Race and Insurance Status are Associated With Different Management Strategies After Thoracic Trauma.

INTRODUCTION: Health-care disparities based on race and socioeconomic status among trauma patients are well-documented. However, the influence of these factors on the management of rib fractures following thoracic trauma is unknown. The aim of this study is to describe the association of race and insurance status on management and outcomes in patients who sustain rib fractures. METHODS: The Trauma Quality Improvement Program database was used to identify adult patients who presented with rib fractures between 2015 and 2016. Patient demographics, injury severity, procedures performed, and outcomes were evaluated. Multivariate logistic regression analysis was used to determine the effect of race and insurance status on mortality and the likelihood of rib fixation surgery and epidural analgesia for pain management. RESULTS: A total of 95,227 patients were identified. Of these, 2923 (3.1%) underwent rib fixation. Compared to White patients, Asians (AOR: 0.57, P = 0.001), Blacks or African-Americans (AA) (AOR: 0.70, P < 0.001), and Hispanics/Latinos (HL) (AOR: 0.78, P < 0.001) were less likely to undergo rib fixation surgery. AA patients (AOR: 0.67, P = 0.004), other non-Whites (ONW) (AOR: 0.61, P = 0.001), and HL (AOR 0.65, P = 0.006) were less likely to receive epidural analgesia. Compared to privately insured patients, mortality was higher in uninsured patients (AOR: 1.72, P < 0.001), Medicare patients (AOR: 1.80, P < 0.001), and patients with other non-private insurance (AOR: 1.23, P < 0.001). CONCLUSIONS: Non-White race is associated with a decreased likelihood of rib fixation and/or epidural placement, while underinsurance is associated with higher mortality in patients with thoracic trauma. Prospective efforts to examine the socioeconomic disparities within this population are warranted.

Treatment of retinopathy of prematurity (ROP) outside International Classification of ROP (ICROP) guidelines.

AIM: To evaluate the incidence and clinical indications for which eyes were treated for retinopathy of prematurity (ROP) outside the guidelines set by International Classification of ROP (ICROP). METHODS: Medical records of the patients treated at a single tertiary care ophthalmology hospital for ROP from January 2016 to December 2019 were retrospectively analysed to evaluate the indications for which they were treated. RESULTS: Out of 241 eyes, 33 eyes (13.7%) were treated outside the guidelines. The reasons for the treatment outside the guidelines were structural changes (n = 24, 72.7%), persistent stage 3 ROP that did not show any sign of regression for 6 weeks (n = 7, 21.2%) and active ROP with fellow eye being treated (n = 2, 6.1%). The recorded specific structural changes were tangential traction with temporal vessel straightening concerning for macular distortion and ectopia (n = 5, 15.2%), and stage 3 neovascularisation or ridge with anteroposterior traction with risk of progression to stage 4 disease (n = 19, 57.6%). Pre-plus disease was present in 11 eyes (33.3%).After the treatment, ROP stages regressed and retinal vessels grew either until the ora or at least into zone III in all the treated eyes. None of the eyes showed worsening of structural changes after treatment. The mean follow-up of the patients was 12.4 ± 11.7 months. CONCLUSION: Experts occasionally recommend treatment in eyes with disease milder than type 1 ROP. This study may help paediatric retinal practitioners in decision-making in borderline cases.

Detection of Coagulopathy in Chronic Renal Disease using Thromboelastography and its comparison with Conventional Tests.

PURPOSE OF THE STUDY: Thromboelastography provides a holistic picture of blood coagulation including fibrin formation, cross, linking and fibrinolysis. Coagulaopathy in end stage renal disease (ESRD) is multifactorial. The present evaluated the thromboelastographic profile of ESRD patients and compared it to conventional tests of coagulation. STUDY DESIGN: In this observational case control study, fifty ESRD patients and 50 controls were recruited. Venous samples were withdrawn and platelet count, International Normalization Ratio and fibrinogen levels were measure. Simultaneously a thromboelastography (TEG) was performed. All samples were drawn prior to initiation of dialysis. RESULTS: The fibrinogen concentration was higher in the ESRD group compared to control (455.51±83.39 vs. 233.84±71.71 mg/dl, P<0.05). The maximum amplitude in ESRD group was 76.94 ± 15.11 mm, which was significantly higher than control group 65.10±10.31 mm (P<0.05).Out of 50 ESRD patients,39 had maximum amplitude (MA) >73mm, 3 had MA <55 mm while 8 patients had normal MA. Further, it was seen that in four out if the five patients whose INR was greater than 1.5. TEG was hypercoaguable. Also, three patients whose platelet count was less than x105/dl had normal thromboelastographs. Two patients with normal platelet count, fibrinogen and INR had hypercoaguable thromboelastographs. Thromboelastography could detect fibrinolysis in 5 patients of end stage renal disease. CONCLUSION: The present study demonstrated that INR, platelet count and fibrinogen levels do not reflect the actual coagulation status in patients of ESRD. Thromboelastography is a better tool to detect coagulopathy in this group of patients.

