis, aim at providing novel ideas for therapeutic strategies of IIRI.

Non-muscle myosin II knockdown improves survival and therapeutic effects of implanted bone marrow-derived mesenchymal stem cells in lipopolysaccharide-induced acute lung injury.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to have some beneficial effects in acute lung injury (ALI), but the therapeutic effects are limited due to apoptosis or necrosis after transplantation into injured lungs. Here, we aim to explore whether Non-muscle myosin II (NM-II) knockdown could enhance BMSCs survival and improve therapeutic effects in ALI. METHODS: MSCs, isolated from rat bone marrow, were transfected with the small interfering RNA (siRNA) targeted to NM-II mRNA by a lentivirus vector. Rats were equally randomized to four groups: the control group was given normal saline via tail vein; the other three groups underwent intratracheal lipopolysaccharide (LPS) instillation followed by administration with either normal saline, BMSCs transduced with lentivirus-enhanced green fluorescent protein (eGFP) empty vector, or BMSCs transduced with lentivirus-eGFP NM-II siRNA. Hematoxylin and eosin staining was used to evaluate lung histopathologic changes and Masson trichrome staining was used to assess lung fibrosis. The myeloperoxidase activity was also tested in lung tissues. The mRNA expression of inflammatory cytokines in lung tissues was determined via quantitative reverse transcription PCR. Sex-determining region of the Y chromosome gene expression was measured by fluorescence in situ hybridization (FISH) assay. The expression of self-renewal activity and apoptosis-associated proteins were measured by Western blot. RESULTS: Transplantation of NM-II siRNA-modified BMSCs could improve histopathological morphology, decrease inflammatory infiltrates, down-regulate the expression levels of inflammatory cytokines, and reduce pulmonary interstitial edema. NM-II siRNA-modified BMSCs showed antifibrotic properties and alleviated the degrees of pulmonary fibrosis induced by endotoxin. In addition, NM-II knockdown BMSCs showed slightly better therapeutic effect on lung inflammation when compared with control BMSCs. The beneficial effects of NM-II siRNA-modified BMSCs may be attributed to enhanced self-renewal activity and decreased apoptosis. CONCLUSIONS: NM-II knockdown could inhibit the apoptosis of implanted BMSCs in lung tissues and improve its self-renewal activity. NM-II siRNA-modified BMSCs have a slightly enhanced ability to attenuate lung injury after LPS challenge.