Inhibitors of Stearoyl-Coenzyme A Desaturase 1 and 5 May Provide a Novel Therapeutic Strategy for the Treatment of Neurological Disorders and Brain Cancer.

Glioblastoma multiforme (GBM) is the most common primary brain cancer and one of the most lethal primary malignancies in humans. Glioblastoma patients have a poor prognosis, with a patient survival rate at five years after diagnosis of less than 5% and a median survival of only 14.6 months. Glioblastoma is highly resistant to radio- and chemotherapy, and there is no effective cure for patients. Effective chemopreventive treatment for brain cancer would have a tremendous impact on brain cancer morbidity and mortality. Autophagic cell death is an important physiological process of all eukaryotic cells. Autophagic cell death is characterized by massive degradation of cellular contents, including portions of the cytoplasm and intracellular organelles, by means of complicated intracellular membrane/vesicle reorganization and lysosomal hydrolysis. Autophagic cell death is important for development and stress responses and has also been observed in several human diseases, including neurodegenerative and muscular disorders as well as resistance to pathogens. Furthermore, like apoptosis, autophagic cell death is suppressed in malignant tumors. A number of studies have reported that autophagy is activated in response to γ-irradiation and various anticancer therapies, particularly in apoptosis-deficient cells. Several molecular and cell signaling pathways have been implicated in regulating autophagy, such as the BECN1, AMPK (AMP-activated protein kinase), MAPK (mitogen-activated kinase) and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin) pathways. However, the detailed mechanisms of the autophagic cell-signaling pathway are still poorly understood. α-Mangostin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a quinonoid constituent isolated from mangosteen, a tropical fruit native to southeast Asia. It has been shown to possess antioxidants and stabilize digestion. α-Mangostin also has anticancer and antiproliferative properties in leukemia as well as prostate, breast and colorectal cancers. However, the effect of α-mangostin on brain cancer and the molecular mechanism of its effect have not yet been fully determined. In this study, we determined the effect of α-mangostin on cell growth inhibition using in vitro and in vivo experimental models. We measured its effect on cell viability and autophagic cell death in two human brain cancer cell lines, GBM8401 and DBTRG-05MG. Furthermore, to establish α-mangostin’s anticancer mechanism, we determined the levels of autophagy-related molecules, which are strongly associated with the cell death signal transduction pathway and also affect the sensitivity of tumor cells to anticancer agents. This study is the first to investigate the anticancer effects of α-mangostin in human glioblastoma cells. α-Mangostin decreases cell viability by inducing autophagic cell death, but not apoptosis. Pretreatment of cells with the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin or knockdown Beclin-1, resulted in the suppression of α-mangostin-mediated cell death. We also found that Liver Kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling is a critical mediator of α-mangostin-induced inhibition of cell growth. Activation of AMPK induces α-mangostin-mediated phosphorylation of raptor, which subsequently associates with 14-3-3γ and results in loss of mTORC1 activity. The phosphorylation of both of mTORC1’s downstream targets, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, is also diminished by activation of AMPK. Furthermore, the inhibition of AMPK expression with shRNAs or an inhibitor of AMPK reduced α-mangostin induced autophagy and raptor phosphorylation, supporting the theory that activation of AMPK is beneficial to autophagy. Further investigation revealed that α-mangostin also induced autophagic cell death in transplanted glioblastoma in nude mice. Together, these results suggest a critical role for AMPK activation in the α-mangostin-induced autophagy of human glioblastoma cells.

ICH in primary or metastatic brain cancer patients with or without anticoagulant treatment: a systematic review and meta-analysis

Risk of Intracranial Hemorrhage with Direct Oral Anticoagulants (DOACs) Versus Low Molecular Weight Heparin (LMWH) in Primary and Secondary Brain Cancers: An up-to-Date Meta-Analysis of Comparative Studies

