Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over-expressed in the malignant brain tumor glioblastoma (GBM). It has been previously shown that epidermal growth factor receptors up-regulate Mcl-1 contributing to a cell survival response. Hypoxia is a poor prognostic marker in glioblastoma despite the fact that hypoxic regions have areas of necrosis. Hypoxic regions of GBM also highly express the pro-cell death Bcl-2 family member BNIP3, yet when BNIP3 is overexpressed in glioma cells, it induces cell death. The reasons for this discrepancy are unclear. Herein we have found that Mcl-1 expression is reduced under hypoxia due to degradation by the E3 ligase FBW7 leading to increased hypoxia induced cell death. This cell death is reduced by EGFR activation leading to increased Mcl-1 expression under hypoxia. Conversely, BNIP3 is over-expressed in hypoxia at times when Mcl-1 expression is decreased. Knocking down BNIP3 expression reduces hypoxia cell death and Mcl-1 expression effectively blocks BNIP3 induced cell death. Of significance, BNIP3 and Mcl-1 are co-localized under hypoxia in glioma cells. These results suggest that Mcl-1 can block the ability of BNIP3 to induce cell death under hypoxia in GBM tumors.     

Emerging evidence for CHFR as a cancer biomarker: from tumor biology to precision medicine

Novel insights in the biology of cancer have switched the paradigm of a “one-size-fits-all” cancer treatment to an individualized biology-driven treatment approach. In recent years, a diversity of biomarkers and targeted therapies has been discovered. Although these examples accentuate the promise of personalized cancer treatment, for most cancers and cancer subgroups no biomarkers and effective targeted therapy are available. The great majority of patients still receive unselected standard therapies with no use of their individual molecular characteristics. Better knowledge about the underlying tumor biology will lead the way toward personalized cancer treatment. In this review, we summarize the evidence for a promising cancer biomarker: checkpoint with forkhead and ring finger domains (CHFR). CHFR is a mitotic checkpoint and tumor suppressor gene, which is inactivated in a diverse group of solid malignancies, mostly by promoter CpG island methylation. CHFR inactivation has shown to be an indicator of poor prognosis and sensitivity to taxane-based chemotherapy. Here we summarize the current knowledge of altered CHFR expression in cancer, the impact on tumor biology and implications for personalized cancer treatment.     

Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor,in combination with gemcitabine in US patients with advanced solid tumors

Purpose

AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients.

Experimental design

In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750–1,000 mg/m² on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy).

Results

Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m² and AZD7762 9 mg cohort).

Conclusions

The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m² was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.     

In vivo anticancer activity of vanillin semicarbazone

Objective

To evaluate the anticancer activity of vanillin semicarbazone (VSC) against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice.

Methods

The compound VSC at three doses (5, 7.5 and 10 mg/kg i.p.) was administered into the intraperitoneal cavity of the EAC inoculated mice to observe its efficiency by studying the cell growth inhibition, reduction of tumour weight, enhancement of survival time as well as the changes in depleted hematological parameters. All such parameters were also studied with a known standard drug bleomycin at the dose of 0.3 mg/kg (i.p.).

Results

Among the doses studied, 10 mg/kg (i.p.) was found to be quite comparable in potency to that of bleomycin at the dose of 0.3 mg/kg (i.p.). The host toxic effects of VSC was found to be negligible.

Conclusions

It can be concluded that VSC can therefore be considered as potent anticancer agent.     

Effects of different temperature regimens on the development of Aedes aegypti (L.) (Diptera: Culicidae) mosquitoes

This study was conducted to determine the effects of increased water temperatures on the development of Aedes aegypti immatures under laboratory conditions in Trinidad, West Indies using temperature regulated water baths to cover a range of temperatures from 24–25 °C to 34–35 °C at a relative humidity of 80%. Two experiments were designed: (1) at constant temperature regimens and (2) under diurnal temperature regimens ranging from 24–25 °C to 34–35 °C. At 24–25 °C egg hatching success was 98% at 48 h, however at 34–35 °C egg hatching rates declined to 1.6% after 48 h. Ae. aegypti larvae reared under constant temperature regimens showed pupation on day 4 with highest pupation occurring at 30 °C (78.4%) However, under diurnal temperature regimens, pupation began on day 4 but only at the higher temperatures of 30–35 °C. Under diurnal temperature regimens ranging from 24 °C to 35 °C significantly more females emerged at higher temperatures, than males. In contrast, at constant temperatures of 24–35 °C no significant difference in M/F ratios were observed. The body size of Ae. aegypti reared at constant temperature regimens was significantly larger than males and females larvae reared under diurnal temperature regimens of 25–30 °C. The results of this study are discussed in the context of changing or increasing water temperatures, seasonal changes in vector populations and vector competence. Using these key factors control strategies are recommended to manage vector populations as expected increases in temperatures impact the Caribbean region.     

