Benjamin E. Leiby

Stat3 promotes metastatic progression of prostate cancer.

There are currently no effective therapies for metastatic prostate cancer because the molecular mechanisms that underlie the metastatic spread of primary prostate cancer are unclear. Transcription factor Stat3 is constitutively active in malignant prostate epithelium, and its activation is associated with high histological grade and advanced cancer stage. In this work, we hypothesized that Stat3 stimulates metastatic progression of prostate cancer. We show that Stat3 is active in 77% of lymph node and 67% of bone metastases of clinical human prostate cancers. Importantly, adenoviral gene delivery of wild-type Stat3 (AdWTStat3) to DU145 human prostate cancer cells increased the number of lung metastases by 33-fold in an experimental metastasis assay compared with controls. Using various methods to inhibit Stat3, we demonstrated that Stat3 promotes human prostate cancer cell migration. Stat3 induced the formation of lamellipodia in both DU145 and PC-3 cells, further supporting the concept that Stat3 promotes a migratory phenotype of human prostate cancer cells. Moreover, Stat3 caused the rearrangement of cytoplasmic actin stress fibers and microtubules in both DU145 and PC-3 cells. Finally, inhibition of the Jak2 tyrosine kinase decreased both activation of Stat3 and prostate cancer cell motility. Collectively, these data indicate that transcription factor Stat3 is involved in metastatic behavior of human prostate cancer cells and may provide a therapeutic target to prevent metastatic spread of primary prostate cancer.

Association between time of admission to the ICU and mortality: a systematic review and metaanalysis.

BACKGROUND The organizational and staffing structure of an ICU influences the outcome of critically ill and injured patients. A change in the ICU staffing structure frequently occurs at nighttime and on weekends (off-hours). We postulated that patients who are admitted to an ICU during off hours may be at an increased risk of death. METHODS We performed a systematic review of the literature to assess whether admission to an ICU during off-hours is associated with an increased mortality. We selected studies that evaluated the association between time of admission to the ICU and mortality, with adjustment for severity of disease. We excluded studies that included pediatric and non-ICU patients. Study characteristics extracted included date of publication, study design, country where study was done, study population, time factor (weekend or night shift), severity adjustment tool, and outcome. RESULTS Ten cohort studies met our inclusion criteria; eight of these studies evaluated nighttime admissions, whereas six studies evaluated weekend admissions. The pooled analysis demonstrated that nighttime admission was not associated with an increased mortality (odds ratio [OR], 1.0 [95% CI, 0.87-1.17]; P = .956); however, patients admitted over the weekend had a significant increase in the adjusted risk of death (OR, 1.08 [95% CI, 1.04-1.13]; P < .001). Significant heterogeneity was found in the studies that evaluated nighttime admissions. CONCLUSIONS Whereas patients admitted to an ICU over the weekend appear to be at an increased risk of death, nighttime admissions were not associated with an increased mortality. The lower level of staffing and intensity of care provided by many hospitals over the weekend may account for this finding. The heterogeneity noted between studies evaluating nighttime admissions likely reflects the diverse organizational structure of the hospitals and ICUs where these studies were carried out.

Obstructive Sleep Apnea Syndrome and Postoperative Complications: Clinical Use of the STOP-BANG Questionnaire

OBJECTIVE To determine whether high risk scores on preoperative STOP-BANG (Snoring, Tiredness during daytime, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, Gender) questionnaires during preoperative evaluation correlated with a higher rate of complications of obstructive sleep apnea syndrome (OSAS). DESIGN Historical cohort study. SETTING Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. PATIENTS Adult patients undergoing elective surgery at a tertiary care center who were administered the STOP-BANG questionnaire for 3 consecutive days in May 2008. MAIN OUTCOME MEASURES Number and types of complications. RESULTS A total of 135 patients were included in the study, of whom 56 (41.5%) had high risk scores for OSAS. The mean (SD) age of patients was 57.9 (14.4) years; 60 (44.4%) were men. Patients at high risk of OSAS had a higher rate of postoperative complications compared with patients at low risk (19.6% vs 1.3%; P < .001). Age, American Society of Anesthesiologists class of 3 or higher, and obesity were associated with an increased risk of postoperative complications. On multivariate analysis, high risk of OSAS and American Society of Anesthesiologists class 3 or higher were associated with higher odds of complications. CONCLUSION The STOP-BANG questionnaire is useful for preoperative identification of patients at higher than normal risk for surgical complications, probably because it identifies patients with occult OSAS.

Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer

Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67−/TOMM20−/COX−/MCT1−); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67−/TOMM20−/COX−/MCT1−). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target “three-compartment tumor metabolism” in head and neck cancers. It is remarkable that two “non-proliferating” populations of cells (Ki-67−/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial “fuels” for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial “stem cell” layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target “metabolic symbiosis.”