Primary brain cancer or brain cancer is the overgrowth of abnormal or malignant cells in the brain or its nearby tissues that form unwanted masses called brain tumors. People with malignant brain tumors suffer a lot, and the expected life span of the patients after diagnosis is often only around 14 months, even with the most vigorous therapies. The blood-brain barrier (BBB) is the main barrier in the body that restricts the entry of potential chemotherapeutic agents into the brain. The chances of treatment failure or low therapeutic effects are some significant drawbacks of conventional treatment methods. However, recent advancements in nanotechnology have generated hope in cancer treatment. Nanotechnology has shown a vital role starting from the early detection, diagnosis, and treatment of cancer. These tiny nanomaterials have great potential to deliver drugs across the BBB. Beyond just drug delivery, nanomaterials can be simulated to generate fluorescence to detect tumors. The current Review discusses in detail the challenges of brain cancer treatment and the application of nanotechnology to overcome those challenges. The success of chemotherapeutic treatment or the surgical removal of tumors requires proper imaging. Nanomaterials can provide imaging and therapeutic benefits for cancer. The application of nanomaterials in the diagnosis and treatment of brain cancer is discussed in detail by reviewing past studies.

Background Stereotactic laser ablation(SLA) or laser interstitial thermal therapy (LITT) has been increasingly adopted as a treatment for primary and metastatic brain cancers. Here, we examined the published economic assessments of SLA, and review the current state of knowledge. Methods The PubMed database was queried for articles investigating the cost-effectiveness of LITT. 3068 articles were screened. Two studies that met the inclusion criteria were included in this review. Results Cost-effectiveness analysis(CEA) favored SLA(n = 8) relative to craniotomy (n = 92) for brain metastases (Mean difference [MD]=−US$6522; 95% confidence interval (CI) –$11,911 to –$1133; p = 0.02). SLA (n = 19) was found to be cost equivalent to craniotomy (n = 248) (MD=–US$1669; 95%(CI) –$8192 to $4854, p = 0.62) for primary brain tumors in general. CEA favored SLA for a subset of primary brain cancers. SLA was found to be cost-effective for difficult to access high-grade gliomas(HGG). When compared to ‘other’ existing treatments, the cost per life-years gained (LYG) through SLA was ∼$29,340, a threshold below that set for new technology adaptation in the U.S. Factors contributing to these cost-effectiveness were: (1) SLA of HGGs was associated with three-months prolongation in survival; (2) SLA of brain metastasis was associated with (i) shorter average length of stay (SLA: 2.3 days; craniotomy: 4.7 days), (ii) decreased discharge to inpatient rehabilitation facility (IRF), skilled nursing facility (SNF), or home healthcare (SLA: 14.8%; craniotomy: 52%), (iii) lowered 30-day readmission (SLA: 0%; craniotomy: 14.1%). Conclusion There is limited data on the cost-effectiveness of SLA. In the available literature, SLA compared favorably to craniotomy in terms of cost-effectiveness as a treatment for primary and metastatic brain cancers.

There is currently no effective therapeutic capable of arresting or inducing regression of primary or metastatic brain cancers. This article presents both pre-clinical and clinical studies supportive that a new bioengineered technology could induce regression and/or elimination of primary and metastatic brain cancers through three disease-modifying mechanisms. Transcranial Radiofrequency Wave Treatment (TRFT) is non-thermal, non-invasive and self-administered in-home to safely provide radiofrequency waves to the entire human brain. Since TRFT has already been shown to stop and reverse the cognitive decline of Alzheimer's Disease in small studies, evidence is provided that three key mechanisms of TRFT action, alone or in synergy, could effectively treat brain cancers: (1) enhancement of brain meningeal lymph flow to increase immune trafficking between the brain cancer and cervical lymph nodes, resulting in a robust immune attack on the brain cancer; (2) rebalancing of the immune system's cytokines within the brain or brain cancer environment to decrease inflammation therein and thus make for an inhospitable environment for brain cancer growth; (3) direct anti-proliferation/antigrowth affects within the brain tumor microenvironment. Importantly, these mechanisms of TRFT action could be effective against both visualized brain tumors and those that are yet too small to be identified through brain imaging. The existing animal and human clinical evidence presented in this perspective article justifies TRFT to be clinically tested immediately against both primary and metastatic brain cancers as monotherapy or possibly in combination with immune checkpoint inhibitors.

