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(1) Successful intracranial delivery of trastuzumab by gene-therapy for treatment of HER2-positive breast cancer brain metastases.[TOP]

Pubmed ID :30342077
Publication Date : //
Trastuzumab is a monoclonal antibody which demonstrates efficacy for HER2 positive breast cancer patients. Recently, an increased incidence of brain metastasis in trastuzumab-treated patients has been reported. The reason for this may be the effectiveness of systemic trastuzumab allowing patients to survive longer thus providing time for brain metastases to develop, along with the lack of penetration of systemic therapies through the blood brain barrier. In recent years, several administration routes to the brain have been evaluated. Albeit advances in the field, there is still a need for improved delivery of therapeutic antibodies to the brain. To address this challenge, we have developed two gene therapy-based methods enabling continuous secretion of active trastuzumab in the brain.

Authors : Zafir-Lavie Inbal, Sherbo Shay, Goltsman Haim, Badinter Felix, Yieni Eilam, Ofek Paula, Miari Reem, Tal Osnat, Liran Atar, Shatil Tamar, Krispel Simi, Shapir Nir, Neil Garry A, Benhar Itai, Panet Amos, Fainaro Ronit Satchi,

(2) Sonodynamic Therapy on Intracranial Glioblastoma Xenografts Using Sinoporphyrin Sodium Delivered by Ultrasound with Microbubbles.[TOP]

Pubmed ID :30341739
Publication Date : //
Sonodynamic therapy (SDT) is a promising noninvasive method for cancer treatment. The anti-tumor effect of sinoporphyrin sodium (DVDMS)-mediated SDT on nude mice bearing intracranial U87 MG-Red-FLuc human glioblastoma was investigated. Focused ultrasound (FUS) with microbubbles (MBs) was utilized to open the blood-brain barrier for enhancing the delivery of the sonosensitizer DVDMS to the brain tumor first, and then the SDT treatment was performed. The in vitro study showed obvious cytotoxicity of DVDMS-mediated SDT (center frequency: 0.996 MHz, acoustic power: 1.7 W, pulse repletion frequency: 1 Hz, duty cycle: 30%, duration: 1 min) on U87 MG-Red-FLuc cells. The results indicated that more DVDMS accumulation in the tumor sites was induced by FUS with MBs by 3.43 folds of unsonicated ones. Longitudinal bioluminescence imaging illustrated that the intracranial glioblastoma progression in nude mice treated with SDT was retarded compared to the untreated group. The median survival time was prolonged to 30.25 days after SDT treatment by 27.37%. The anti-proliferation effect and cell apoptosis induction was further confirmed by immunohistochemical examinations. These results of the study suggested that SDT using the sonosensitizer DVDMS delivered by FUS with MBs may provide a new promising therapeutic strategy against glioblastoma.

Authors : Pi Zhaoke, Huang Yongpeng, Shen Yuanyuan, Zeng Xiaojun, Hu Yaxin, Chen Tie, Li Chenyang, Yu Hao, Chen Siping, Chen Xin,

(3) Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems.[TOP]

Pubmed ID :30337641
Publication Date : //
XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors.

Authors : Shang Enyuan, Zhang Yiru, Shu Chang, Ishida Chiaki Tsuge, Bianchetti Elena, Westhoff Mike-Andrew, Karpel-Massler Georg, Siegelin Markus D,

(4) Microglia induces Gas1 expression in human brain tumor-initiating cells to reduce tumorigenecity.[TOP]

Pubmed ID :30327548
Publication Date : //
We reported previously that microglia decreased the growth of human brain tumor-initiating cells (BTICs). Through microarray analyses of BTICs exposed in vitro to microglia, we found the induction of several genes ascribed to have roles in cell cycle arrest, reduced cell proliferation and differentiation. Herein, we tested the hypothesis that one of these genes, growth arrest specific 1 (Gas1), is a novel growth reduction factor that is induced in BTICs by microglia. We found that microglia increased the expression of Gas1 transcript and protein in glioblastoma patient-derived BTIC lines. Using neurosphere assay we show that RNAi-induced reduction of Gas1 expression in BTICs blunted the microglia-mediated BTIC growth reduction. The role of Gas1 in mediating BTIC growth arrest was further validated using orthotopic brain xenografts in mice. When microglia-induced Gas1-expressing BTIC cells (mGas1-BTICs) were implanted intra-cranially in mice, tumor growth was markedly decreased; this was mirrored in the remarkable increase in survival of mGas1-BT025 and mGas1-BT048 implanted mice, compared to mice implanted with non-microglia-exposed BTIC cells. In conclusion, this study has identified Gas1 as a novel factor and mechanism through which microglia arrest the growth of BTICs for anti-tumor property.

Authors : Sarkar Susobhan, Poon Candice C, Mirzaei Reza, Rawji Khalil S, Hader Walter, Bose Pinaki, Kelly John, Dunn Jeffrey F, Yong V Wee,

(5) Novel K7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction.[TOP]

Pubmed ID :30327146
Publication Date : //
Neuronal voltage-gated potassium channels, K7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule K7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. K7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual K7 isoforms was investigated in human detrusor tissue using a panel of K7 openers with distinct activity profiles among K7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric K7.4 did not reduce detrusor contraction. This may suggest that the homomeric K7.4 channel plays a less significant role in bladder contraction and further investigation is needed.

