Neuromuscular blocking agent re-exposure in a retrospective cohort with neuromuscular blocking agent-associated anaphylaxis.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are one of the most common causes of perioperative anaphylaxis. Although skin test positivity may help identify reactive NMBAs, it is unclear whether skin test negativity can guarantee the safety of systemically administered NMBAs. OBJECTIVE: This study aimed to evaluate the real-world safety of alternative NMBAs screened using skin tests in patients with suspected NMBA-induced anaphylaxis. METHODS: A retrospective cohort of suspected NMBA-induced anaphylaxis were recruited among patients at Seoul National University Hospital from June 2009 to May 2021, and their characteristics and outcomes were assessed. RESULTS: A total of 47 cases (0.017%) of suspected anaphylaxis occurred in 282,707 patients who received NMBAs. Cardiovascular manifestations were observed in 95.7%, whereas cutaneous findings were observed in 59.6%. Whereas 83% had a history of undergoing general anesthesia, 17% had no history of NMBA use. In skin tests, the overall positivity to any NMBA was 94.6% (81.1% to culprit NMBAs) and the cross-reactivity was 75.7%, which is related to the chemical structural similarity among NMBAs; the cross-reactivity and chemical structure similarity of rocuronium were 85.3% and 0.814, respectively, with vecuronium; this is in contrast to 50% and 0.015 with cisatracurium and 12.5% and 0.208 with succinylcholine. There were 15 patients who underwent subsequent surgery with a skin test-negative NMBA; whereas 80.0% (12/15) safely completed surgery, 20.0% (3/15) experienced hypotension. CONCLUSION: Similarities in chemical structure may contribute to the cross-reactivity of NMBAs in skin tests. Despite the high negative predictability of skin tests for suspected NMBA-induced anaphylaxis, the potential risk of recurrent anaphylaxis has not been eliminated.

Multi-MicroRNA Analysis Can Improve the Diagnostic Performance of Mammography in Determining Breast Cancer Risk.

The objective of this study was to determine whether multi-microRNA analysis using a combination of four microRNA biomarkers (miR-1246, 202, 21, and 219B) could improve the diagnostic performance of mammography in determining breast cancer risk by age group (under 50 vs. over 50) and distinguish breast cancer from benign breast diseases and other cancers (thyroid, colon, stomach, lung, liver, and cervix cancers). To verify breast cancer classification performance of the four miRNA biomarkers and whether the model providing breast cancer risk score could distinguish between benign breast disease and other cancers, the model was verified using nonlinear support vector machine (SVM) and generalized linear model (GLM) and age and four miRNA qRT-PCR analysis values (dCt) were input to these models. Breast cancer risk scores for each Breast Imaging-Reporting and Data System (BI-RADS) category in multi-microRNA analysis were analyzed to examine the correlation between breast cancer risk scores and mammography categories. We generated two models using two classification algorithms, SVM and GLM, with a combination of four miRNA biomarkers showing high performance and sensitivities of 84.5% and 82.1%, a specificity of 85%, and areas under the curve (AUCs) of 0.967 and 0.965, respectively, which showed consistent performance across all stages of breast cancer and patient ages. The results of this study showed that this multi-microRNA analysis using the four miRNA biomarkers was effective in classifying breast cancer in patients under the age of 50, which is challenging to accurately diagnose. In addition, breast cancer and benign breast diseases can be classified, showing the possibility of helping with diagnosis by mammography. Verification of the performance of the four miRNA biomarkers confirmed that multi-microRNA analysis could be used as a new breast cancer screening aid to improve the accuracy of mammography. However, many factors must be considered for clinical use. Further validation with an appropriate screening population in large clinical trials is required. This trial is registered with (KNUCH 2022-04-036).

