Targeting the CDK7-MDK axis to suppresses irinotecan resistance in colorectal cancer.

AIMS: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer. MAIN METHODS: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan. KEY FINDINGS: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan. SIGNIFICANCE: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.

Time to positivity of Klebsiella pneumoniae in blood cultures as prognostic marker in patients with intra-abdominal infection: A retrospective study.

Klebsiella pneumoniae is a common causative pathogen of intra-abdominal infection with concomitant bacteraemia, leading to a significant mortality risk. The time to positivity (TTP) of blood culture is postulated to be a prognostic factor in bacteraemia caused by other species. Therefore, this study aimed to investigate the prognostic value of TTP in these patients. The single-centred, retrospective, observational cohort study was conducted between 1 July 2016 and 30 June 2021. All adult emergency department patients with diagnosis of intra-abdominal infection and underwent blood culture collection which yield K. pneumoniae during this period were enrolled. A total of 196 patients were included in the study. The overall 30-day mortality rate was 12.2% (24/196), and the median TTP of the studied cohort was 12.3 h (10.5-15.8 h). TTP revealed a moderate 30-day mortality discriminative ability (area under the curve 0.73, p < 0.001). Compared with the late TTP group (>12 h, N = 109), patients in the early TTP (≤12 h, N = 87) group had a significantly higher risk of 30-day morality (21.8% vs. 4.6%, p < 0.01) and other adverse outcomes. Furthermore, TTP (odds ratio [OR] = 0.79, p = 0.02), Pitt bacteraemia score (OR = 1.30, p = 0.03), and implementation of source control (OR = 0.06, p < 0.01) were identified as independent factors related to 30-day mortality risk in patients with intra-abdominal infection and K. pneumoniae bacteraemia. Therefore, physicians can use TTP for prognosis stratification in these patients.

Risk Factors and Outcomes of Community-Acquired Carbapenem-Resistant Klebsiella pneumoniae Infection in Elderly Patients.

The increasing prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is a global concern. Elderly patients have a diminished immune response and functional reserve, and are thus more vulnerable to bacterial infection. This study aimed to investigate the risk factors and outcomes in elderly patients with community-acquired CRKP infections. We performed a retrospective cohort study in a tertiary medical center between 1 January 2021, and 31 December 2021. All elderly patients who visited the emergency department during this period with culture-positive K. pneumoniae were enrolled, and their baseline demographics, laboratory profiles, management strategies, and outcomes were recorded and analyzed. We identified 528 elderly patients with K. pneumonia infection, and the proportion of patients with CRKP infection was 10.2% (54/528). Recent intensive care unit (ICU) admission and prior carbapenem use are independent risk factors for CRKP infection in elderly patients. Compared to patients with carbapenem-sensitive K. pneumoniae infection, those with CRKP infection had a significantly higher risk of adverse outcomes, including ICU care, respiratory failure, septic shock, and 90-day mortality. CRKP infection was also identified as an independent risk factor for 90-day mortality. Clinicians should be aware of the increasing prevalence of CRKP infections in elderly patients and judiciously choose appropriate antibiotics for these patients.

The Prognostic Value of Time to Positivity of Klebsiella Pneumoniae in Blood Cultures of Elderly Patients With Intra-Abdominal Infection.

Background: Elderly patients with intra-abdominal infection are more vulnerable to sepsis progression, especially in those who had concomitant bacteremia. The time to positivity (TTP) of blood cultures in patients with bacteremia is considered to be a prognostic factor for some bacterial species. This study aimed to investigate the prognostic value of TTP in elderly patients with intra-abdominal infection and Klebsiella pneumoniae bacteremia. Methods: A retrospective observational, case-control study was conducted at a single tertiary referral medical center. All elderly (aged ≥ 65 years) patients diagnosed with intra-abdominal infection and Klebsiella pneumoniae bacteremia in the emergency department between July 1, 2016, and June 30, 2021 were enrolled. The baseline characteristics, TTP of blood cultures, management strategy, and outcomes of each eligible patient were recorded and analyzed. The primary outcome was to examine the association between TTP and the 30-day mortality risk in enrolled patients. Results: A total of 101 patients were included in the study. The overall 30-day mortality rate was 11.9% (12/101). The median TTP of Klebsiella pneumoniae in the eligible patients was 12.5 (11-16) hours. There was a stepwise significantly decreased mortality rate as TTP increased (p = 0.04). The TTP had a moderate mortality discrimination ability (area under receiver operating characteristic curve = 0.75, 95% CI = 0.65-0.83, p < 0.01). Furthermore, the Pittsburg bacteremia score (hazard ratio [HR] = 2.19, p < 0.01) and TTP (HR = 0.82, p = 0.04) were identified as independent factors associated with 30-day mortality. Conclusions: TTP was associated with 30-day mortality risk in elderly patients with Klebsiella pneumoniae bacteremia and intra-abdominal infection. Clinicians can utilize TTP for risk stratification, and initiate prompt treatment in those patients with shorter TTP.

