Network Biology of Tumor Stem-like Cells Identified a Regulatory Role of CBX5 in Lung Cancer

Mounting evidence links cancers possessing stem-like properties with worse prognosis. Network biology with signal processing mechanics was explored here using expression profiles of a panel of tumor stem-like cells (TSLCs). The profiles were compared to their parental tumor cells (PTCs) and the human embryonic stem cells (hESCs), for the identification of gene chromobox homolog 5, CBX5, as a potential target for lung cancer. CBX5 was found to regulate the stem-like properties of lung TSLCs and was predictive of lung cancer prognosis. The investigation was facilitated by finding target genes based on modeling epistatic signaling mechanics via a predictive and scalable network-based survival model. Topologically-weighted measurements of CBX5 were synchronized with those of BIRC5, DNMT1, E2F1, ESR1, MLH1, MSH2, RB1, SMAD1 and TAF5. We validated our findings in another Taiwanese lung cancer cohort, as well as in knockdown experiments using sh-CBX5 RNAi both in vitro and in vivo.National Science Council (China) (NSC grant 100-2325-B-010-010-MY3/98-2314-B-010-024-MY2/97-3111-B075-001-MY3/ 96-2314-075-056-MY3)National Yang-Ming University (Ministry of Education, Aim for the Top University Plan: 96ADD122, 96ADD125, 96ADT191, 97ACD113, 97ACT302, 98ACT302, 98ACD107, 98ACT192 and Brain Research Center-3T-MRI project)))Taipei Veterans General Hospital (98-C1-099/E1-003/ER3-001)Taipei Veterans General Hospital (Joint Projects of VGHUST (98-G6-6/ 98-P1-01/99-P6-39)Chi Mei Medical Center (CMYM9801)Yen-Tjing-Ling Medical Foundation (96/97/98)Taipei City Hospital (96-002-62-092)Technology Development Program for Academia (TDPA; 98-EC-17-A-19-S2-0107)Taiwan. Department of Industrial Technology, Ministry of Economic AffairsNational Science Council (China) (NSC 101-2325-B-010 -009)Taiwan. Department of Health. Cancer Research Center of Excellence (DOH101-TD-C-111-007

Fluoroquinolone therapy for bloodstream infections caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae

AbstractBackground/PurposeFor extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae infections, carbapenems are recommended as first line therapy, and clinical data on the therapeutic efficacy of fluoroquinolones (FQs) is limited. This study compares the efficacy of FQs and carbapenems for bloodstream infections caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.MethodsBetween 2008 and 2010, adults with ESBL-producing E. coli or K. pneumoniae bacteremia at two medical centers were reviewed. Adults receiving definitive FQ or carbapenem therapy were compared in a propensity score-matched analysis, and 30-day mortality was the primary endpoint.ResultsA total of 299 patients were eligible. Patients receiving a FQ (n = 24), either ciprofloxacin or levofloxacin, had a lower 30-day mortality rate than those with carbapenem therapy (8.3%, 2/24 vs. 23.3%, 64/275; p = 0.12). Multivariate regression analysis revealed that a critical illness [Pitt bacteremia score ≥ 4 points; odds ratio (OR), 7.09; p < 0.001], rapidly fatal underlying disease (OR, 5.73; p < 0.001), and hospital-associated infection (OR, 2.57; p = 0.01) were independently associated with 30-day mortality. By contrast, FQ definitive therapy was a protective factor compared with carbapenems (OR, 0.18; p = 0.04). There were 72 matched cases with carbapenem therapy in a propensity score-matched analysis, and a difference in the 30-day mortality rate of two groups was noted (8.3% vs. 29.2%; p = 0.05).ConslusionFor ESBL-producing E. coli or K. pneumoniae bacteremia, ciprofloxacin or levofloxacin, if active in vitro, can be considered as a carbapenem-sparing alternative