Clinicopathologic implication of microRNA-197 in diffuse large B cell lymphoma.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) contains heterogeneous subtypes with various molecular dysregulation at the gene, protein and microRNA levels. Compared with the GCB subtype, the non-germinal center B-like (non-GCB)/activated B cell-like (ABC) subtype exhibits frequent progression despite standard immunochemotherapy. We aimed to investigate the effects of miR-197 on the progression and chemosensitivity of DLBCL with respect to the GCB and non-GCB/ABC subtypes. METHODS: To screen distinctively expressed microRNAs, microRNA expression patterns were analyzed in 10 DLBCL cases by microarray chip assays. Using quantitative real-time polymerase chain reaction (qRT-PCR), associations between miR-197 expression levels and clinicopathologic variables were investigated in 51 DLBCL tissue samples. The effects of miR-197 on doxorubicin chemosensitivity were investigated using the OCI-Ly1 and SUDHL9 cell lines. RESULTS: MicroRNA expression profiling by hierarchical clustering revealed that miR-197 was one of the distinctively expressed microRNAs in DLBCL. Quantitative analysis using qRT-PCR revealed that miR-197 levels were not correlated with clinicopathologic variables, including the international prognostic index, but low miR-197 levels were significantly associated with lymphoma progression defined by refractoriness, relapse or death in the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-treated subgroup (n = 43; p = 0.004). Among the three molecular groups, i.e., the GCB, non-GCB/miR-197low and non-GCB/miR-197high groups, progression was most frequently observed in the non-GCB/miR-197low group in the full cohort (p = 0.013) and the R-CHOP cohort (p = 0.008). In survival analysis, low miR-197 levels were independently predictive of shorter progression-free survival in the R-CHOP cohort (p = 0.031; HR = 27.9) and the non-GCB subgroup (p = 0.037; HR = 21.5) but not in the GCB subgroup. Using SUDHL9 (ABC type) and OCI-Ly1 (GCB type) cells, the effects of doxorubicin on reducing cell viability were enhanced by miR-197 transfection. In apoptosis assays, miR-197 transfection enhanced doxorubicin-induced apoptosis in SUDHL9 cells but not in OCI-Ly1 cells, suggesting a chemosensitizing effect of miR-197 in ABC DLBCL. CONCLUSIONS: These results suggest the role of miR-197 as a biomarker with potential therapeutic implications.

The Importance of the Circadian Clock in Regulating Plant Metabolism.

Carbohydrates are the primary energy source for plant development. Plants synthesize sucrose in source organs and transport them to sink organs during plant growth. This metabolism is sensitive to environmental changes in light quantity, quality, and photoperiod. In the daytime, the synthesis of sucrose and starch accumulates, and starch is degraded at nighttime. The circadian clock genes provide plants with information on the daily environmental changes and directly control many developmental processes, which are related to the path of primary metabolites throughout the life cycle. The circadian clock mechanism and processes of metabolism controlled by the circadian rhythm were studied in the model plant Arabidopsis and in the crops potato and rice. However, the translation of molecular mechanisms obtained from studies of model plants to crop plants is still difficult. Crop plants have specific organs such as edible seed and tuber that increase the size or accumulate valuable metabolites by harvestable metabolic components. Human consumers are interested in the regulation and promotion of these agriculturally significant crops. Circadian clock manipulation may suggest various strategies for the increased productivity of food crops through using environmental signal or overcoming environmental stress.

OsWRKY51, a rice transcription factor, functions as a positive regulator in defense response against Xanthomonas oryzae pv. oryzae.

KEY MESSAGE: OsWRKY51 functions as a positive transcriptional regulator in defense signaling against Xanthomonas oryzae pv. oryzae by direct DNA binding to the promoter of defense related gene, OsPR10a. OsWRKY51 in rice (Oryza sativa L.) is induced by exogenous salicylic acid (SA) and inoculation with Xanthomonas oryzae pv. oryzae (Xoo). To examine the role of OsWRKY51 in the defense response of rice, we generated OsWRKY51 overexpressing and underexpressing transgenic rice plants. OsWRKY51-overexpressing transgenic rice lines were more resistant to Xoo and showed greater expression of defense-related genes than wild-type (WT) plants, while OsWRKY51-underexpressing lines were more susceptible to Xoo and showed less expression of defense-associated genes than WT plants. Transgenic lines overexpressing OsWRKY51 showed growth retardation compared to WT plants. In contrast, transgenic lines underexpressing OsWRKY51 by RNA interference showed similar plant height with WT plants. Transient expression of OsWRKY51-green fluorescent protein fusion protein in rice protoplasts revealed that OsWRKY51 was localized in the nucleus. OsWRKY51 bound to the W-box and WLE1 elements of the OsPR10a promoter. Based on these results, we suggest that OsWRKY51 is a positive transcriptional regulator of defense signaling and has direct DNA binding ability to the promoter of OsPR10a, although it is reported to be a negative regulator in GA signaling.

