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In the 1920s Otto Warburg first described high glucose uptake, aerobic glycolysis, and high lactate production in tumors. Since then high glucose uptake has been utilized in the development of PET imaging for cancer. However, despite a deepened understanding of the molecular underpinnings of glucose metabolism in cancer, this fundamental difference between normal and malignant tissue has yet to be employed in targeted cancer therapy in the clinic. In this review, we highlight attempts in the recent literature to target cancer cell metabolism and elaborate on the challenges and controversies of these strategies in general and in the context of tumor cell heterogeneity in cancer. [ABSTRACT FROM AUTHOR]

Normal tissues are organized hierarchically with a small number of stem cells, able to self-renew and give rise to all the differentiated cells found in the respective specialized tissues. The undifferentiated, multipotent state of normal stem cells is codetermined by the constituents of a specific anatomical space that hosts the normal stem cell population, called the “stem cell niche.” Radiation interferes not only with the stem cell population but also with the stem cell niche, thus modulating a complex regulatory network. There is now mounting experimental evidence that many solid cancers share this hierarchical organization with their tissue of origin, with the cancer stem cells also occupying specialized niches. In this review, we highlight some of the best-characterized aspects of normal tissue stem cells, cancer stem cells, and their niches in the bone marrow, gut, and brain, as well as their responses to ionizing radiation. [Copyright &y& Elsevier]

Abstract: Background: Psychiatric emergency situations (PES) are of high importance to the German prehospital physician-based emergency medical system. So far, however, no prospective studies regarding the incidence of PES have been performed, neither have effects of training programs on diagnostic and therapeutic accuracy been studied. Method: The protocols of two emergency medical services (EMS) were collected and analyzed prospectively. Emergency physicians (EPs) in Kaiserslautern (KL) attended a standardized educational program and underwent daily supervision. EPs in Homburg (HOM) had not been informed about the study. In KL, sociodemographic variables were collected. An investigator who was not involved in the individual EMS mission assessed the correct classification of PES. Results: Among all calls for an EP, 11.8% were classified as PES. There was no difference between the two centers. Correct classification of PES in KL was significantly higher than that in HOM (94.3% vs. 80.6%). Documentation of suicidal behavior was deficient in both centers. EPs in KL gave verbal crisis intervention significantly more often, administered less medication overall, and dispensed more specific drugs in psychotic disorders and significantly less drugs in substance abuse disorders. Patients were more often treated at the scene and were less often transported to a hospital. Some sociodemographic variables were associated with psychiatric morbidity of treatment. Conclusion: Accounting for 12% of all missions, psychiatric emergencies are a frequent reason for calls for EPs, equaling trauma-related and neurological emergencies. The most frequent reasons for calls were alcohol intoxication, states of agitation and suicidal behavior. The diagnostic and therapeutic accuracy of EPs may be improved with a concise standardized teaching program. [Copyright &y& Elsevier]

INTRODUCTION: Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors that greatly influence the outcome of radiation therapy. This study was designed to determine how varying cycles of hypoxia/reoxygenation affect the response of cervical carcinoma cells irradiated under oxic and hypoxic conditions and whether this could be modulated by proteasome inhibition. MATERIALS AND METHODS: Plateau-phase SiHa cervical carcinoma cells in culture were exposed to varying numbers of 30-minute cycles of hypoxia/reoxygenation directly before irradiation under oxic or hypoxic conditions. 26S Proteasome activity was blocked by addition of MG-132. Clonogenic survival was measured by a colony-forming assay. RESULTS: Under oxic conditions, repeated cycles of hypoxia/reoxygenation decreased the clonogenic survival of SiHa cells. This effect was even more pronounced after the inhibition of 26S proteasome complex. In contrast, under hypoxic conditions, SiHa cells were radioresistant, as expected, but this was increased by proteasome inhibition. CONCLUSIONS: Proteasome inhibition radiosensitizes oxygenated tumor cells but may also protect tumor cells from ionizing radiation under certain hypoxic conditions. [ABSTRACT FROM AUTHOR]

Data from a range of well-controlled clinical trials, observational studies, and clinical use support the efficacy of risperidone for both acute and long-term therapy of schizophrenic psychoses. With regard to positive symptoms, the efficacy of risperidone was shown to be at least comparable with that of haloperidol. However, risperidone differs from conventional antipsychotics because it is more effective against the negative symptoms, has beneficial effects on affective and cognitive symptoms, and carries less risk of extrapyramidal side effects (EPS). To date, risperidone is the only atypical antipsychotic to have shown a significantly lower relapse rate compared with haloperidol in a long-term double-blind trial. This review describes comprehensive trial data and therapeutic observations gained with risperidone in the treatment of schizophrenia since its approval. [Copyright &y& Elsevier]