TREATING PEDIATRIC ASTHMA WITH HOLISTIC APPROACHES OF TRADITIONAL CHINESE MEDICINE: A RETROSPECTIVE STUDY

Background: Asthma is a chronic disease increasingly found in children. To find more economical and efficient alternatives to treat pediatric asthma, the Bureau of National Health Insurance of Taiwan launched the Traditional Chinese Medicine Holistic Treatment Program (TCMHTP). The effect of traditional Chinese medicine (TCM) holistic treatments on pediatric asthma was evaluated based on data collected from the program. Materials and Methods: A retrospective study was performed by analyzing a dataset from Changhua Christian Hospital, Taiwan, between January 1st, 2006 and December 31st, 2010. Patients aged between 2 and 15 years, who had been diagnosed with asthma, and had participated in the TCMHTP were recruited, whereas those with other severe diseases were excluded. We analyzed the frequency of emergency department visits (EDV), inpatient admission rate (IAR), and length of hospitalization (LH) of the patients, before and after TCM treatments. Spectral analysis of heart rate variability (HRV) was also conducted. Results: Fifty-eight patients were recruited. The average age of the patients receiving TCM treatments was 5.67±3.03 years. The frequency of EDV decreased from 0.94±0.85 to 0.67±1.19 times annually (p=0.095), the annual IAR decreased from 0.62±0.78 to 0.26±0.67 (p=0.002) and the average LH decreased from 3.32±4.25 to 0.80±1.64 (p=0.000) days per year. Parasympathetically mediated HRV decreased significantly from 60.42±15.33 to 54.89±16.45 nu (p=0.016). Conclusion: The present study revealed that an appropriate period of TCM holistic treatment intervention can not only significantly lower exacerbations and hospitalization frequency but also reduce vagal tone in asthmatic children

TONGUE DIAGNOSIS OF TRADITIONAL CHINESE MEDICINE FOR RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease with unknown etiology that causes the immune system to attack the joints (synoviums), causing chronic inflammation. According to the traditional Chinese medicine (TCM), RA falls into the category of Impediment disease (「Bi」 syndrome), i.e., poor circulation of qi and blood (stasis). Tongue diagnosis is an important method of TCM to detect blood stasis. In this study, 74 RA patients, meeting the pre-set criteria, were recruited via rheumatology outpatient clinic and examined by experienced rheumatologist physicians. Two images-one of the tongue and the other, sublingual vessels-of the same patient were taken by a Canon digital camera in a darkroom with uniform lighting conditions. Relevant features of the tongue were extracted by utilizing image processing techniques. Every tongue was classified into corresponding patterns based on the features identified. The subjects included 62 females and 12 males with an average age of 49.86±13.81 years old, an average morbidity period of 4.56±3.92 years, an average rheumatoid factor(RF) of 225.3±373.8 IU/mL and an average erythrocyte sedimentation rate of (ESR) 40.9±31.9m/hr. According to our study, 86% of the patients with RA have tongues with sublingual vessels with a width of more than 2.7mm, a length of more than 3/5 from tongue tipto sublingual caruncle , or a count of sublingual vessels more than 2. Moreover, since RA index is highly correlated with blood stasis in TCM, a logistic regression is conducted to predict the probability of presence of RA using RF and ESR as explanatory variables. Also, the logistic regression analysis of RA with respect to the conventional tongue diagnosis criteria was performed. Based on the aforementioned studies, we concluded that tongue diagnosis is helpful in detecting blood stasis of RA

Inflammation-based prognostic scores predict the prognosis of locally advanced cervical esophageal squamous cell carcinoma patients receiving curative concurrent chemoradiotherapy: a propensity score-matched analysis