Comparative structural and immunological analysis of outer membrane proteins and dermonecrotic toxin in Bordetella bronchiseptica canine isolate.

Bordetella bronchiseptica is a pathogen causing respiratory infections in mammals. With the improving understanding of companion animals' welfare, addressing the side effects of bordetella vaccine gains importance in dogs. Studies on diverse subunit vaccines are actively pursued in humans to safely and effectively control bordetellosis. Therefore, our objective was to develop a canine bordetella vaccine inspired by human vaccine development. We evaluated the immunogenicity of the two bacterial components: the outer membrane proteins (OMPs) and the dermonecrotic toxin (DNT) from a canine isolate of B. bronchiseptica. In-silico analysis identified eight domains of DNT, and Domain 3 was selected as the most promising antigen candidate. Additionally, the OMPs were extracted and examined using SDS-PAGE and Western blot analysis. The distinct immunological characteristic of OMPs and DNT-3 were examined individually and in combination. Gene expression and cytokine production were also evaluated in DH82 cells after stimulation with those antigens. Treatment with OMPs resulted in higher level of Th1 related cytokines, while DNT-3 induced a predominant response associated with Th17 and Th2 in the cytokine production. Synergistic effects were observed exclusively on IL-23, indicating increase of a potential risk of side effects when OMPs and DNT act together. These findings provide valuable insights into the reactogenicity of conventional Bordetella vaccines. Further, the presented preclinical data in this study offer an alternative method of the development for an optimal next-generation Bordetella vaccine for companion animals and humans, replacing the acellular vaccines containing both toxin and protein components.

Overexpression of PIP2;5 aquaporin alleviates effects of low root temperature on cell hydraulic conductivity and growth in Arabidopsis.

The effects of low root temperature on growth and root cell water transport were compared between wild-type Arabidopsis (Arabidopsis thaliana) and plants overexpressing plasma membrane intrinsic protein 1;4 (PIP1;4) and PIP2;5. Descending root temperature from 25°C to 10°C quickly reduced cell hydraulic conductivity (L(p)) in wild-type plants but did not affect L(p) in plants overexpressing PIP1;4 and PIP2;5. Similarly, when the roots of wild-type plants were exposed to 10°C for 1 d, L(p) was lower compared with 25°C. However, there was no effect of low root temperature on L(p) in PIP1;4- and PIP2;5-overexpressing plants after 1 d of treatment. When the roots were exposed to 10°C for 5 d, L(p) was reduced in wild-type plants and in plants overexpressing PIP1;4, whereas there was still no effect in PIP2;5-overexpressing plants. These results suggest that the gating mechanism in PIP1;4 may be more sensitive to prolonged low temperature compared with PIP2;5. The reduction of L(p) at 10°C in roots of wild-type plants was partly restored to the preexposure level by 5 mm Ca(NO(3))(2) and protein phosphatase inhibitors (75 nm okadaic acid or 1 µm Na(3)VO(4)), suggesting that aquaporin phosphorylation/dephosphorylation processes were involved in this response. The temperature sensitivity of cell water transport in roots was reflected by a reduction in shoot and root growth rates in the wild-type and PIP1;4-overexpressing plants exposed to 10°C root temperature for 5 d. However, low root temperature had no effect on growth in plants overexpressing PIP2;5. These results provide strong evidence for a link between growth at low root temperature and aquaporin-mediated root water transport in Arabidopsis.

Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization.

BACKGROUND: Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-κB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. METHODS: Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-ß) and low (TNF-α) expression in M2 macrophages, and molecules in NF-κB pathway (IKKα and Iκ-B) were evaluated by RT-qPCR or western blot. RESULTS: EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-ß and increased TNF-α. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKα suppression and concomitant I-κB accumulation; increase of IL-6 and TGF-ß; and, decrease of TNF-α. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-κB pathway elicited by EGCG-treated exosomes. CONCLUSIONS: Our data demonstrate that EGCG up-regulates miR-16 in tumor cells, which can be transferred to TAM via exosomes and inhibits TAM infiltration and M2 polarization. We suggest a novel mechanism by which EGCG exerts anti-tumor activity via regulation of TAM in tumor microenvironment.

Heparin-conjugated pluronic nanogels as multi-drug nanocarriers for combination chemotherapy.

Combination chemotherapy using more than two therapeutic agents with different modes of action is a promising strategy that can be used to enhance the therapeutic efficacy of cancer treatment, even though it is a complicated treatment modality. The aim of this study was to investigate how a novel multidrug nanocarrier is effective for combination chemotherapy in vitro and, more specifically, whether combined agents with different modes of action and physicochemical properties show synergistic cytotoxicity with the use of this nanocarrier. A heparin-Pluronic (Hep-Pr) nanogel encapsulating both paclitaxel and DNase was shown to be efficient for intracellular delivery with respect to size, encapsulation efficiency, and intracellular uptake/fates. As a result of these properties, a Hep-Pr nanogel combined with paclitaxel and DNase exhibited a dose-dependent synergistic cytotoxicity compared to single drug and free-drug treatments, whose combination indices were 0.93 and 0.45 at higher concentrations (250 and 500 µg/mL). Therefore, Hep-Pr nanogels have the potential to deliver multitherapeutic agents with different characteristics and thereby enhance the therapeutic efficacy of combination cancer chemotherapy.

Comparison of mortality among hemorrhage-control methods performed for hemodynamically unstable patients with traumatic pelvic fractures: A multi-center study.

BACKGROUND: /Objective: We aimed to analyze the effects of hemorrhage control methods on the mortality of patients with hemodynamic instability due to pelvic fracture and investigate independent mortality risk factors in these patients. METHODS: Ninety-seven pelvic bone fracture patients with hemodynamic instability who visited the emergency departments of two university hospitals over 5 years were enrolled. These patients were categorized based on 28-day mortality (survival group) and acute hemorrhage mortality (non-survival group). Forty-seven patients (48.5%) underwent pelvic angiography; 45 (46.4%), pre-peritoneal pelvic packing; and 19 (19.6%), external fixation. RESULTS: Differences in hemorrhage control methods did not significantly affect mortality. However, there was a significant difference in mortality between the groups with and without hemorrhage control methods. Multivariate logistic regression analysis revealed that patient age, trauma and injury severity score (probability of survival), and blood transfusion amount within 24 h were independent risk factors for 28-day mortality. Meanwhile, patient age, Glasgow coma scale (GCS) score, systolic blood pressure (SBP), and blood transfusion amount within 24 h were independent risk factors for mortality due to acute hemorrhage. CONCLUSION: Rapid and appropriate application of hemorrhage control methods can reduce acute hemorrhage-related mortality in hemodynamically unstable patients with pelvic fractures. Moreover, none of the hemorrhage control methods were superior for the decreasing mortality rate in these patients.

Adjuvant intravenous immunoglobulin administration on postoperative critically ill patients with secondary peritonitis: a retrospective study.