The role of Runx2 in facilitating autophagy in metastatic breast cancer cells.

Breast cancer metastases cause significant patient mortality. During metastases, cancer cells use autophagy, a catabolic process to recycle nutrients via lysosomal degradation, to overcome nutritional stress for their survival. The Runt-related transcription factor, Runx2, promotes cell survival under metabolic stress, and regulates breast cancer progression and bone metastases. Here, we identify that Runx2 enhances autophagy in metastatic breast cancer cells. We defined Runx2 function in cellular autophagy by monitoring microtubule-associated protein light chain (LC3B-II) levels, an autophagy-specific marker. The electron and confocal microscopic analyses were utilized to identify alterations in autophagic vesicles. The Runx2 knockdown cells accumulate LC3B-II protein and autophagic vesicles due to reduced turnover. Interestingly, Runx2 promotes autophagy by enhancing trafficking of LC3B vesicles. Our mechanistic studies revealed that Runx2 promotes autophagy by increasing acetylation of α-tubulin sub-units of microtubules. Inhibiting autophagy decreased cell adhesion and survival of Runx2 knockdown cells. Furthermore, analysis of LC3B protein in clinical breast cancer specimens and tumor xenografts revealed significant association between high Runx2 and low LC3B protein levels. Our studies reveal a novel regulatory mechanism of autophagy via Runx2 and provide molecular insights into the role of autophagy in metastatic cancer cells.

Subway-Related Trauma: An Urban Public Health Issue with a High Case-Fatality Rate.

BACKGROUND: Between 1990 and 2003, there were 668 subway-related fatalities in New York City. However, subway-related trauma remains an understudied area of injury-related morbidity and mortality. OBJECTIVE: The objective of this study was to characterize the injuries and events leading up to the injuries of all patients admitted after subway-related trauma. METHODS: We conducted a retrospective case series of subway-related trauma at a Level I trauma center from 2001 to 2016. Descriptive epidemiology of patient demographics, incident details, injuries, and outcomes were analyzed. RESULTS: Over 15 years, 254 patients were admitted for subway-related trauma. The mean (standard error of the mean) age was 41 (1.0) years, 80% were male (95% confidence interval [CI] 74-84%) and median Injury Severity Score was 14 (interquartile range [IQR] 5-24). The overall case-fatality rate was 10% (95% CI 7-15%). The most common injuries were long-bone fractures, intracranial hemorrhage, and traumatic amputations. Median length of stay was 6 days (IQR 1-18 days). Thirty-seven percent of patients required surgical intervention. At the time of injury, 55% of patients (95% CI 49-61%) had a positive urine drug or alcohol screen, 16% (95% CI 12-21%) were attempting suicide, and 39% (95% CI 33-45%) had a history of psychiatric illness. CONCLUSIONS: Subway-related trauma is associated with a high case-fatality rate. Alcohol or drug intoxication and psychiatric illness can increase the risk of this type of injury.

K time & maximum amplitude of thromboelastogram predict post-central venous cannulation bleeding in patients with cirrhosis: A pilot study.