Prediction of 30-Day Mortality Using the Quick Pitt Bacteremia Score in Hospitalized Patients with Klebsiella pneumoniae Infection.

Purpose: Klebsiella pneumoniae is an important causative pathogen of nosocomial infections, resulting in poor prognosis owing to its hypervirulence and antibiotic resistance. A simplified quicker version of the Pitt bacteremia score (PBS) (qPitt) for acute illness severity measurement was developed recently. The goal of this study was to explore the prognostic value of qPitt in patients with K. pneumoniae infection. Patients and Methods: Demographic information and management strategies were retrospectively collected from the records of all adult patients who visited the emergency department between January 1, 2021, and December 31, 2021, with culture-positive K. pneumoniae. The qPitt score was calculated based on: temperature <36°C, systolic blood pressure ≤90 mmHg or vasopressor administration, respiratory rate ≥25 times/min or need of mechanical ventilation, altered mental status, and cardiac arrest event. The 30-day mortality prediction abilities of the qPitt were compared with the PBS, the sequential organ failure assessment (SOFA), and the quick sequential organ failure assessment (qSOFA) using receiver operating characteristic curves. Results: Data from 867 patients (57.8% men) with a mean age of 66.9 were compiled. The 30-day mortality rate of the enrolled patients was 13.4%, and the area under the curve (AUC) of the scoring systems were as follows: SOFA, 0.91 (95% confidence interval [CI]=0.89-0.93), qPitt, 0.87 (95% CI=0.84-0.89), PBS, 0.87 (95% CI=0.85-0.89), and qSOFA, 0.73 (95% CI=0.70-0.76). The AUC of qPitt was significantly higher than that of qSOFA (p<0.01) and similar to that of PBS (p=0.65).The qPitt also demonstrated excellent mortality discrimination ability in non-bacteremic patients, AUC= 0.85 (95% CI=0.82-0.88). Conclusion: The qPitt revealed excellent 30-day mortality prediction ability and also predicted mortality in non-bacteremic patients with K. pneumoniae infection. Clinicians can use this simplified scoring system to stratify patients earlier and initiate prompt treatment in high-risk patients.

Comparison between culture-positive and culture-negative septic shock in patients in the emergency department.

Culture results of patients with septic shock affect their management strategies, including antibiotic administration. This study aimed to compare clinical characteristics and outcomes of patients with culture-negative septic shock (CNSS) and culture-positive septic shock (CPSS) in the emergency department. We also assessed the differences in duration and de-escalation timing of antibiotic administration between the two groups. This single-center, retrospective, case-control study included adult patients diagnosed with septic shock in the emergency department between January 1, 2019 and March 31, 2020. They were divided into the CNSS and CPSS groups based on their culture results. The baseline characteristics, infection sites, culture types, and clinical outcomes were recorded and compared. Patients with CPSS (63.7%, 311/488) and CNSS (36.3%, 177/488) were identified. The CPSS and CNSS groups had comparable clinical outcomes, including mechanical ventilation (29.6% vs. 32.8%, p = 0.46), renal replacement therapy (19.3% vs. 23.2%, p = 0.31), 30-day mortality (35.7% vs. 36.7%, p = 0.82), and in-hospital mortality (39.5% vs. 41.8%, p = 0.63). The CNSS group had a significantly shorter duration (13 [8 - 19] vs. 16 [10 - 23], days, p = 0.04) and earlier de-escalation timing (5 [2 - 9] vs. 9 [7 - 12], day, p = 0.02) of antibiotic administration than the CPSS group. Patients with CNSS and CPSS had similar clinical characteristics and proportion of adverse outcomes. Physicians can evaluate the feasibility of early de-escalation or discontinuation of antibiotic administration in patients with CNSS showing clinical improvement.