BACKGROUND: The use of intravenous immunoglobulin (IVIG) in sepsis patients from bowel perforation is still debatable. However, few studies have evaluated the effect of IVIG as an adjuvant therapy after source control. This study aimed to analyze the effect of IVIG in critically ill patients who underwent surgery due to secondary peritonitis. METHODS: In total, 646 medical records of surgical patients who were treated for secondary peritonitis were retrospectively analyzed. IVIG use, initial clinical data, and changes in Sequential Organ Failure Assessment (SOFA) score over the 7-day admission in the intensive care unit for sepsis check, base excess, and delta neutrophil index (DNI) were analyzed. Mortalities and periodic profiles were assessed. Propensity scoring matching as comparative analysis was performed in the IVIG group and non-IVIG group. RESULTS: General characteristics were not different between the two groups. The survival curve did not show a significantly reduced mortality in the IVIG. Moreover, the IVIG group did not have a lower risk ratio for mortality than the non-IVIG group. However, when the DNI were compared during the first 7 days, the reduction rate in the IVIG group was statistically faster than in the non-IVIG group (P<0.01). CONCLUSIONS: The use of IVIG was significantly associated with faster decrease in DNI which means faster reduction of inflammation. Since the immune system is rapidly activated, the additional use of IVIG after source control surgery in abdominal sepsis patients, especially those with immunocompromised patients can be considered. However, furthermore clinical studies are needed.

Sustained cytoplasmic delivery and anti-viral effect of PLGA nanoparticles carrying a nucleic acid-hydrolyzing monoclonal antibody.

PURPOSE: Cytoplasmic delivery of a monoclonal antibody (mAb) with nucleic acid-hydrolyzing activity (3D8 scFv) using poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) was investigated for persistent anti-viral effect. METHODS: 3D8 scFv-loaded PLGA (3D8-PLGA) NPs were prepared via a double emulsion method that was previously optimized. Flow cytometry and confocal microscopy was carried out to confirm the cellular uptake and cytoplasmic localization. immunochemical and fluorescence resonance energy transfer (FRET) assays tested the cytoplasmic release and hydrolyzing effect of 3D8 scFv, respectively. Anti-viral activity test was performed using MTT assay with vesicular stomatitis virus (VSV)-infected HeLa cells. RESULTS: 3D8-PLGA NPs were much more effectively taken into cells in dose- and time-dependent manner and localized in the cytosolic region, compared to free 3D8 scFv. 3D8 scFv was released and hydrolyzed RNAs in the cytoplasm, exhibiting the maxima at a period of time (12-24 h). Anti-viral activity test revealed that 3D8-PLGA NP has dose- and time-dependent anti-viral effect and the maximum effect at the dose of 2 mg/ml and the incubation of 3 days. CONCLUSIONS: Cytoplasmic delivery of 3D8 scFv via PLGA NPs could enhance the viability of infected cells in sustained manner due to preserved activity, much improved cellular uptake and sustained release.

Treatment with mANT2 shRNA enhances antitumor therapeutic effects induced by MUC1 DNA vaccination.

In this study, we developed a combination therapy (pcDNA3/hMUC1+mANT2 shRNA) to enhance the efficiency of MUC1 DNA vaccination by combining it with mANT2 short hairpin RNA (shRNA) treatment in immunocompetent mice. mANT2 shRNA treatment alone increased the apoptosis of BMF cells (B16F1 murine melanoma cell line coexpressing an MUC1 and Fluc gene) and rendered BMF tumor cells more susceptible to lysis by MUC1-associated CD8(+) T cells. Furthermore, combined therapy enhanced MUC1 associated T-cell immune response and antitumor effects, and resulted in a higher cure rate than either treatment alone (pcDNA3/hMUC1 or mANT2 shRNA therapy alone). Human MUC1 (hMUC1)-loaded CD11c(+) cells in the draining lymph nodes of BMF-bearing mice treated with the combined treatment were found to be most effective at generating hMUC1-associated CD8(+)IFNγ(+) T cells. Furthermore, the in vitro killing activities of hMUC1-associated cytotoxic T cells (CTLs) in the combined therapy were greater than in the respective monotherapies. Cured animals treated with the combined treatment rejected a rechallenge by BMF cells, but not a rechallenge by B16F1-Fluc cells at 14 days after treatment, and showed MUC1 antigen-associated immune responses. These results suggest that combined therapy enhances antitumor activity, and that it offers an effective antitumor strategy for treating melanoma.