CD44 is a nexus between prognosis and therapeutics for brain cancer management.

In the United States, 22020 new cases of cancer in central nervous system (CNS) are expected to occur in 2010 (CBTRUS 2010). Although the incidence of cancers in CNS is much lower than that of malignancies in other organs such as lung, breast and colorectal cancers, CNS cancers are the second lethal cancer for males younger than 40 years (Jemal et al. 2010). In addition, with the unconstraint growth, brain cancers can often involve eloquent area. As a result, the neurological and psychological deficits may severely damage the health-related quality of life (QOL) in patients with brain cancers. Improvement of QOL and the prognosis of brain cancers is the goal of both physicians and basic investigators. Glioblastoma multiforme (GBM) is the most frequent primary brain cancer, accounting for 17% of all primary tumours in CNS. In the past five decades, despite the advances in the fields of neurosurgery, radiotherapy and pharmaceutics, the prognosis of patients with GBM remains dismal, with a 5-year survival of only 9.8%(Stupp et al. 2009). The nature of extensive proliferation, diffuse infiltration and resistance to conventional treatments makes the chance to cure GBM slim. Exploration of mechanisms underlying therapeutic resistance of GBM and developing novel strategies against GBM are of urgent necessity. The emergence of brain tumour stem cell (BTSC) theory is a great breakthrough in the field of neuro-oncology. BTSC theory assumes that brain tumour is a hierarchy of cancer cells maintained by a small population of cells sharing characteristics of normal embryonic and somatic stem cells. BTSC theory is confirmed by the isolation of BTSCs from established brain tumour cell lines and freshly surgical samples. Accumulated evidence suggests that BTSCs are responsible for the initiation, progression, recurrence and treatment resistance. Therefore, BTSCs are promising therapeutic targets. In this chapter, we aim to summarize advances in BTSC biology with the focus on the treatment strategies against BTSCs.

Advances made in treatment of a childhood brain cancer have extended the lives of many children and adolescents. Treatment success, however, brings the opportunity to assess late effects; most worrying among these are secondary malignant neoplasms (SMN). Even though the cumulative incidence is quite small, long-term follow-up is required because treatment-induced cancers can occur years after initial treatment. The purpose of this project was to determine what treatments and what host characteristics of children treated for a primary brain cancer are associated with an increase in the risk of a SMN in long-term survivors. Data were analyzed from 2,056 5-year survivors, of primary brain cancer in the surveillance, epidemiology, and end results (SEER) database between 1973 and 1998. Thirty-nine patients developed a SMN. Cox regression models were used to evaluate the independent contribution of a number of risk factors. The most important risk factor for developing a SMN in 5-year survivors was the era in which the primary cancer was treated. Compared to treatment prior to 1979, patients treated between 1979 and 1984 had a 4.7-fold increase in risk (P = 0.001), while those treated after 1985 had a 6.7-fold increase in risk. (P = 0.002). Patients treated most recently carry the greatest risk of SMN development even after controlling for radiotherapy. This could be due to the increase in intensive treatment compared to earlier years. Although the absolute excess risk of SMN remains quite low, continued surveillance is needed to evaluate long-term effects of new therapies for primary brain tumors.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