BACKGROUND & OBJECTIVES: Coagulation and haemostasis are dynamic processes. The haemostatic changes in liver disease affect all aspects of coagulation. The prothrombin time (PT)/ international normalized ratio (INR) was developed to monitor oral anticoagulant therapy and the activated partial thromboplastin time to investigate inheritable single factor deficiencies. Viscoelastic tests such as thromboelastogram (TEG) give information about dynamics of clot formation (coagulation factor and anticoagulant activity), clot strength (platelets and fibrinogen) and clot stability (finbrinolysis and factor XIII). Administration of blood products before invasive procedures is still guided by INR and platelet count in patients of liver disease. This study was aimed to evaluate the validity of TEG to predict post-procedural bleed after central venous cannulation in patients with cirrhosis. METHODS: Ninety patients aged 20-70 yr diagnosed with liver cirrhosis requiring elective central venous catheter (CVC) insertion were studied. Platelet count, INR, serum creatinine, TEG and Child-Turcotte-Pugh (CTP) score were recorded before the procedure. Right-sided internal jugular vein was cannulated. On the basis of presence or absence of post-procedural bleed, patients were divided into bleeding and non-bleeding groups. The CTP score, component of TEG (R - reaction time, K - coagulation time, MA - maximum amplitude and α - angle) and laboratory parameters of both the groups were compared. RESULTS: Bleeding was seen more when CTP scores were ≥10 (P=0.05). The K time of 3.05 min or more on thromboelastograph was a significant predictor of bleeding [area under the curve (AUC) 0.694, P=0.047]. MA of 48.8 mm or more was a significant predictor of non-bleeding. INR ≥2.6 was a significant predictor of bleeding (AUC 0.765, P=0.005). K time had a low-positive predictive value of 20 per cent and the positive and negative likelihood ratios of 1.87 and 0.48, respectively. INTERPRETATION & CONCLUSIONS: Our results show that the cut-off value for INR ≥2.6 and K time ≥3.05 min predict bleeding and MA ≥48.8 mm predicts non-bleeding in patients with cirrhosis undergoing central venous pressure catheter cannulation.

Role of Runx2 in crosstalk between Mek/Erk and PI3K/Akt signaling in MCF-10A cells.

Crosstalk among mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3' kinase (PI3K) signaling pathways integrates extracellular cues to regulate mammary epithelial cell growth, proliferation, differentiation, and survival. The runt-related transcription factor, Runx2, is expressed in normal mammary epithelium and promotes differentiation, however, its function in regulation of the MAPK and PI3K signaling crosstalk is not known. We determined the function of Runx2 expression in growth factor-mediated phosphorylation of Erk1/2 and Akt, key downstream kinases in MAPK and PI3K pathway crosstalk in MCF-10A mammary epithelial cells. The Runx2-mediated alterations in cell signaling and associated changes in phenotype were determined by real-time quantitative PCR, Western blotting, immunofluorescence, and flow cytometry approaches. The results revealed that ectopic Runx2 expression differentially downregulates the growth factor (EGF vs. IGF or insulin)-induced pErk1/2 and pAkt levels. Additionally, the ectopic Runx2 expression increases FOXO1 levels, cell cycle G1 stage and promotes survival of MCF-10A cells. Furthermore, we demonstrate that Runx2 expression increases EGF-induced phosphorylation of epidermal growth factor receptor (pEGFR) and relieves Mek/Erk-mediated negative regulation of pEGFR and pAkt levels. Altogether, our results identify functions of Runx2 in MAPK and PI3K signaling crosstalk in MCF-10A cells that could be critical in understanding the mammary epithelial cell growth and survival.

Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells.

INTRODUCTION: The Runt-related transcription factor Runx2 is critical for skeletal development but is also aberrantly expressed in breast cancers, and promotes cell growth and invasion. A de-regulated serine/threonine kinase Akt signaling pathway is implicated in mammary carcinogenesis and cell survival; however, the mechanisms underlying Runx2 role in survival of invasive breast cancer cells are still unclear. METHODS: The phenotypic analysis of Runx2 function in cell survival was performed by gene silencing and flow cytometric analysis in highly invasive MDA-MB-231 and SUM-159-PT mammary epithelial cell lines. The expression analysis of Runx2 and pAkt (serine 473) proteins in metastatic breast cancer specimens was performed by immunohistochemistry. The mRNA and protein levels of kinases and phosphatases functional in Akt signaling were determined by real-time PCR and Western blotting, while DNA-protein interaction was studied by chromatin immunoprecipitation assays. RESULTS: The high Runx2 levels in invasive mammary epithelial cell lines promoted cell survival in Akt phosphorylation (pAkt-serine 473) dependent manner. The analysis of kinases and phosphatases associated with pAkt regulation revealed that Runx2 promotes pAkt levels via mammalian target of rapamycin complex-2 (mTORC2). The recruitment of Runx2 on mTOR promoter coupled with Runx2-dependent expression of mTORC2 component Rictor defined Runx2 function in pAkt-mediated survival of invasive breast cancer cells. CONCLUSIONS: Our results identified a novel mechanism of Runx2 regulatory crosstalk in Akt signaling that could have important consequences in targeting invasive breast cancer-associated cell survival.

