Gedunin modulates cellular growth and apoptosis in glioblastoma cell lines.

BACKGROUND: Glioblastomas are characterized by aggressive behavior. Surgery, radiotherapy, and alkylating agents, including temozolomide are the most common treatment options for glioblastoma. Often, conventional therapies fail to treat these tumors since they develop drug resistance. There is a need for newer agents to combat this deadly tumor. Natural products such as gedunin have shown efficacy in several human diseases. A comprehensive study of gedunin, an heat shock protein (HSP)90 inhibitor, has not been thoroughly investigated in glioblastoma cell lines with different genetic modifications. AIMS: A key objective of this study was to determine how gedunin affects the biological and signaling mechanisms in glioblastoma cells, and to determine how those mechanisms affect the proliferation and apoptosis of glioblastoma cells. METHODS: The viability potentials of gedunin were tested using MTT, cell counts, and wound healing assays. Gedunin's effects on glioma cells were further validated using LDH and colony formation assays. In addition, we investigated the survival and apoptotic molecular signaling targets perturbed by gedunin using Western blot analysis and flow cytometry. RESULTS: Our results show that there was a reduction in cell viability and inhibition of wound healing in the cells tested. Western blot analysis of the gene expression data revealed genes such as EGFR and mTOR/Akt/NF kappa B to be associated with gedunin sensitivity. Gedunin treatment induced apoptosis by cleaving poly ADP-ribose polymerase, activating caspases, and downregulating BCL-xL. Based on these results, gedunin suppressed cell growth and HSP client proteins, resulting in apoptosis in glioblastoma cell lines. CONCLUSION: Our data provide in vitro support for the anticancer activity of gedunin in glioma cells by downregulating cancer survival proteins.

Insecure attachment and eating disorder symptoms: Intolerance of uncertainty and emotion regulation as mediators.

OBJECTIVE: Literature on eating disorder (ED) symptoms of Black, Indigenous, and People of Color (BIPOC) group is extremely scarce. This study aimed to understand the mechanisms underlying the associations between insecure attachment and ED symptoms and examine whether these mechanisms differed between White and BIPOC groups. METHOD: The study investigated direct and indirect relationship between attachment anxiety/avoidance and ED symptoms via intolerance of uncertainty (IU) and emotion regulation strategies of suppression and reappraisal. Further, we examined whether the proposed mechanisms equally represented White versus BIPOC using Multigroup Structural Equation Model (MG-SEM). A total of 1227 college students (48.50% BIPOC and 51.50% White) completed research questionnaires. RESULTS: Results showed that IU and suppression mediated the relations between insecure attachment and ED symptoms for both White and BIPOC groups. Uniquely, reappraisal mediated the relations between insecure attachment and ED symptoms for the White group, but not for the BIPOC group. DISCUSSION: The implications of the findings for culturally informed practice are discussed, including targeting increasing tolerability of uncertainties and improving emotion regulation to mitigate ED symptoms for those with insecure attachment.

Luteolin enhances erlotinib's cell proliferation inhibitory and apoptotic effects in glioblastoma cell lines.

The epidermal growth factor (EGFR) receptor is frequently overexpressed in glioblastoma multiforme IV (GBM). Increased expression of EGFR leads to increased proliferation, decreased apoptosis, and increased resistance to chemotherapeutic agents. A small molecule called erlotinib inhibits EGFR receptors by binding to their adenosine triphosphate (ATP) binding sites. It is FDA approved to treat a variety of EGFR-mediated cancers. Several clinical trials have explored a combination of erlotinib with other agents to treat glioblastoma since it is believed that erlotinib would benefit patients with GBM with EGFR mutations or expression. Luteolin, a natural flavonoid, inhibits cell growth and induces apoptosis in cancer cells. We investigated the combined effects of erlotinib and luteolin on proliferation and apoptosis on glioblastoma cell lines overexpressing EGFR or glioma cells expressing truncated EGFR (ΔEGFR). In a concentration-dependent fashion, the combination of luteolin and erlotinib reduced cell proliferation (p < 0.05) and induced apoptosis by cleaving PARP and increasing caspase expression. In addition, the combination of luteolin and erlotinib reduced the phosphorylation of downstream EGFR cell signaling molecules such as Akt, NF kappa B, and STAT3 in a concentration-dependent manner. These findings suggest that combining luteolin with erlotinib offers a potential treatment strategy for glioblastoma multiforme IV.

Comparison of 4F-PCC and aPCC time to administration and outcomes for oral anticoagulant-related ICH.