Prognostic Values of the Timing of Antibiotic Administration and the Sepsis Bundle Component in Elderly Patients With Septic Shock: A Retrospective Study.

INTRODUCTION: Elderly patients are more susceptible to sepsis and septic shock. Early administration of broad-spectrum antibiotics is a key element of the sepsis management of bundle. Our study aimed to investigate the association between the timing of antibiotics administration and the risk of adverse outcomes in elderly patients with septic shock, and to examine the prognostic value of other bundle elements. METHOD: This is a single-center, retrospective, case-control study including elderly patients (aged ≥ 65 years) diagnosed with septic shock in the emergency department between October 1, 2018, and December 31, 2019. Eligible patients were divided into early (within 1 h) and late (beyond 1 h) groups according to the time interval between septic shock recognition and initial antibiotic administration. The characteristics, sepsis-related severity scores, management strategy, and outcomes were recorded. A multivariate logistic regression model was used to identify the independent prognostic factors. RESULTS: A total of 331 patients were included in the study. The overall 90-day mortality rate was 43.8% (145/331). There were no significant differences in baseline characteristics, sepsis-related severity scores, and management strategy between the two groups. There was no significant difference between the early and late groups in the rate of intensive care unit transfer (46.4% vs. 46.6%, P = 0.96), endotracheal intubation (28.3% vs. 27.5%, P = 0.87), renal replacement therapy (21.7% vs. 21.8%, P = 1.00), or 90-day mortality (44.2% vs. 43.5%, P = 0.90). Serum lactate level (hazard ratio [HR] = 1.15, P < 0.01) and source control (HR = 0.56, P = 0.03) were identified as independent factors associated with 90-day mortality. CONCLUSION: The timing of antibiotic administration was not associated with adverse outcomes in elderly patients with septic shock. Serum lactate level and source control implementation were independent prognostic factors in these patients.

Red Cell Distribution Width as a Prognostic Factor and Its Comparison with Lactate in Patients with Sepsis.

Sepsis remains the leading cause of death in critically ill patients. Thus, regular measurement of lactate levels has been proposed in sepsis guidelines. Elevated red cell distribution width (RDW) is associated with mortality risk in patients with sepsis. This study aimed to investigate the association between RDW and the risk of other adverse outcomes in patients with sepsis and to compare the mortality discriminative ability between lactate and RDW levels. This is a single-centered, retrospective, case-control study that included 504 adult patients with sepsis in the emergency department between 1 January 2020 and 31 December 2020. Eligible patients were divided into normal (RDW ≤ 14.5%) and high (RDW > 14.5%) groups. The baseline characteristics and adverse outcomes were recorded and compared. Compared with the normal RDW group, the patients in the high RDW group had a significantly higher rate of ICU admission (48.8% vs. 32.4%, p = 0.03), septic shock (39.2% vs. 23.5%, p < 0.01), and 30-day in-hospital mortality (32.0% vs. 20.7%, p < 0.01). Furthermore, the RDW (area under curve (AUC) = 0.71) had superior mortality discriminative ability compared to lactate (AUC = 0.63) levels (p = 0.02). Clinicians could rely on this simple and rapid parameter for risk stratification to initiate prompt treatment for patients with sepsis.

Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives.

Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD.

Patients with cirrhosis during the COVID-19 pandemic: Current evidence and future perspectives.

The outbreak of coronavirus disease-2019 (COVID-19) has resulted in a global public health emergency. Patients with cirrhosis were deemed more susceptible to viral infection because of their dysregulated immune response. Similar to the general population, cirrhotic patients exhibit various degrees of COVID-19-related liver injury, which could be attributed to direct virus cytotoxicity, systemic immune system activation, drug-related liver injury, reactivation of pre-existing liver disease, and hypoxic hepatitis. The clinical symptoms in patients with cirrhosis and COVID-19 were similar to those in the general population with COVID-19, with a lower proportion of patients with gastrointestinal symptoms. Although respiratory failure is the predominant cause of mortality in cirrhotic patients with COVID-19, a significant proportion of them lack initial respiratory symptoms. Most evidence has shown that cirrhotic patients have relatively higher rates of morbidity and mortality associated with COVID-19. Advanced cirrhosis was also proposed as an independent factor affecting a poor prognosis and the need to consider COVID-19 palliative care. General measures implemented to prevent the transmission of the virus are also essential for cirrhotic patients, and they should also receive standard cirrhosis care with minimal interruptions. The efficacy of the available COVID-19 vaccines in cirrhotic patients still needs investigation.