Gastric Non-Hodgkin Lymphoma in a Helicobacter pylori-Infected Patient.

Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a rare gastric malignant neoplasm. While the association between Heliobacter pylori infection and gastric mucosa-assisted lymphoid tissue lymphoma is well established, data supporting its association with DLBCL are less robust. Here we present a rare case of PG-DLBCL diagnosed with H. pylori. An 82-year-old man presented to clinic with complaints of worsening epigastric pain. He underwent an endoscopy which revealed 1 large nonbleeding gastric ulcer. Histopathological and immunohistochemical analysis confirmed PG-DLBCL. He was started on H. pylori eradication (HPE) and subsequently completed 6 cycles of R-mini-CHOP chemotherapy. Since then, the patient maintained clinical and radiological remission for more than a year without recurrence. PG-DLBCL is an aggressive Non-hodgkin lymphoma (NHL) that usually presents late. It has been shown that HPE without chemotherapy in DLBCL codiagnosed with H. pylori is not an effective strategy. Thus, the standard of care for patients would be HPE and chemotherapy as in our patient. More research is needed to better understand association between H. pylori and DLBCL.

Current state of care for diabetic retinopathy in India.

In this article we review the current state of care of diabetic retinopathy in India. We discuss the magnitude of the problem; diabetes, and diabetic retinopathy in India. We highlight the causes of vision loss in diabetic retinopathy. The current level of awareness among general population and physicians is a concern. Current screening strategies practiced in India and the situational analysis of ophthalmologists in India are also reviewed. We review the current management of diabetic macular edema and proliferative diabetic retinopathy. To know the current practice pattern among retinal surgeons in India, a survey was done and the results of the survey are presented. There are few studies in the Indian population which have found some genetic risk and protective factors and a summary of these studies are also presented in this article.

Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP-3B/GDF10) in lung cancer cells.

BACKGROUND: The Runt-related transcription factor Runx2 is essential for bone development but is also implicated in progression of several cancers of breast, prostate and bone, where it activates cancer-related genes and promotes invasive properties. The transforming growth factor ß (TGF-ß) family member bone morphogenetic protein-3B (BMP-3B/GDF10) is regarded as a tumor growth inhibitor and a gene silenced in lung cancers; however the regulatory mechanisms leading to its silencing have not been identified. RESULTS: Here we show that Runx2 is highly expressed in lung cancer cells and downregulates BMP-3B. This inverse relationship between Runx2 and BMP-3B expression is further supported by increased expression of BMP-3B in mesenchymal cells from Runx2 deficient mice. The ectopic expression of Runx2, but not DNA binding mutant Runx2, in normal lung fibroblast cells and lung cancer cells resulted in suppression of BMP-3B levels. The chromatin immunoprecipitation studies identified that the mechanism of Runx2-mediated suppression of BMP-3B is due to the recruitment of Runx2 and histone H3K9-specific methyltransferase Suv39h1 to BMP-3B proximal promoter and a concomitant increase in histone methylation (H3K9) status. The knockdown of Runx2 in H1299 cells resulted in decreased histone H3K9 methylation on BMP-3B promoter and increased BMP-3B expression levels. Furthermore, co-immunoprecipitation studies showed a direct interaction of Runx2 and Suv39h1 proteins. Phenotypically, Runx2 overexpression in H1299 cells increased wound healing response to TGFß treatment. CONCLUSIONS: Our studies identified BMP-3B as a new Runx2 target gene and revealed a novel function of Runx2 in silencing of BMP-3B in lung cancers. Our results suggest that Runx2 is a potential therapeutic target to block tumor suppressor gene silencing in lung cancer cells.

EphrinA1-EphA2 interaction-mediated apoptosis and FMS-like tyrosine kinase 3 receptor ligand-induced immunotherapy inhibit tumor growth in a breast cancer mouse model.