INTRODUCTION: Intracranial hemorrhages (ICHs) are associated with increased morbidity and mortality. Use of oral anticoagulants are a potential risk factor for ICH, and reversal of the anticoagulant with agents such as Four-Factor Prothrombin Complex Concentrate (4F-PCC) or Activated Prothrombin Complex Concentrate (aPCC) is vital to prevent hematoma expansion. The objective of the study was to the compare the time to administration and outcomes of 4F-PCC or aPCC in patients with ICH taking an oral anticoagulant. METHODS: This was a multicenter, retrospective cohort chart review of patients with ICH taking an oral anticoagulants who received 4F-PCC or aPCC over a two year period. The primary outcome of the study was to the compare the time to administration of 4F-PCC or aPCC in patients with ICH on an oral anticoagulant. Secondary outcomes included evaluating mortality rate, modified Rankin scale (mRs) score, presence of worsening bleed volume on first computed tomography (CT) six hours after the initial reading, and hospital and intensive care unit (ICU) length of stay. The tertiary outcome was to evaluate the effect of risk factors for delay on time to administration, with delay being greater than 60 min. RESULTS: A total of 350 patient charts were reviewed and 193 patients (4F-PCC [n = 99] and aPCC [n = 94]) were included in the study. There was no significant difference in the primary outcome of median time to administration for the 4F-PCC group (141 min, IQR [93-185]) compared to aPCC (121 min, IQR [107-194]; p = 0.08). No difference was identified between the two groups for all secondary outcomes. Only time to CT results was found to be a risk factor for administration delay (OR, 1.160; 95% CI, 1.073-1.255; p < 0.001). DISCUSSION: In patients with ICH taking oral anticoagulants, there was no significant difference in the time to administration between 4F-PCC and aPCC. More prospective randomized controlled trials are warranted to determine an ideal reversal time to improve patient outcomes.

Lophira alata Suppresses Phorbol Ester-Mediated Increase in Cell Growth via Inhibition of Protein Kinase C-α/Akt in Glioblastoma Cells.

BACKGROUND: Medicinal plants serve as sources of compounds used to treat other types of cancers. The root of the plant Lophira alata (Ochnaceae) has been used as a component of traditional herbal decoctions administered to cancer patients in southwestern Nigeria. However, the mechanism of the cytotoxic effects of Lophira alata alone or in the presence of phorbol ester has not been investigated in brain tumor cells. OBJECTIVE: This study aimed to examine the cytotoxic potential of the methanolic fraction of Lophira alata root on malignant glioma invasive cellular growth and survival. METHODS: The methanolic fraction of Lophira alata (LAM) was subjected to high-performance liquid chromatography to determine the fingerprints of the active molecules. The antiproliferative effects of Lophira alata were assessed using the MTT and LDH assays. Protein immunoblots were carried out to test the effects of Lophira alata, alone or in the presence of phorbol ester, on survival signaling pathways, such as Akt, mTOR, and apoptotic markers such as PARP and caspases. RESULTS: The methanolic fraction of Lophira alata (LAM) induced a concentration-dependent and time-dependent decrease in glioma cell proliferation. In addition, LAM attenuated phorbol ester-mediated signaling of downstream targets such as Akt/mTOR. Gene silencing using siRNA targeting PKC-alpha attenuated LAM-mediated downregulation of Akt. In addition, LAM induced both PARP and caspase cleavages. The HPLC fingerprint of the fraction indicates the presence of flavonoids. CONCLUSION: LAM decreases cell proliferation and induces apoptosis in glioma cell lines and thus could serve as a therapeutic molecule in the management of gliomas.

Development and validation of a 3D-printed bolus cap for total scalp irradiation.

PURPOSE: The goal of total scalp irradiation (TSI) is to deliver a uniform dose to the scalp, which requires the use of a bolus cap. Most current methods for fabricating bolus caps are laborious, yet still result in nonconformity and low reproducibility, which can lead to nonuniform irradiation of the scalp. We developed and validated patient-specific bolus caps for TSI using three-dimensional (3D) printing. METHODS AND MATERIALS: 3D-printing materials were radiologically analyzed to identify a material with properties suitable for use as a bolus cap. A Python script was developed within a commercial treatment planning system to automate the creation of a ready-to-print, patient-specific 3D bolus cap model. A bolus cap was printed for an anthropomorphic head phantom using a commercial vendor and a computed tomography simulation of the anthropomorphic head phantom and bolus cap was used to create a volumetric-modulated arc therapy TSI treatment plan. The planned treatment was delivered to the head phantom and dosimetric validation was performed using thermoluminescent dosimeters (TLD). The developed procedure was used to create a bolus cap for a clinical TSI patient, and in vivo TLD measurements were acquired for several fractions. RESULTS: Agilus-60 was validated as a new 3D-printing material suitable for use as bolus. A 3D-printed Agilus-60 bolus cap had excellent conformality to the phantom scalp, with a maximum air gap of 4 mm. TLD measurements showed that the bolus cap generated a uniform dose to the scalp within a 2.7% standard deviation, and the delivered doses agreed with calculated doses to within 2.4% on average. The patient bolus was conformal and the average difference between TLD measured and planned doses was 5.3%. CONCLUSIONS: We have developed a workflow to 3D-print highly conformal bolus caps for TSI and demonstrated these caps can reproducibly generate a uniform dose to the scalp.

Perceived family functioning among adolescents with and without loss of control eating.