Gene silencing by cell-penetrating, sequence-selective and nucleic-acid hydrolyzing antibodies.

Targeting particular mRNAs for degradation is a fascinating approach to achieve gene silencing. Here we describe a new gene silencing tool exploiting a cell-penetrating, nucleic-acid hydrolyzing, single-domain antibody of the light-chain variable domain, 3D8 VL. We generated a synthetic library of 3D8 VL on the yeast surface by randomizing residues located in one of two beta-sheets. Using 18-bp single-stranded nucleic acids as target substrates, including the human Her2/neu-targeting sequence, we selected 3D8 VL variants that had approximately 100-1000-fold higher affinity and approximately 2-5-fold greater selective hydrolyzing activity for target substrates than for off targets. 3D8 VL variants efficiently penetrated into living cells to be accumulated in the cytosol and selectively decreased the amount of target sequence-carrying mRNAs as well as the proteins encoded by these mRNAs with minimal effects on off-target genes. In particular, one 3D8 VL variant targeting the Her2 sequence showed more efficient downregulation of Her2 expression than a small-interfering RNA targeting the same Her2 sequence, resulting in apoptotic cell death of Her2-overexpressing breast cancer cells. Our results demonstrate that cell-penetrating 3D8 VL variants with sequence-selective, nucleic-acid-hydrolyzing activity can selectively degrade target mRNAs in the cytosol, providing a new gene silencing tool mediated by antibody.

Comparison between external fixation and pelvic binder in patients with pelvic fracture and haemodynamic instability who underwent various haemostatic procedures.

Haemostatic procedures such as preperitoneal pelvic packing (PPP), pelvic angiography (PA), and internal iliac artery ligation are used for haemorrhage control in pelvic fracture patients with haemodynamic instability. Pelvic external fixation (PEF) and pelvic binder (PB) are usually applied with haemostatic procedures to reduce the pelvic volume. This study aimed to compare the clinical outcomes between patients who underwent PEF and PB. Among 173 patients with pelvic fracture admitted to the emergency room of three regional trauma centres between January 2015 and December 2018, the electronic charts of haemodynamically unstable patients were retrospectively analysed. Among the 84 patients included in the analysis, 20 underwent PEF with or without PB, and 64 underwent only PB. There were significant differences in tile classification and laparotomy between the PEF and PB groups (p = 0.023 and p = 0.032). PPP tended to be more frequently preformed in the PEF group (p = 0.054), whereas PA tended to be more commonly performed in the PB group than in the PEF group (p = 0.054). After propensity score matching to adjust for differences in patient characteristics and adjunct haemostatic procedure, there was no significant difference in 7-day, 30-day, and overall mortality rates between the PEF and PB groups (10.5% vs 21.1%, p = 0.660, 21.1% vs 26.3%, p = 1.000, and 26.3% vs 26.3%, p = 1.000). Cox proportional hazard regression analysis and multivariate analysis for correction of covariates (age, lactate, and abdominal injury) showed that PEF was not an independent factor for 30-day mortality compared with PB (adjusted hazard ratio, 0.526; 95% confidence interval, 0.092-3.002; p = 0.469). Among the volume reduction procedures performed with other haemostatic procedures in patients with pelvic fracture and haemodynamic instability, PEF did not significantly reduce the 30-day mortality rate compared to PB.

Multiple biomarkers are more accurate than a combination of carbohydrate antigen 125 and human epididymis protein 4 for ovarian cancer screening.