BACKGROUND: The receptor tyrosine kinase EphA2 is overexpressed in several types of cancers and is currently being pursued as a target for breast cancer therapeutics. The EphA2 ligand EphrinA1 induces EphA2 phosphorylation and intracellular internalization and degradation, thus inhibiting tumor progression. The hematopoietic growth factor, FMS-like tyrosine kinase 3 receptor ligand (Flt3L), promotes expansion and mobilization of functional dendritic cells. METHODS: We tested the EphrinA1-EphA2 interaction in MDA-MB-231 breast cancer cells focusing on the receptor-ligand-mediated apoptosis of breast cancer cells. To determine whether EphrinA1-EphA2 interaction-associated apoptosis and Flt3L-mediated immunotherapy would have an additive effect in inhibiting tumor growth, we used an immunocompetent mouse model of breast cancer to evaluate intratumoral (i.t.) inoculation strategies with human adenovirus (HAd) vectors expressing either EphrinA1 (HAd-EphrinA1-Fc), Flt3L (HAd-Flt3L) or a combination of EphrinA1-Fc + Flt3L (HAd-EphrinA1-Fc + HAd-Flt3L). RESULTS: In vitro analysis demonstrated that an EphrinA1-EphA2 interaction led to apoptosis-related changes in breast cancer cells. In vivo, three i.t. inoculations of HAd-EphrinA1-Fc showed potent inhibition of tumor growth. Furthermore, increased inhibition in tumor growth was observed with the combination of HAd-EphrinA1-Fc and HAd-Flt3L accompanied by the generation of an anti-tumor adaptive immune response. CONCLUSIONS: The results obtained in the present study, indicating the induction of apoptosis and inhibition of mammary tumor growth, show the potential therapeutic benefits of HAd-EphrinA1-Fc. In combination with HAd-Flt3L, this represents a promising strategy for effectively inducing mammary tumor regression by HAd vector-based therapy.

Vitrectomy for optic disk pit with macular schisis and outer retinal dehiscence.

PURPOSE: To describe the outcomes of vitrectomy for optic disc pit-related maculopathy with central outer retinal dehiscence. METHODS: This prospective interventional case series included seven patients with optic disc pit with macular schisis and central outer retinal dehiscence who underwent vitrectomy with internal limiting membrane peeling, barrage laser photocoagulation, and gas tamponade and were followed for at least 6 months. The surgical outcomes in terms of restoration of macular anatomy and visual improvement were recorded at each visit by fundus photography and optical coherence tomography. RESULTS: The mean age of the patients was 21.3 ± 8.6 years (range, 10-35 years), and the mean duration of defective vision was 6.7 ± 8.5 months (range, 1-24 months). Preoperatively, the median best-corrected visual acuity (BCVA) was 20/60 (range, 20/40 to 20/120). Full-thickness macular holes were noticed in 4 patients 1 month postoperatively. Gas tamponade was repeated in two patients with large macular holes. By the final follow-up, macular holes had closed and BCVA improved in all patients except one. Final mean central macular thickness was 176.83 ± 55.74 µ, the range being 109 µ to 256 µ. The median postoperative BCVA was 20/30 (range, 20/20 to 20/80). Six of 7 patients (85.7%) had improvement in BCVA postoperatively (mean, +2 lines; range, 1-4 lines). Five patients (71%) achieved a postoperative BCVA of ≥20/30. Best-corrected visual acuity dropped by one line in the patient with persistent macular hole. CONCLUSION: Vitrectomy with internal limiting membrane peeling can achieve excellent final surgical outcomes in optic pit maculopathy with outer retinal dehiscence despite the potential for macular hole formation.

Influence of Anaemia on Multifactorial Disease Retinopathy of Prematurity: A Prospective Observational Study.