Biological and Histological Parameters as Predictors of Relapse in Ulcerative Colitis: A Prospective Study

Background/Aim:

Ulcerative colitis is a chronic inflammatory disease of unknown etiology characterized by periods of remission and relapses. This study has been carried out in a group of North Indian patients, where the disease has shown an increasing prevalence and frequent relapses. Hence, there is a need to predict relapse for better management and to reduce morbidity. To assess the importance of biological and histological parameters in predicting relapse when the disease is in quiescent phase.

Materials and Methods:

A prospective study of twenty-six patients with quiescent ulcerative colitis was carried out in Dayanand Medical College and Hospital, Punjab. Only patients with clinical and endoscopic remission at the time of screening visit were included. Hemoglobin, erythrocyte sedimentation rate (ESR), C- reactive protein (CRP) and serum Interleukin-6 (IL-6) levels were measured. The baseline colonoscopic mucosal biopsies were retrieved and studied. Follow-up was conducted for one year at monthly interval or earlier if relapse occurred.

Results:

Fifteen out of twenty-six patients (57.69%) had evidence of clinical relapse during the follow-up. Hemoglobin, ESR, CRP and IL-6 levels were not found to be significant predictors of relapse. Increased number of eosinophils and neutrophils in the lamina propria were observed to be associated with significantly higher relapse rate.

Conclusion:

A higher risk of relapse in patients with quiescent colitis can be predicted by the presence of increased number of eosinophils and neutrophils in the lamina propria.     

Alternaria in patients with allergic rhinitis

Inhalation of fungal spores is shown to participate in the development of allergic rhinitis symptoms. In this study, relation between presence of Alternaria in the human nasal cavity and allergic rhinitis is assessed. In a case-control study, 58 allergic rhinitis patients were compared with a well-matched control group of fifty healthy volunteers for sensitization to Alternaria (by skin prick test) and detection of Alternaria in their nasal mucous by conventional methods (microscopy with Methylene Blue stain and culture in Sabourad dextrose agar). Severity of the disease was determined according to the ARIA classification. Pearson chi-square test was applied to compare the proportional difference between the study groups for detection of Alternaria in the nasal cavity, and sensitization to Alternaria. Relation between detection of Alternaria and allergic rhinitis was significant [OR = 18.18 (4.02-82.50)] In addition, sensitization to Alternaria showed a significant relation with the disease [OR = 2.8 (2.1-3.8)]. There was a significant relation between the presence of Alternaria in the nasal cavity and sensitization to Alternaria [OR = 10.4 (3.8-28.3)]. Both sensitization to Alternaria and presence of Alternaria in the nasal cavity did not have a significant relation with the severity of allergic rhinitis. This study suggests Alternaria as a major allergen that its presence in the nasal cavity and subsequent development of sensitization have significant role in the induction of allergic rhinitis.     

Decreasing operators' radiation exposure during coronary procedures

Aim : Transradial coronary procedures are associated with decreased vascular access site complications and other benefits compared to the femoral approach. There is some concern however about high‐recorded radiation doses for interventional cardiologists using the transradial route. We therefore designed and investigated the effect of a transradial radiation protection board (TRPB) on operator radiation exposure during coronary procedures. Methods and Results : One hundred and six patients were randomly assigned by time period to undergo radial coronary procedures either with or without a TRPB. This is a grooved arm board with a detachable 0.5‐mm lead equivalent shield designed to rest between the patient's arm and side. Individual case‐specific radiation exposures were measured using electronic personal dosimeter worn on the left outer pocket of the lead apron at chest level. The TRPB was used in addition to standard lead apron and thyroid shielding, below‐table leaded flaps, and leaded glass. Operator radiation exposure was significantly decreased in the TRPB group overall: 28 [18–65] μSV versus 19.5 [10.5–35] μSV, P = 0.003. There were no significant differences in procedure duration, total fluoroscopy dose, or contrast load between the two groups. Conclusion : Identification of methods to reduce operator radiation dose is important. The use of the TRPB can significantly reduce radiation exposure to radial operators. © 2010 Wiley‐Liss, Inc.