OBJECTIVE: The objective of this study was to compare and evaluate the diagnostic value of serum carbohydrate antigen 125 (CA125) and/or human epididymis protein 4 (HE4) and a panel of novel multiple biomarkers in patients with ovarian tumors to identify more accurate and effective markers for screening ovarian cancer. METHODS: Candidate ovarian cancer biomarkers were selected based on a literature search. Dozens of candidate biomarkers were examined using 143 serum samples from patients with ovarian cancer and 157 healthy serum samples as noncancer controls. To select the optimal marker panel for an ovarian cancer classification model, a set of biomarker panels was created with the number of possible combinations of eight biomarkers. Using the set of biomarkers as an input variable, the optimal biomarker panel was selected by examining the performance of the biomarker panel set using the Random Forest algorithm as a non-linear classification method and a 10-fold cross-validation technique. RESULTS: The final selected optimal combination of five biomarkers (CA125, HE4, cancer antigen 15-3, apolipoprotein [Apo] A1, and ApoA2) exhibited a sensitivity of 93.71% and specificity of 93.63% for ovarian cancer detection during validation. CONCLUSION: Combining multiple biomarkers is a valid strategy for ovarian cancer diagnosis and can be used as a minimally invasive screening method for early ovarian cancer. A panel of five optimal biomarkers, including CA125 and HE4, was verified in this study. These can potentially be used as clinical biomarkers for early detection of ovarian cancer.

Impact of Enforcement of the Act to Improve Training Conditions and the Status of Medical Residents in Emergency Abdominal Surgery.

PURPOSE: In 2018, the Act to Improve Training Conditions and the Status of Medical Residents (AITR) was fully implemented in South Korea. This study aimed to investigate the effects of AITR implementation on the clinical outcomes of patients who underwent emergency abdominal surgery. MATERIALS AND METHODS: A total of 2571 patients who underwent emergency abdominal surgery after visiting the emergency room (ER) between 2015 and 2019 was included. Electronic medical records were retrospectively reviewed. In addition, a comparative analysis was performed for patient groups treated before and after AITR implementation. RESULTS: The median patient age was 48.0 years, and 49.2% of them were male. Appendicitis was the most common diagnosis (82.6%), followed by major abdominal emergencies (9.9%) and cholecystitis (7.5%). The median time from arrival to surgery was 439 min, and 52 (2.0%) patients died. A comparison of patients who underwent surgery before (pre-AITR; 1453, 56.5%) and after (post-AITR; 1118, 43.5%) AITR implementation revealed a significant difference in age, number of residents on a 24-h shift, and diagnosis. The time from ER arrival to surgery was not significantly longer after AITR implementation than before AITR implementation (434 min vs. 443 min, p=0.230). AITR was not a significant risk factor for mortality (p=0.225). CONCLUSION: The time from ER arrival to emergency surgery did not increase significantly after AITR implementation, and there was no difference in the patients' clinical outcomes.

Current management and clinical outcomes for patients with haemorrhagic shock due to pelvic fracture in Korean regional trauma centres: A multi-institutional trial.

INTRODUCTION: The purpose of this study was to evaluate the current management and clinical outcomes in patients with hemodynamic instability due to pelvic fracture in three regional trauma centres in Korea. PATIENTS AND METHODS: Three regional trauma centres participated in this study, and 157 patients who were admitted between January 2015 and December 2018 were enroled. Clinical data were collected prospectively as part of the Korean trauma data bank and were analysed retrospectively. RESULTS: The mean age was 59.3 years, and 107 of 157 (68.2%) were male patients. The most common cause of injury was auto-pedestrian accidents, followed by falls and motor vehicle crashes. The mean admission systolic blood pressure and serum lactate level were 86.7 mmHg and 6.68 mmol/L, respectively. Twenty-four patients (15.3%) had a cardiac arrest in the emergency department (ED). The mean injury severity score was 39.1, and the mean probability of survival (Trauma and Injury Severity Score) was 48.7%. Sixty-six patients (42%) underwent pelvic angiography; 89 (56.7%), preperitoneal pelvic packing (PPP); 27 (17.2%), resuscitative endovascular balloon occlusion of the aorta (REBOA); 20 (12.7%), pelvic external fixation (PEF); and 13 patients (8.3%), internal iliac artery ligation (IIAL). Seventy-three patients (46.5%) died, including 40 (25.5%) who died from acute haemorrhage. With each year, the rates of REBOA and pelvic binder use continued to increase (p<0.001 and p = 0.005, respectively), but the number of PEF cases significantly decreased (p = 0.006). Age, initial lactate, low revised trauma score (RTS), combined abdominal injury, REBOA, and 4-hour requirement of packed red blood cells were independent risk factors associated with mortality, whereas during the period of 2017 and 2018, there were protective factors. The risk factors of mortality due to haemorrhage were cardiac arrest in the ED, RTS, combined chest and abdominal injuries, and IIAL. CONCLUSIONS: Since the establishment of regional trauma centres, the clinical outcomes of patients with hemodynamic instability due to pelvic fracture have significantly improved. As a haemostatic procedure for these patients, PEF has been used less frequently, while pelvic binder and REBOA showed significant increase in their use.