Stat5 promotes metastatic behavior of human prostate cancer cells in vitro and in vivo.

There are no effective therapies for disseminated prostate cancer. Constitutive activation of Stat5 in prostate cancer is associated with cancer lesions of high histological grade. We have shown that Stat5 is activated in 61% of distant metastases of clinical prostate cancer. Active Stat5 increased metastases formation of prostate cancer cells in nude mice by 11-fold in an experimental metastases assay. Active Stat5 promoted migration and invasion of prostate cancer cells, and induced rearrangement of the microtubule network. Active Stat5 expression was associated with decreased cell surface E-cadherin levels, while heterotypic adhesion of prostate cancer cells to endothelial cells was stimulated by active Stat5. Activation of Stat5 and Stat5-induced binding of prostate cancer cells to endothelial cells were decreased by inhibition of Src but not of Jak2. Gene expression profiling indicated that 21% of Stat5-regulated genes in prostate cancer cells were related to metastases, while 7.9% were related to proliferation and 3.9% to apoptosis. The work presented here provides the first evidence of Stat5 involvement in the induction of metastatic behavior of human prostate cancer cells in vitro and in vivo. Stat5 may provide a therapeutic target protein for disseminated prostate cancer.

Transcription Factor Signal Transducer and Activator of Transcription 5 Promotes Growth of Human Prostate Cancer Cells In vivo

Purpose: Signal transducer and activator of transcription 5a/b (Stat5a/b) is the key mediator of prolactin effects in prostate cancer cells via activation of Janus-activated kinase 2. Prolactin is a locally produced growth factor in human prostate cancer. Prolactin protein expression and constitutive activation of Stat5a/b are associated with high histologic grade of clinical prostate cancer. Moreover, activation of Stat5a/b in primary prostate cancer predicts early disease recurrence. Here, we inhibited Stat5a/b by several different methodologic approaches. Our goal was to establish a proof of principle that Stat5a/b is critical for prostate cancer cell viability in vitro and for prostate tumor growth in vivo. Experimental Design: We inhibited Stat5a/b protein expression by antisense oligonucleotides or RNA interference and transcriptional activity of Stat5a/b by adenoviral expression of a dominant-negative mutant of Stat5a/b in prostate cancer cells in culture. Moreover, Stat5a/b activity was suppressed in human prostate cancer xenograft tumors in nude mice. Stat5a/b regulation of Bcl-XL and cyclin D1 protein levels was shown by antisense suppression of Stat5a/b protein expression followed by Western blotting. Results and Conclusions: We show here that inhibition of Stat5a/b by antisense oligonucleotides, RNA interference, or adenoviral expression of dominant-negative Stat5a/b effectively kills prostate cancer cells. Moreover, we show that Stat5a/b is critical for human prostate cancer xenograft growth in nude mice. The effects of Stat5a/b on the viability of prostate cancer cells involve Stat5a/b regulation of Bcl-XL and cyclin D1 protein levels but not the expression or activation of Stat3. This work establishes Stat5a/b as a therapeutic target protein for prostate cancer. Pharmacologic inhibition of Stat5a/b in prostate cancer can be achieved by small-molecule inhibitors of transactivation, dimerization, or DNA binding of Stat5a/b.

Effect of antenatal corticosteroids on survival for neonates born at 23 weeks of gestation.

OBJECTIVE: To estimate if exposure to antenatal corticosteroids was associated with decreased rate of death in neonates born at 23 weeks of gestation. METHODS: This is a retrospective cohort study performed at three tertiary centers of neonates born at 23 weeks of gestation between 1998 and 2007. Stillbirths, voluntary terminations, or parental elected nonresuscitations were excluded. Clinical and demographic variables were examined to determine possible confounding variables. A multivariable logistic regression model was used to assess the effect of steroids on the odds of death after adjustment for these confounders. RESULTS: The sample included 181 neonates. Of the multiple variables examined (institution, race, diagnosis, illicit drug use, antibiotics, assisted reproduction, birth weight, gender, and route of delivery), only multiple gestations were significantly associated (P≤.15) with steroid use and increased odds of death (odds ratio [OR] 3.66, 95% confidence interval [CI] 1.05–12.73) and controlled for in the final model. The multivariable model revealed those exposed to antenatal corticosteroids had decreased odds of death (OR 0.32, 95% CI 0.12–0.84), with no significant differences in the occurrence of necrotizing enterocolitis among survivors (15.4% compared with 28.6%, P=.59) or severe intraventricular hemorrhage (23.1% compared with 57.1%, P=.17). In analyzing the effect of steroid dose, only a complete course of corticosteroids was associated with a decreased odds of death (OR 0.18, 95% CI 0.06–0.54). CONCLUSION: Neonates at 23 weeks of gestation whose mothers completed a course of antenatal corticosteroids had an associated 82% reduction in odds of death. LEVEL OF EVIDENCE: II

Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials.