Effectiveness of sepsis bundle application and outcomes predictors to cirrhotic patients with septic shock.

INTRODUCTION: Cirrhotic patients with septic shock have a poorer prognosis compared with the general population. Our study aimed to investigate the survival benefit of the implementation of hour-1 bundle proposed by Surviving Sepsis Campaign, and to analyze the predictors associated with short-term mortality of these patients. METHODS: A single-center, retrospective case-control study was conducted among adult patients who visited the emergency department between January 1, 2018 and December 31, 2019. All patients with a diagnosis of liver cirrhosis and septic shock were enrolled. Their baseline characteristics, laboratory results, source of sepsis, and sepsis bundle management were recorded. We further divided the patients into survivor and non-survivor groups to identify independent prognostic factors. RESULTS: A total of 88 patients were eligible for this study. The overall 30-day mortality rate was 53.4% (47/88). The proportion of hour-1 bundle achievement was 30.7% (27/88). There were no significant mortality differences between the hour-1 bundle achievement and non-achievement groups (44.4% vs. 57.4%, p = 0.35). Compared with the patients in the survivor group, patients in the non-survivor group had significantly more advanced stage of cirrhosis and a lower proportion of receiving source control (4.3% vs. 22.0%, p = 0.02). The chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score (adjusted hazard ratio [AHR] =1.52, p < 0.01), serum lactate (AHR =1.03, p < 0.01), and source control (AHR =0.54, p = 0.02) were identified as independent prognostic factors in the multivariate regression model. Furthermore, the CLIF-SOFA score (area under curve [AUC]: 0.81) and lactate levels (AUC: 0.77) revealed good mortality discrimination ability in cirrhotic patients with septic shock. CONCLUSIONS: The application of the hour-1 bundle did not reveal a significant survival benefit to cirrhotic patients with septic shock. Clinicians could utilize CLIF-SOFA scores and lactate levels for mortality risk stratification and put more emphasis on the feasibility of source control to improve their prognosis.

A modified cardiac triage strategy reduces door to ECG time in patients with ST elevation myocardial infarction.

Timely performing electrocardiography (ECG) is crucial for early detection of ST-elevation myocardial infarction (STEMI). For shortening door-to-ECG time, a chief complaint-based "cardiac triage" protocol comprising (1) raising alert among medical staff with bedside triage tags, and (2) immediate bedside ECG after focused history-taking was implemented at the emergency department (ED) in a single tertiary referral center. All patients diagnosed with STEMI visiting the ED between November 2017 and January 2020 were retrospectively reviewed to investigate the effectiveness of strategy before and after implantation. Analysis of a total of 117 ED patients with STEMI (pre-intervention group, n = 57; post-intervention group, n = 60) showed significant overall improvements in median door-to-ECG time from 5 to 4 min (p = 0.02), achievement rate of door-to-ECG time < 10 min from 45 to 57% (p = 0.01), median door-to-balloon time from 81 to 70 min (p < 0.01). Significant trends of increase in achievement rates for door-to-ECG and door-to-balloon times (p = 0.032 and p = 0.002, respectively) was noted after strategy implementation. The incidences of door-to-ECG time > 10 min for those with initially underestimated disease severity (from 90 to 10%, p < 0.01) and walk-in (from 29.2 to 8.8%, p = 0.04) were both reduced. In conclusion, a chief complaint-based "cardiac triage" strategy successfully improved the quality of emergency care for STEMI patients through reducing delays in diagnosis and treatment.

Lymphocyte-to-monocyte ratio predicts mortality in cirrhotic patients with septic shock.