BACKGROUND: Retinopathy of prematurity (ROP), a preventable cause of childhood blindness, is a severe complication of preterm (PT) birth treatment. PURPOSE: The purpose of this study is to analyse the risk factors (RF) associated with the development and progression of ROP. Particular focus is on the contribution of anaemia towards the development and progression of ROP. METHODS: This study is a prospective observational study done in the Department of Paediatrics at Meenakshi Mission Hospital & Research Centre, Madurai, over 12 months from May 2013 to April 2014. The study included all consecutively admitted neonates born in and out of the hospital with gestational age (GA) less than or equal to 35 weeks or birth weight (BW) less than or equal to 2 kg and assessed for the gestational, perinatal, and postnatal RF. In addition, at the time of ROP screening, haemoglobin (Hb) and haematocrit (Hct) were checked. The statistical analysis was performed by Stata 11.1 (StataCorp LLC, College Station, TX). RESULT: The incidence of ROP in our study (46.7%) is higher than previously reported in India. In our study, GA and weight of the neonate at birth have a significant association with ROP incidence. Anaemia in our study is significantly associated with ROP incidence but not as an independent RF. The outcome of various stages of ROP is statistically significant, showing early stages 1 and 2 have more chances of spontaneous regression, and stages 3 and 4 are more likely to need treatment. Two cases in our study with stage 4 ROP had no complications, and none had stage 5 disease. CONCLUSION: Anaemia should be avoided or corrected in PT newborns as it is a potential and avoidable RF for ROP development. The limitation of our study is the small sample size, and probably more extensive randomized trials will help make this association clear. We recommend ROP screening for PT babies with GA less than 35 weeks and BW less than 2 kg who have the RF amounting to screening and done as per protocol.

Disparity in Transport of Critically Injured Patients to Trauma Centers: Analysis of the National Emergency Medical Services Information System (NEMSIS).

BACKGROUND: Patient morbidity and mortality decrease when injured patients meeting CDC Field Triage Criteria (FTC) are transported by emergency medical services (EMS) directly to designated trauma centers (TCs). This study aimed to identify potential disparities in the transport of critically injured patients to TCs by EMS. STUDY DESIGN: We identified all patients in the National EMS Information System (NEMSIS) database in the National Association of EMS State Officials East region from January 1, 2018, to December 31, 2019, with a final prehospital acuity of critical or emergent by EMS. The cohort was stratified into patients transported to TCs or non-TCs. Analyses consisted of descriptive epidemiology, comparisons, and multivariable logistic regression analysis to measure the association of demographic features, vital signs, and CDC FTC designation by EMS with transport to a TC. RESULTS: A total of 670,264 patients were identified as sustaining an injury, of which 94,250 (14%) were critically injured. Of those 94,250 critically injured, 56.0% (52,747) were transported to TCs. Among all critically injured women (n = 41,522), 50.4% were transported to TCs compared with 60.4% of critically injured men (n = 52,728, p < 0.001). In a multivariable logistic regression model, critically injured women were 19% less likely to be taken to a TC compared with critically injured men (OR 0.81, 95% CI 0.71-0.93, p = 0.003). CONCLUSIONS: Critically injured female patients are less likely to be transported to TCs when compared with their male counterparts. Performance improvement processes that assess EMS compliance with field triage guidelines should explicitly evaluate for sex-based disparities. Further studies are warranted.

Bone metastatic breast cancer cells display downregulation of PKC-ζ with enhanced glutamine metabolism.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer among women and its metastases results in poor survival rates in patients. The ability to alter metabolism is a key attribute cancer cells use to survive within different metastatic microenvironments and cause organ failure. We hypothesized that evaluation of metabolic alterations within tumor cells could provide a better understanding of cancer metastasis. Therefore, to investigate underlying metabolic alterations during metastases, we utilized human MDA-MB-231 and mouse 4T1 models that closely mimic human breast cancer metastasis. METHODS: The glycolysis and glutamine pathway-related changes were examined in bone metastatic cells by XF-24 extracellular flux analyzer and western blotting. The expression levels of genes related to metabolism were examined by PCR arrays. RESULTS: The MDA-MB-231 cells isolated after bone metastases showed reduced glucose uptake and glycolysis compared to parental cells, suggesting that these cells could alter metabolic requirements for survival. To understand these metabolic changes, we investigated glutamine, a common and naturally occurring non-essential amino acid. Interestingly, in reduced glucose conditions both cell lines showed dependence on glutamine for cell survival, and with glutamine withdrawal significantly increasing apoptotic cell death. Glutamine was also critical for normal cell proliferation even in the presence of high glucose concentrations. To further understand this metabolic switch in metastatic cells, we examined the genes related to metabolism and identified a more than seven-fold downregulation of protein kinase C zeta (PKC-ζ) expression levels in bone-derived MDA-MB-231 cells compared to the parental population. The PKC-ζ levels were also significantly reduced in metastatic 4T1 cells compared to non-metastatic MT1A2 cells. Since PKC-ζ deficiency promotes glutamine utilization via the serine biosynthesis pathway, we examined glutamine metabolism. The ectopic expression of PKC-ζ inhibited glutamine conversion to glutamate, while mutant PKC-ζ reversed this effect. Furthermore, the gene expression levels of enzymes involved in serine biosynthesis, phosphoserine phosphatase (PSPH), phosphoserine aminotransferase (PSAT1), and phosphoglycerate dehydrogenase (PHGDH) showed upregulation following glucose deprivation with PKC-ζ deficiency. The PHGDH upregulation was inhibited by ectopically expressing wild type but not mutated PKC-ζ in glucose-deprived conditions. CONCLUSIONS: Our results support the upregulation of serine biosynthesis pathway genes and downregulation of PKC-ζ as potential metabolic alterations for bone metastatic breast cancer cells.