PURPOSE AMLAL-101 is a novel agent which preferentially targets α3, α5 subtypes of ɣ-amino butyric acid receptors and shows anti-tumor activity against disparate cancer types. AMLAL-101 is being advanced as an ‘add-on’ to potentiate treatment of primary and metastatic brain cancers. However, AMLAL-101 must penetrate the blood-brain barrier (BBB) and show sufficient brain retention. The primary purpose of this study was to determine the plasma pharmacokinetics (PK) and quantitative estimate of the BBB permeability of AMLAL-101. METHODS We performed intracranial microdialysis, employing jugular vein cannulated Sprague-Dawley rats which facilitated simultaneous serial blood and brain extracellular fluid (ECF) sampling. AMLAL-101 was injected i.p. at 5 mg/kg and serial blood and brain ECF samples collected up to 10 h post-dosing. Plasma and ECF samples were analyzed by LC/MS-MS and plasma and ECF concentration vs time PK profiles determined. In vivo recovery analysis was performed using retrodialysis and rapid equilibrium dialysis employed to determine the extent of protein binding. RESULTS AMLAL-101 plasma protein binding was 85% and in vivo recovery from ECF was 25%. AMLAL-101 peak concentration (Cmax) in plasma and brain ECF were 15 µM and 13.8 µM, respectively. The plasma and brain ECF area under the concentration (AUC0-10) were 27.5 h.µg/mL and 24.10 h.µg/mL, respectively. The brain partitioning of unbound AMLAL-101 (Kp,uu; determined either as a ratio of brain ECF Cmax:unbound plasma Cmax or brain ECF AUC: unbound plasma AUC), were 6.13 and 4.13, respectively. The elimination half-life of AMLAL-101 was 3 h for both brain ECF and plasma. CONCLUSIONS These results suggest that AMLAL-101 has the requisite BBB permeability required for brain cancer therapeutics. AMLAL-101 shows significant brain retention when compared to a chemically similar agent that does not show anti-cancer activity, which may contribute to efficacy of AMLAL-101 as an anti-tumor agent for treatment of brain cancers.

Regrettably, despite undeniable advances in cancer diagnosis and therapy, primary brain cancer (or brain cancer) remains one of the deadliest forms of malignant tumors, where glioblastoma (GBM) is known as the most malignant diffuse glioma of astrocytic lineage. Fortunately, to improve this scenario, remarkable progress in nanotechnology has brought new promise and raised expectations in cancer treatment. Nanomedicine, principally an area amalgamating nanotechnology with biology and medicine, has demonstrated a pivotal role, starting with the earliest detection and diagnosis while also offering novel multimodal cancer therapy alternatives. In the vast realm of nanotechnology, nanozymes, a type of nanomaterial with intrinsic enzyme-like activities and characteristics connecting the fields of nanocatalysts, enzymology, and biology, have emerged as powerful nanotools for cancer theranostics. Hence, this fascinating field of research has experienced exponential growth in recent years. As it is virtually impossible to cover all the literature on this broad domain of science in one paper, this review focuses on presenting a multidisciplinary approach, with its content extending from fundamental knowledge of nanozymes and enzyme-mimicking catalysis to the most recent advances in nanozymes for therapy targeting brain cancers. Although we are at the very early stages of research, it can be envisioned that the strategic development of nanozymes in brain cancer theranostics will positively offer disruptive nanoplatforms for future nano-oncology.

Occupational exposures to magnetic fields and neurodegenerative disease risks

Inflammation-targeted nanomedicine against brain cancer: From design strategies to future developments

The development of immunotherapies has revolutionized intervention strategies for a variety of primary cancers. Despite this promising progress, treatment options for primary brain cancer and brain metastasis remain limited and still largely depend on surgical resection, radio- and/or chemotherapy. The paucity in the successful development of immunotherapies for brain cancers can in part be attributed to the traditional view of the brain as an immunologically privileged site. The presence of the blood-brain barrier and the absence of lymphatic drainage were believed to restrict the entry of blood-borne immune and inflammatory cells into the central nervous system (CNS), leading to an exclusion of the brain from systemic immune surveillance. However, recent insight from pre-clinical and clinical studies on the immune landscape of brain cancers challenged this dogma. Recruitment of blood-borne immune cells into the CNS provides unprecedented opportunities for the development of tumor microenvironment (TME)-targeted or immunotherapies against primary and metastatic cancers. Moreover, it is increasingly recognized that in addition to genotoxic effects, ionizing radiation represents a critical modulator of tumor-associated inflammation and synergizes with immunotherapies in adjuvant settings. This review summarizes current knowledge on the cellular and molecular identity of tumor-associated immune cells in primary and metastatic brain cancers and discusses underlying mechanisms by which ionizing radiation modulates the immune response. Detailed mechanistic insight into the effects of radiation on the unique immune landscape of brain cancers is essential for the development of multimodality intervention strategies in which immune-modulatory effects of radiotherapy are exploited to sensitize brain cancers to immunotherapies by converting immunologically “cold” into “hot” environments.