INTRODUCTION: Patients with liver cirrhosis and septic shock have a significantly higher risk of mortality and morbidity compared with non-cirrhotic patients. The peripheral blood lymphocyte-to-monocyte ratio (LMR) can determine the prognosis of cirrhotic patients. Our study aimed to investigate the usefulness of LMR as a predictive marker of mortality risk in cirrhotic patients with septic shock. METHODS: This single-center, retrospective case-control study included adult patients who visited the emergency department between January 1, 2018 and June 30, 2020 and diagnosed with liver cirrhosis and septic shock. They were divided into survivor and non-survivor groups according to their survival status at the 60-day follow-up. We used a Cox proportional hazards regression model to identify independent factors associated with mortality risk and tested the mortality discriminative ability of those factors using the area under a receiver operating characteristic curve. RESULTS: A total of 93 patients were eligible for this study. Compared with the patients in the survivor group, those in the non-survivor group had significantly higher Child-Pugh (11 ± 2 vs. 9 ± 2, p < 0.001) and MELD scores (29 ± 6 vs. 22 ± 8, p < 0.001), higher serum international normalized ratio (1.7 vs.1.4, p = 0.03), bilirubin (6.0 vs. 3.3 mg/dL, p = 0.02), lactate (5.4 vs. 2.7 mmol/L, p < 0.01), creatinine (2.2 vs. 1.6 mg/dL, p = 0.04), higher neutrophil-to-lymphocyte ratio (13.0 vs. 10.3, p = 0.02), and lower LMR (1.1 vs. 2.3, p < 0.01). The LMR (adjusted hazard ratio [aHR] = 1.54, p = 0.01) and lactate (aHR = 1.03, p < 0.01) were identified as independent predictive factors for mortality in the multivariate regression model. Furthermore, LMR (area under curve [AUC]: 0.87) revealed a superior discrimination ability in mortality prediction compared with the Child-Pugh (AUC: 0.72) and MELD (AUC: 0.76) scores. CONCLUSIONS: The LMR can be used to predict mortality risk in cirrhotic patients with septic shock.

Comparing Mortality Risk Predictive Ability of Different Scoring Systems in Cirrhotic Patients with Bacteremia.

Patients with liver cirrhosis and bacteremia have substantially higher risk of mortality and morbidity. Our study aimed to investigate scoring systems that can predict the mortality risk in patients with cirrhosis and bacteremia. A single-center, retrospective cohort study was performed among adult patients who visited the emergency department from January 2015 to December 2018. All patients diagnosed with liver cirrhosis and bacteremia were enrolled and divided into survivor and nonsurvivor groups for comparison based on their 30-day in-hospital mortality event. The Pitt bacteremia score (PBS), model for end-stage liver disease (MELD) score, Child-Pugh score, and quick sequential Organ Failure Assessment (qSOFA) score were calculated and compared using the area under the receiver operating characteristic (AUROC) curves. A total of 127 patients (survivor: 86; nonsurvivor: 41) were eligible for this study. Compared with the nonsurvivor group, patients in the survivor group had significantly lower MELD score (22 ± 7 vs. 29 ± 5, p < 0.001), lower proportion of high qSOFA (score ≥ 2) (23.3% vs. 51.2%, p < 0.01), and high PBS (score ≥ 4) (7.0% vs. 34.1%, p < 0.001) category. There was also a significantly different distribution in Child-Pugh classification between the two groups (p < 0.01). The survivor group had significantly lower proportion of acute-on-chronic liver failure (27.9% vs. 68.3%, p < 0.001) and fewer number of organ failures (p < 0.001). In comparison of the discriminative ability in mortality risk prediction, PBS (AUROC = 0.83, 95% CI = 0.75-0.90, p < 0.001) and MELD scores (AUROC = 0.78, 95% CI = 0.70-0.86, p < 0.001) revealed a better predictive ability than Child-Pugh (AUROC = 0.69, 95% CI = 0.59-0.70, p < 0.01) and qSOFA scores (AUROC = 0.65, 95% CI = 0.54-0.75, p < 0.01). PBS and MELD scores both demonstrated a superior ability of predicting mortality risk in cirrhotic patients with bacteremia.

Comparing the Prognosis of Patient with Alcohol and Nonalcohol-Associated Cirrhosis with Bacteremia.