Ionizing radiation shares with cytokines, such as TNF-α, an ability to generate free radicals in cells and activate downstream proinflammatory responses through NF-κB-dependent signal transduction pathways. Support for the role of free radicals in triggering such responses comes from the use of free radical scavengers like N-acetyl-L-cysteine (NAC). The nature of the link between free radical generation and NF-κB activation is, however, unclear. In this study, we explore the possibility that scavenging of free radicals by NAC might not be the mechanism by which it inhibits NF-κB activation, but rather that NAC acts through inhibition of proteasome function. The effect of NAC on the chymotryptic function of the 26s and 20s proteasome complex was measured in extracts from EVC 304 bladder carcinoma cells by assessing degradation of fluorogenic substrates. NAC inhibited 26s but not 20s proteasome activity, suggesting that it interferes with 19s regulatory subunit function. NAC blocked radiation-induced NF-κB activity in ECV 304 cells and RAW 264.7 macrophages, as measured by a gel shift assay, at doses that inhibited proteasome activity. This provides a possible mechanism whereby NAC could block NF-κB activation and affect the expression of other molecules that are dependent on the ubiquitin/proteasome system for their degradation, other than by scavenging free radicals. [Copyright &y& Elsevier]

Purpose To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model. Methods and Materials The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non–small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated. Results Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations. Conclusion The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from stereotactic ablative radiation therapy. The DLQ model also predicted the remarkable GBM radioresistance, a result that is highly consistent with clinical observations. The radioresistance putatively stemmed from accelerated DCC regrowth that rapidly restored compartmental equilibrium between CSCs and DCCs. [ABSTRACT FROM AUTHOR]

Pro-inflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of pro-inflammatory cytokine TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both obesity and in the response of tissues to radiation, 2 known risk factors for the development of breast cancer. Here, we demonstrated the loss of one TNFR2 allele led to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal end buds. Furthermore, loss of one TNFR2 allele increased the incidence of breast cancer in MMTV-Wnt1 mice and resulted in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathway and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression. These findings unravel the imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations. [ABSTRACT FROM AUTHOR]

Purpose: The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Radiation therapy (RT) is an important treatment modality for managing breast cancer; however, we previously showed that RT can also reprogram a fraction of the surviving breast cancer cells into breast cancer-initiating cells (BCICs), which are thought to contribute to disease recurrence. In this study, we characterize mebendazole (MBZ) as a drug with potential to prevent the occurrence of radiation-induced reprogramming and improve the effect of RT in patients with TNBC.Methods and Materials: A high-throughput screen was used to identify drugs that prevented radiation-induced conversion of TNBC cells into cells with a cancer-initiating phenotype and exhibited significant toxicity toward TNBC cells. MBZ was one of the drug hits that fulfilled these criteria. In additional studies, we used BCIC markers and mammosphere-forming assays to investigate the effect of MBZ on the BCIC population. Staining with propidium iodide, annexin-V, and γ-H2AX was used to determine the effect of MBZ on cell cycle, apoptosis, and double-strand breaks. Finally, the potential for MBZ to enhance the effect of RT in TNBC was evaluated in vitro and in vivo.Results: MBZ efficiently depletes the BCIC pool and prevents the ionizing radiation-induced conversion of breast cancer cells into therapy-resistant BCICs. In addition, MBZ arrests cells in the G2/M phase of the cell cycle and causes double-strand breaks and apoptosis. MBZ sensitizes TNBC cells to ionizing radiation in vitro and in vivo, resulting in improved tumor control in a human xenograft model of TNBC.Conclusions: The data presented in this study support the repurposing of MBZ as a combination treatment with RT in patients with TNBC. [ABSTRACT FROM AUTHOR]

Purpose: To test the hypothesis that the radiation response of cancer stem cells (CSCs) in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) differs and is not reflected in the radiation response of the bulk tumor populations, that radiation therapy (RT) can dedifferentiate non-stem HNSCC cells into CSCs, and that radiation-induced dedifferentiation depends on the HPV status.Methods and Materials: Records of a cohort of 162 HNSCC patients were reviewed, and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for CSCs, we characterized HPV-positive and HPV-negative lines via flow cytometry, sphere-forming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation, and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and quantitative reverse transcription-polymerase chain reaction for re-expression of reprogramming factors.Results: Patients with HPV-positive tumors have superior overall survival and local-regional control. Human papillomavirus-positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. Human papillomavirus-negative HNSCC cell lines lack hierarchy owing to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared with HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors.Conclusions: Supporting the favorable prognosis of HPV-positive HNSCCs, we show that (1) HPV-positive HNSCCs have a lower frequency of CSCs; (2) RT can dedifferentiate HNSCC cells into CSCs; and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor. [ABSTRACT FROM AUTHOR]

Purpose: To explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for γ-secretase inhibitors if combined with radiation. Methods and Materials: Using MCF-7 and T47D breast cancer cell lines, we used real-time reverse transcription–polymerase chain reaction to study the Notch pathway in response to radiation. Results: We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dose–dependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a γ-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool. Conclusions: Our results indicate that, if combined with radiation, γ-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells. [ABSTRACT FROM AUTHOR]