Introduction The present study investigated the crucial role of inflammation-based prognostic scores in locally advanced cervical esophageal squamous cell carcinoma (ESCC) patients who underwent curative concurrent chemoradiotherapy (CCRT). Methods There were 411 ESCC patients enrolled, including 63 cervical ESCC patients. Using the propensity score matching method, 63 thoracic ESCC patients were matched to the 63 cervical ESCC patients. The inflammation-based prognostic scores included the neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), albumin level, c-reactive protein (CRP) level, modified Glasgow prognostic score (mGPS), and CRP/albumin ratio. The chi-square test and Kaplan–Meier method were used for categorical variable data and overall survival, respectively. A Cox regression model was performed for univariate and multivariable analyses. Results With respect to cervical ESCC, NLR ≥ 2.5 (P = 0.019), PLR ≥ 103 (P = 0.013), CRP value >10 mg/l (P = 0.040), mGPS ≥ 1 (P = 0.040), and CRP/albumin ratio ≥ 9.5 (P = 0.033) were significant predictors of worse overall survival (OS) in the univariate analysis. In a multivariable analysis, PLR ≥ 103 (P = 0.010, HR: 2.66, 95% CI [1.27–5.58]) and mGPS ≥ 1 (P = 0.030, HR: 2.03, 95% CI [1.07–3.86]) were the independent prognostic parameters of worse OS. The prognostic value of these biomarkers in the matched thoracic ESCC patients was similar and compatible with the results in the cervical ESCC group in the univariate and multivariable analyses. Conclusions Our study suggests that these inflammation-based prognostic scores are helpful in clinical practice, and PLR and mGPS may predict the prognosis for locally advanced cervical ESCC patients who receive curative CCRT

The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection

Background: Highly pathogenic influenza viruses cause high levels of morbidity, including excessive infiltration of leukocytes into the lungs, high viral loads and a cytokine storm. However, the details of how these pathological features unfold in severe influenza infections remain unclear. Accumulation of Gr1 + CD11b + myeloid cells has been observed in highly pathogenic influenza infections but it is not clear how and why they accumulate in the severely inflamed lung. In this study, we selected this cell population as a target to investigate the extreme inflammatory response during severe influenza infection. Results: We established H1N1 IAV-infected mouse models using three viruses of varying pathogenicity and noted the accumulation of a defined Gr1 + CD11b + myeloid population correlating with the pathogenicity. Herein, we reported that CCR2+ inflammatory monocytes are the major cell compartments in this population. Of note, impaired clearance of the high pathogenicity virus prolonged IFN expression, leading to CCR2+ inflammatory monocytes amplifying their own recruitment via an interferon-alpha/beta receptor 1 (IFNAR1)-triggered chemokine loop. Blockage of IFNAR1-triggered signaling or inhibition of viral replication by Oseltamivir significantly suppresses the expression of CCR2 ligands and reduced the influx of CCR2+ inflammatory monocytes. Furthermore, trafficking of CCR2+ inflammatory monocytes from the bone marrow to the lung was evidenced by a CCR2-dependent chemotaxis. Importantly, leukocyte infiltration, cytokine storm and expression of iNOS were significantly reduced in CCR2-/- mice lacking infiltrating CCR2+ inflammatory monocytes, enhancing the survival of the infected mice. Conclusions: Our results indicated that uncontrolled viral replication leads to excessive production of inflammatory innate immune responses by accumulating CCR2+ inflammatory monocytes, which contribute to the fatal outcomes of high pathogenicity virus infections

Predicting the Severity and Prognosis of Trismus after Intensity-Modulated Radiation Therapy for Oral Cancer Patients by Magnetic Resonance Imaging

To develop magnetic resonance imaging (MRI) indicators to predict trismus outcome for post-operative oral cavity cancer patients who received adjuvant intensity-modulated radiation therapy (IMRT), 22 patients with oral cancer treated with IMRT were studied over a two-year period. Signal abnormality scores (SA scores) were computed from Likert-type ratings of the abnormalities of nine masticator structures and compared with the Mann-Whitney U-test and Kruskal–Wallis one-way ANOVA test between groups. Seventeen patients (77.3%) experienced different degrees of trismus during the two-year follow-up period. The SA score correlated with the trismus grade (r = 0.52, p<0.005). Patients having progressive trismus had higher mean doses of radiation to multiple structures, including the masticator and lateral pterygoid muscles, and the parotid gland (p<0.05). In addition, this group also had higher SA-masticator muscle dose product at 6 months and SA scores at 12 months (p<0.05). At the optimum cut-off points of 0.38 for the propensity score, the sensitivity was 100% and the specificity was 93% for predicting the prognosis of the trismus patients. The SA score, as determined using MRI, can reflect the radiation injury and correlate to trismus severity. Together with the radiation dose, it could serve as a useful biomarker to predict the outcome and guide the management of trismus following radiation therapy