Bone Metastatic Breast Cancer: Advances in Cell Signaling and Autophagy Related Mechanisms.

Bone metastasis is a frequent complication of breast cancer with nearly 70% of metastatic breast cancer patients developing bone metastasis during the course of their disease. The bone represents a dynamic microenvironment which provides a fertile soil for disseminated tumor cells, however, the mechanisms which regulate the interactions between a metastatic tumor and the bone microenvironment remain poorly understood. Recent studies indicate that during the metastatic process a bidirectional relationship between metastatic tumor cells and the bone microenvironment begins to develop. Metastatic cells display aberrant expression of genes typically reserved for skeletal development and alter the activity of resident cells within the bone microenvironment to promote tumor development, resulting in the severe bone loss. While transcriptional regulation of the metastatic process has been well established, recent findings from our and other research groups highlight the role of the autophagy and secretory pathways in interactions between resident and tumor cells during bone metastatic tumor growth. These reports show high levels of autophagy-related markers, regulatory factors of the autophagy pathway, and autophagy-mediated secretion of matrix metalloproteinases (MMP's), receptor activator of nuclear factor kappa B ligand (RANKL), parathyroid hormone related protein (PTHrP), as well as WNT5A in bone metastatic breast cancer cells. In this review, we discuss the recently elucidated mechanisms and their crosstalk with signaling pathways, and potential therapeutic targets for bone metastatic disease.

Weight-based enoxaparin with anti-factor Xa assay-based dose adjustment for venous thromboembolic event prophylaxis in adult trauma patients results in improved prophylactic range targeting.

BACKGROUND: Venous thromboembolism (VTE) is a common morbidity in trauma patients. Standard VTE chemoprophylaxis is often inadequate. We hypothesized that weight-based dosing would result in appropriate prophylaxis more reliably than fixed dosing. METHODS: All patients admitted to a Level 1 trauma center over a 6-month period were included unless contra-indications for VTE prophylaxis existed. A prospective adjusted-dosing group was compared to a retrospective uniform-dosing group. The adjusted-dosing approach consisted of initial weight-based dosing of 0.5 mg/kg subcutaneously (subQ) every 12 h (q12h). Peak anti-factor Xa was measured. Patients outside of the prophylactic range had their dose adjusted by ± 10 mg. The uniform-dosing group received 30 mg subQ q12h, without adjustments. RESULTS: Eighty-four patients were included: 44 in the retrospective control cohort and 40 in the prospective experimental cohort. More patients were sub-prophylactically dosed in the uniform-dosing group relative to the adjusted-dosing group (25% vs 5%, p = 0.03). There was no difference in overall prophylactic range targeting, because the supra-prophylactically dosed patients in the adjusted-dosing group eliminated the effect (p = 0.173). However, after a single dose adjustment, zero patients were outside of prophylactic range (25% versus 0%, RR = infinite, p = 0.003). In the uniform-dosing group, anti-Xa level correlated with body surface area (BSA; R2 = 0.33, p < 0.0001) and weight (R2 = 0.26, p = 0.0005). Weight-based dosing both pre- and post-readjustment normalized the correlation of anti-Xa with BSA (R2 = 0.07, p = 0.1) and weight (R2 = 0.07, p = 0.1). CONCLUSIONS: Weight-based VTE prophylaxis with anti-Xa-based dose adjustment improves prophylactic range targeting relative to uniform dosing and eliminates variances secondary to BSA and weight in trauma patients.