Currently, pay lines for National Institutes of Health (NIH) grants are at a historical low. In this climate of fierce competition, knowledge about the funding situation in a small field like radiation oncology becomes very important for career planning and recruitment of faculty. Unfortunately, these data cannot be easily extracted from the NIH''s database because it does not discriminate between radiology and radiation oncology departments. At the start of fiscal year 2013 we extracted records for 952 individual grants, which were active at the time of analysis from the NIH database. Proposals originating from radiation oncology departments were identified manually. Descriptive statistics were generated using the JMP statistical software package. Our analysis identified 197 grants in radiation oncology. These proposals came from 134 individual investigators in 43 academic institutions. The majority of the grants (118) were awarded to principal investigators at the full professor level, and 122 principal investigators held a PhD degree. In 79% of the grants, the research topic fell into the field of biology, 13% in the field of medical physics. Only 7.6% of the proposals were clinical investigations. Our data suggest that the field of radiation oncology is underfunded by the NIH and that the current level of support does not match the relevance of radiation oncology for cancer patients or the potential of its academic work force. [Copyright &y& Elsevier]

Abstract: Patient inclusion in antipsychotic drug decisions is recommended by international treatment guidelines. For N =300 in patients with schizophrenia, we analysed patients'' preferences for inclusion in decisions and physicians'' estimates which patients actually participated in drug choice. Path analysis was used to examine the relationships between patients'' preferences/actual participation and clinical variables measured. Forty percent of the patients expressed a wish to participate in clinical decisions. Those patients wishing to participate in medical decisions had less insight into the necessity of treatment. Psychiatrists gave better ratings of the doctor–patient relationship to those patients whom they rated as having participated in their drug choice. These patients had more positive attitudes towards antipsychotic medication. There was no relationship between the desire to participate and actual participation in the drug choice. When working with patients exhibiting poor insight and negative drug attitudes, psychiatrists use authoritative decision-making styles despite the patient''s desire to participate. [Copyright &y& Elsevier]

At a meeting of the Translation Research Program of the Radiation Therapy Oncology Group held in early 2008, attendees focused on updating the current state of knowledge in cancer stem cell research and discussing ways in which this knowledge can be translated into clinical use across all disease sites. This report summarizes the major topics discussed and the future directions that research should take. Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use. [Copyright &y& Elsevier]

Abstract: Objective: The prescription rate of antipsychotic depots for patients suffering from schizophrenia is currently low. Among these patients the assumable acceptance rate of depot as treatment of choice is markedly higher, but psychiatrists do report that patients frequently reject the offer of depot treatment. In a first step to highlight this contradiction we aimed at identifying attributes of patients that indicate their qualification for depot treatment in the eyes of the psychiatrists. Method: We surveyed 201 psychiatrists about their evaluation of patients'' attributes potentially influencing their qualification for depot treatment. Multidimensional and cluster analyses were applied to detect associated attributes. A second sample of further 248 psychiatrists was asked about their proposal of depot treatment to patients depending on the number of relapses in the past. Results: Two clusters of attributes were identified characterizing patients'' qualification for depot treatment. In cluster I episodes of non-compliance and relapses in the past were considered as favoring the qualification. cluster II included a high level of insight, openness to drug treatment and profound knowledge about the disease representing attributes that increase patients'' qualification. Patients were significantly more likely to be offered depot treatment after their fourth reexacerbation compared to their first relapse. Conclusions: Attributes comprised in cluster I highly qualify a patient for depot treatment which is in line with the current prescription stereotype. This conservative notion of depot use is supplemented by an alternative cluster II patient profile. Patients fitting this cluster also potentially qualify for depot treatment according to the surveyed psychiatrists and should be offered depot in clinical routine considering the advantages of this form of administration. [Copyright &y& Elsevier]

BACKGROUND: Cancer anemia causes fatigue and correlates with poor treatment outcome. Erythropoietin has been introduced in an attempt to correct these defects. However, five recent clinical trials reported a negative impact of erythropoietin on survival and/or tumor control, indicating that experimental evaluation of a possible direct effect of erythropoietin on cancer cells is required. Cancer recurrence is thought to rely on the proliferation of cancer initiating cells (CICs). In breast cancer, CICs can be identified by phenotypic markers and their fate is controlled by the Notch pathway. METHODS: In this study, we investigated the effect of erythropoietin on CICs in breast cancer cell lines. Levels of erythropoietin receptor (EpoR), CD24, CD44, Jagged-1 expression, and activation of Notch-1 were assessed by flow cytometry. Self-renewing capacity of CICs was investigated in sphere formation assays. RESULTS: EpoR expression was found on the surface of CICs. Recombinant human Epo (rhEpo) increased the numbers of CICs and self-renewing capacity in a Notch-dependent fashion by induction of Jagged-1. Inhibitors of the Notch pathway and PI3-kinase blocked both effects. CONCLUSIONS: Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors. [ABSTRACT FROM AUTHOR]