AIMS: Patients with liver cirrhosis are more susceptible to bacteremia and more likely to have a poor prognosis in comparison to healthy individuals. Studies on the role of alcohol in cirrhotic patients with bacteremia are limited. Our study aimed to investigate the clinical characteristics and prognostic differences between the patients with alcohol and non-alcohol-associated cirrhosis with bacteremia. METHODS: A single-center, retrospective cohort study was conducted among adult patients who presented to the emergency department from January 2015 to December 2018. All patients diagnosed with liver cirrhosis and bacteremia were enrolled and divided into alcohol-associated and non-alcohol-associated groups according to the etiology of their cirrhosis. We compared their clinical characteristics, laboratory results, microbiological data, and infection source as well as outcome measurements between the two groups. RESULTS: A total of 112 cirrhotic patients with bacteremia (alcohol-associated: 67; non-alcohol-associated: 45) were eligible for this study. In comparison with the non-alcohol-associated group, patients in the alcohol-associated group had a significantly higher rate of intensive care unit transfer (41.8% vs. 22.2%, P = 0.04), septic shock occurrence (56.7% vs. 35.6%, P = 0.04) and 30-day mortality risk (37.3% vs. 15.6%, P = 0.02). Moreover, alcohol-associated cirrhosis and Model for End-Stage Liver Disease score were independent predictors of 30-day mortality in cirrhotic patients with bacteremia. CONCLUSIONS: The etiology of liver cirrhosis influences the outcomes of patients with bacteremia as well as the severity of their cirrhosis.

BMI1-KLF4 axis deficiency improves responses to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer.

PURPOSE: Neoadjuvant concurrent chemoradiotherapy (CCRT) is a gold standard treatment for patients with stage II/III rectal cancer. B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) is a member of the polycomb group of proteins that are involved in regulating gene expression. High levels of BMI1 have been demonstrated to contribute to the malignant phenotypes of several cancers; however, its relevance in rectal cancer treated with CCRT is largely unknown. METHODS AND MATERIALS: We used two patient cohorts to address the clinical relevance of BMI1 in human cancers. In addition, HT-29 and HCT-116 cells were chosen as our in vitro models to verify the role of BMI1 in cell response to ionizing radiation. Stemness-related proteins were analyzed by western blotting and cell survival was determined using clonogenic assays. RESULTS: BMI1 overexpression was found to significantly correlate with advanced pre-treatment nodal status (N1-N2; p < 0.001), post-treatment tumor stage (T1-T2; p = 0.015), inferior tumor regression grade (p = 0.001), and also an independent prognosis factor in 172 rectal cancer patients receiving CCRT. Serial cell-based functional examination indicated that BMI1 deficiency sensitized cells to radiation treatment by modulating the gene expression of Kruppel-like factor 4 (KLF4) and enhanced radiosensitivity in microsatellite stable (MSS) colorectal cancers. Overexpression of KLF4 partially overcame BMI1-deficiency-mediated γ-H2AX expression after ionizing radiation exposure. Consistent with in vitro data, an analysis of an additional 30 rectal cancer tissue specimens revealed a positive correlation between BMI1 and KLF4 (p = 0.02). CONCLUSION: Higher levels of BMI1 are associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT.

Afebrile Bacteremia in Adult Emergency Department Patients with Liver Cirrhosis: Clinical Characteristics and Outcomes.

Cirrhotic patients with bacteremia are at an increased risk of organ failure and mortality. In addition, they can develop serious infection without fever because of their impaired immune response. Our study aimed to investigate the clinical characteristics and outcomes in afebrile bacteremic patients with liver cirrhosis. A single-center, retrospective cohort study was performed on adult patients who visited the emergency department from January 2015 to December 2018. All patients with bacteremia and diagnosis of liver cirrhosis were enrolled and classified as either afebrile or febrile. In total, 104 bacteremic patients with liver cirrhosis (afebrile: 55 patients and, febrile: 49) were included in the study. Compared with the febrile group, patients in the afebrile group showed a significantly higher rate of inappropriate antibiotics administration (43.6% vs. 20.4%, p = 0.01). They were also at an increased risk of 30-day mortality (40% vs. 18.4%, p = 0.02), intensive care unit transfer (38.2% vs. 18.4%, p = 0.03) and endotracheal intubation (27.3% vs. 10.2%, p = 0.03). The afebrile state was also an independent risk factor associated with 30-day mortality in cirrhotic patients with bacteremia. Clinicians should perform a prudent evaluation in cirrhotic patients and carefully monitor for possible signs of serious infection even in the absence of fever.