Determination of risk factors associated with surgical site infection in patients undergoing preperitoneal pelvic packing for unstable pelvic fracture.

BACKGROUND: Several recent studies have shown that preperitoneal pelvic packing (PPP) effectively produces hemostasis in patients with unstable pelvic fractures. However, few studies have examined the rate of surgical site infections (SSIs) in patients undergoing PPP following an unstable pelvic fracture. The purpose of the present study was to evaluate factors associated with SSI in such patients. METHODS: We retrospectively reviewed the medical charts of 188 patients who developed hemorrhagic shock due to pelvic fracture between April 2012 and May 2021. Forty-four patients were enrolled in this study. RESULTS: SSI occurred in 15 of 44 patients (34.1%). The SSIs occurred more frequently in cases of repacking during the second-look surgery (0 vs. 4 [26.7%], P=0.010) and combined bladder-urethra injury (1 [3.4%] vs. 4 [26.7%], P=0.039). The incidence of SSIs was not significantly different between patients undergoing depacking within or after 48 hours (12 [41.4%] vs. 5 [33.3%], P=0.603). The mean time to diagnosis of SSI was 8.1±3.9 days from PPP. The most isolated organism was Staphylococcus epidermidis. CONCLUSIONS: Repacking and combined bladder-urethra injury are potential risk factors for SSI in patients with unstable pelvic fracture. Close observation is recommended for up to 8 days in patients with these risk factors. Further, 48 hours after PPP, removing the packed gauze on cessation of bleeding and not performing repacking can help prevent SSI. Additional analyses are necessary with a larger number of patients with the potential risk factors identified in this study.

SOCS1 counteracts ROS-mediated survival signals and promotes apoptosis by modulating cell cycle to increase radiosensitivity of colorectal cancer cells.

As negative regulators of cytokine signaling pathways, suppressors of cytokine signaling (SOCS) proteins have been reported to possess both pro-tumor and anti-tumor functions. Our recent studies have demonstrated suppressive effects of SOCS1 on epithelial to mesenchymal signaling in colorectal cancer cells in response to fractionated ionizing radiation or oxidative stress. The objective of the present study was to determine the radiosensitizing action of SOCS1 as an anti-tumor mechanism in colorectal cancer cell model. In HCT116 cells exposed to ionizing radiation, SOCS1 over-expression shifted cell cycle arrest from G2/M to G1 and promoted radiation-induced apoptosis in a p53-dependent manner with down-regulation of cyclin B and up-regulation of p21. On the other hand, SOCS1 knock-down resulted in a reduced apoptosis with a decrease in G1 arrest. The regulatory action of SOCS1 on the radiation response was mediated by inhibition of radiation-induced Jak3/STAT3 and Erk activities, thereby blocking G1 to S transition. Radiation-induced early ROS signal was responsible for the activation of Jak3/Erk/STAT3 that led to cell survival response. Our data collectively indicate that SOCS1 can promote radiosensitivity of colorectal cancer cells by counteracting ROS-mediated survival signal, thereby blocking cell cycle progression from G1 to S. The resulting increase in G1 arrest with p53 activation then contributes to the promotion of apoptotic response upon radiation. Thus, induction of SOCS1 expression may increase therapeutic efficacy of radiation in tumors with low SOCS1 levels. [BMB Reports 2022; 55(4): 198-203].