Youth with loss of control eating (LOC) have poorer social relationships than youth without LOC. However, perceived family functioning among youth reporting LOC is relatively unexplored. We examined perceived family functioning among 990 twins (age = 17.47 ±â€¯0.71 years, 53% female) from the Colorado Center for Antisocial Drug Dependence with (n = 158) and without (n = 832) LOC. LOC was assessed with one binary item. Associations between family functioning and LOC were examined using general linear models that accounted for dependence in twin data. Girls with greater family conflict had higher odds of endorsing LOC (p = .02), but not after accounting for depressive symptoms (p = .26). Further analysis indicated that depressive symptoms mediated the association between LOC and family conflict (p = .04). This finding is consistent with an interpersonal model, which proposes that interpersonal difficulties lead to negative emotional states, which promotes LOC as a method of coping with negative affect. Family cohesion and expressiveness were not associated with LOC in girls, and none of the family functioning variables were associated with LOC in boys (ps > .05). Future studies are needed to clarify these relations and to determine any relevant treatment indications.

Luteolin Decreases Epidermal Growth Factor Receptor-Mediated Cell Proliferation and Induces Apoptosis in Glioblastoma Cell Lines.

Glioblastomas are a subtype of gliomas, which are the most aggressive and deadly form of brain tumours. The epidermal growth factor receptor (EGFR) is over-expressed and amplified in glioblastomas. Luteolin is a common bioflavonoid found in a variety of fruits and vegetables. The aim of this study was to explore the molecular and biological effects of luteolin on EGF-induced cell proliferation and the potential of luteolin to induce apoptosis in glioblastoma cells. In vitro cell viability assays demonstrated that luteolin decreased cell proliferation in the presence or absence of EGF. Immunoblots revealed that luteolin decreased the protein expression levels of phosphorylated Akt, mTOR, p70S6K and MAPK in the presence of EGF. Furthermore, our results revealed the ability of luteolin to induce caspase and PARP cleavages in glioblastoma cells in addition to promoting cell cycle arrest. Our results demonstrated that luteolin has an inhibitory effect on downstream signalling molecules activated by EGFR, particularly the Akt and MAPK signalling pathways, and provided a rationale for further clinical investigation into the use of luteolin as a therapeutic molecule in the management of glioblastoma.

Perfectionism and Contingent Self-Worth in Relation to Disordered Eating and Anxiety.

Perfectionism has been proposed as a transdiagnostic risk factor linked to eating disorders and anxiety. In the current study, we examine domains of contingent self-worth as potential moderators of the relationships between maladaptive perfectionism and disordered eating and anxiety using two waves of data collection. Undergraduate females (N = 237) completed online surveys of the study's core constructs at two points separated by about 14 months. At a bivariate level, maladaptive perfectionism was positively associated with disordered eating and anxiety. Maladaptive perfectionism and both appearance and relationship contingent self-worth interacted to predict increases in disordered eating. Neither of the interactive models predicted change in anxiety. Findings highlight maladaptive perfectionism as a transdiagnostic construct related to both disordered eating and anxiety. Interactive findings suggest that targeting maladaptive perfectionism and contingent self-worth (appearance, relationship) in prevention and treatment efforts could mitigate risk for the development or increase of disordered eating.

Examining impulsivity as a moderator of the relationship between body shame and bulimic symptoms in Black and White young women.

Impulsivity has been linked to bulimic symptomatology in a number of studies; however, few have examined this relationship among Black women. We investigated the correlations between impulsivity and bulimic symptoms, and tested impulsivity as a moderator of the body shame/bulimic symptoms relationship among a sample of female undergraduates (N=276; 97 Blacks, 179 Whites). These participants provided data on body shame, impulsivity, and bulimic symptoms (EDE-Q binge eating frequency, BULIT-R, EDI-Bulimia). Among Blacks, impulsivity was significantly positively associated with all bulimic symptoms measures; among Whites, impulsivity was only positively correlated with binge eating frequency. Furthermore, among Blacks, the combination of high body shame and high impulsivity was associated with the highest levels of bulimic symptoms; these findings were not observed among Whites. This study highlights the importance of impulsivity and body shame in identifying bulimic symptomatology among Black women.

The feasibility and impact of midnight routine blood draws on laboratory orders and processing time.

OBJECTIVES: To evaluate the feasibility of midnight routine blood draws and assess their impact on test result availability and stat laboratory orders. METHODS: We changed the timing of routine blood draws from early morning to midnight on five inpatient wards during the period November 16 to 30, 2011. RESULTS: For the entire institution, of all orders placed each day, laboratory test orders placed from 4:00 to 8:00 am decreased from 55% to 39%, and those placed from 12:00 to 4:00 am increased from 12% to 30%. Stat orders per day decreased during the intervention period (301 ± 53 vs 344 ± 55, P = .04). Morning specimens were more likely to be available by 9:00am (78.1% vs 58.9%, P < .001), and their turnaround time improved by 25.8 minutes (158 vs 184 minutes, P < .001). Patient survey revealed potential preference for midnight blood draws. CONCLUSIONS: Midnight is a feasible alternative for the timing of routine blood draws. Redesigning inflow of laboratory orders improved efficiency of laboratory processing and reduced stat orders.