Received July 30, 2010, and in revised form September 14, 2010. Accepted for publication September 20, 2010. Background: There is debate as to the vasopressor agent of choice in patients with septic shock. According to current guidelines either dopamine or norepinephrine may be considered as the first-line agent for the management of refractory hypotension of septic shock. Objective: The aim of this systematic review was to evaluate randomized clinical trials which compared norepinephrine versus dopamine in critically ill patients with septic shock or in a population of critically ill patients with shock predominantly secondary to sepsis. Data Sources: MEDLINE, Embase, Scopus, Cochrane Register of Controlled Trials and citation review of relevant primary and review articles. Study Selection: Randomized clinical trials that compared norepinephrine with dopamine in critically ill adults with sepsis and reported the 28-day or in-hospital mortality. Data Extraction: We abstracted data on study design, study setting, patient population, 28-day mortality or in-hospital mortality, rate of arrhythmias, hospital length of stay, and ICU length of stay. Data Synthesis: Six studies met our inclusion criteria. These studies included a total of 2043 participants, with 995 in the norepinephrine and 1048 in the dopamine groups. There were 479 (48%) deaths in the norepinephrine group and 555 (53%) deaths in the dopamine group. There was statistically significant superiority of norepinephrine over dopamine for the outcome of in-hospital or 28-day mortality: pooled RR: 0.91 (95% CI 0.83 to 0.99; P = .028). We also found a statistically significant decrease in the rate of cardiac arrhythmias in the norepinephine group as compared to the dopamine group: pooled RR: 0.43 (95% CI 0.26 to 0.69; P ≤ .001). A subgroup analysis that pooled studies in which all the randomized patients had septic shock demonstrated that norepinephrine improved in-hospital or 28-day mortality; however, the results were no longer statistically significant. Conclusions: The analysis of the pooled studies that included a critically ill population with shock predominantly secondary to sepsis showed superiority of norepinephrine over dopamine for in-hospital or 28-day mortality.

Transcription Factor Stat3 Stimulates Metastatic Behavior of Human Prostate Cancer Cells in Vivo, whereas Stat5b Has a Preferential Role in the Promotion of Prostate Cancer Cell Viability and Tumor Growth

Identification of the molecular changes that promote viability and metastatic behavior of prostate cancer is critical for the development of improved therapeutic interventions. Stat5a/b and Stat3 are both constitutively active in locally-confined and advanced prostate cancer, and both transcription factors have been reported to be critical for the viability of prostate cancer cells. We recently showed that Stat3 promotes metastatic behavior of human prostate cancer cells not only in vitro but also in an in vivo experimental metastases model. In this work, we compare side-by-side Stat5a/b versus Stat3 in the promotion of prostate cancer cell viability, tumor growth, and induction of metastatic colonization in vivo. Inhibition of Stat5a/b induced massive death of prostate cancer cells in culture and reduced both subcutaneous and orthotopic prostate tumor growth, whereas Stat3 had a predominant role over Stat5a/b in promoting metastases formation of prostate cancer cells in vivo in nude mice. The molecular mechanisms underlying the differential biological effects induced by these two transcription factors involve largely different sets of genes regulated by Stat5a/b versus Stat3 in human prostate cancer model systems. Of the two Stat5 homologs, Stat5b was more important for supporting growth of prostate cancer cells than Stat5a. This work provides the first mechanistic comparison of the biological effects induced by transcription factors Stat5a/b versus Stat3 in prostate cancer.

A prospective study of symptoms and quality of life in men with chronic prostatitis/chronic pelvic pain syndrome: the National Institutes of Health Chronic Prostatitis Cohort study.

PURPOSE We present the results of 2 years of symptom and quality of life followup of men with CP/CPPS enrolled in the CPC. MATERIALS AND METHODS We followed 445 subjects from 6 clinical centers across North America for 2 years with outcome measures that included the NIH-CPSI, quality of life, and GRA. All subjects were treated according to usual care practices at each clinical site. RESULTS Of the 445 subjects 293 had complete data at 2 years. Withdrawals were younger, had been diagnosed more recently and had higher baseline symptoms. Among the 293 men the mean improvement at 2 years was 5 points on the 43-point NIH-CPSI total score. Most of the observed improvement occurred in the first 3 months of followup. Among all 445 subjects, retaining withdrawals in the denominator, 31% considered themselves moderately or markedly improved at 2 years. Although group mean symptom scores were stable and improved slightly over time, some individual subjects reported large fluctuations. No baseline demographic or clinical factors significantly predicted changes in symptom scores over time. CONCLUSIONS CP/CPPS is a chronic disease characterized by substantial variation in symptoms within and among subjects. There is no evidence that the disorder worsens significantly during 2 years of followup, and for about a third of men with long-standing symptoms there may be moderate to marked improvement during this period.