Authors : Seefeld Mark A, Lin Hong, Holenz Joerg, Downie Dave, Donovan Brian, Fu Tingting, Pasikanti Kishore, Zhen Wei, Cato Matthew, Chaudhary Khuram W, Brady Pat, Bakshi Tania, Morrow Dwight, Rajagopal Sridharan, Samanta Swapan Kumar, Madhyastha Naveena, Kuppusamy Bharathi Mohan, Dougherty Robert W, Bhamidipati Ravi, Mohd Zainuddin, Higgins Guy A, Chapman Mark, Rouget Céline, Lluel Philippe, Matsuoka Yasuji,

(6) IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.[TOP]

Pubmed ID :30305738
Publication Date : //
Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.

Authors : Song Minkyung, Sandoval Tito A, Chae Chang-Suk, Chopra Sahil, Tan Chen, Rutkowski Melanie R, Raundhal Mahesh, Chaurio Ricardo A, Payne Kyle K, Konrad Csaba, Bettigole Sarah E, Shin Hee Rae, Crowley Michael J P, Cerliani Juan P, Kossenkov Andrew V, Motorykin Ievgen, Zhang Sheng, Manfredi Giovanni, Zamarin Dmitriy, Holcomb Kevin, Rodriguez Paulo C, Rabinovich Gabriel A, Conejo-Garcia Jose R, Glimcher Laurie H, Cubillos-Ruiz Juan R,

(7) High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain.[TOP]

Pubmed ID :30300753
Publication Date : //
PET imaging of amyloid-beta (Aβ) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new anti-Aβ treatments. Available PET radioligands visualizing Aβ bind to insoluble fibrils, i.e. Aβ plaques. Levels of prefibrillar Aβ forms, e.g. soluble oligomers and protofibrils, correlate better than plaques with disease severity and these soluble species are the neurotoxic form of Aβ leading to neurodegeneration. The goal was to create an antibody-based radioligand, recognizing not only fibrillary Aβ, but also smaller and still soluble aggregates. We designed and expressed a small recombinant bispecific antibody construct, di-scFv 3D6-8D3, targeting the Aβ N-terminus and the transferrin receptor (TfR). Natively expressed at the blood-brain barrier (BBB), TfR could thus be used as a brain-blood shuttle. Di-scFv 3D6-8D3 bound to Aβ1-40 with high affinity and to TfR with moderate affinity. Di-scFv [I]3D6-8D3 was injected in two transgenic mouse models overexpressing human Aβ and wild-type control mice and PET scanned at 14, 24 or 72 h after injection. Di-scFv [I]3D6-8D3 was retained in brain of transgenic animals while it was cleared from wild-type lacking Aβ. This difference was observed from 24 h onwards, and at 72 h, 18 months old transgenic animals, with high load of Aβ pathology, displayed SUVR of 2.2-3.5 in brain while wild-type showed ratios close to unity. A subset of the mice were also scanned with [C]PIB. Again wt mice displayed ratios of unity while transgenes showed slightly, non-significantly, elevated SUVR of 1.2, indicating improved sensitivity with novel di-scFv [I]3D6-8D3 compared with [C]PIB. Brain concentrations of di-scFv [I]3D6-8D3 correlated with soluble Aβ (p < 0.0001) but not with total Aβ, i.e. plaque load (p = 0.34). We have successfully created a small bispecific antibody-based radioligand capable of crossing the BBB, subsequently binding to and visualizing intrabrain Aβ in vivo. The radioligand displayed better sensitivity compared with [C]PIB, and brain concentrations correlated with soluble neurotoxic Aβ aggregates.

Authors : Fang Xiaotian T, Hultqvist Greta, Meier Silvio R, Antoni Gunnar, Sehlin Dag, Syvänen Stina,

(8) Human Umbilical Cord Blood Plasma Alleviates Age-related Olfactory Dysfunction by Attenuating Peripheral TNF-α expression.[TOP]

Pubmed ID :30293545
Publication Date : //
Social requirements are needed for living in an aging society and individual longevity. Among them, improved health and medical cares, appropriate for an aging society are strongly demanded. Human cord blood-derived plasma (hUCP) has recently emerged for its unique anti-aging effects. In this study, we investigated brain rejuvenation, particularly olfactory function, that could be achieved by a systemic administration of young blood and its underlying mechanisms. Older than 24-month-old mice were used as an aged group and administered with intravenous injection of hUCP repetitively, eight times. Anti-aging effect of hUCP on olfactory function was evaluated by buried food finding test. To investigate the mode of action of hUCP, brain, serum and spleen of mice were collected for further ex vivo analyses. Systemic injection of hUCP improved aging-associated olfactory deficits, reducing time for finding food. In the brain, although an infiltration of activated microglia and its expression of cathepsin S remarkably decreased, significant changes of proinflammatory factors were not detected. Conversely, peripheral immune balance distinctly switched from predominance of Type 1 helper T (Th1) cells to alternative regulatory T cells (Tregs). These findings indicate that systemic administration of hUCP attenuates age-related neuroinflammation and subsequent olfactory dysfunction by modulating peripheral immune balance toward Treg cells, suggesting another therapeutic function and mechanism of hUCP administration.

Authors : Lee Byung-Chul, Kang Insung, Lee Seung-Eun, Lee Jin Young, Shin Nari, Kim Jae-Jun, Choi Soon Won, Kang Kyung-Sun,

(9) Prokineticin-2 promotes chemotaxis and alternative A2 reactivity of astrocytes.[TOP]

Pubmed ID :30277602
Publication Date : //
Astrocyte reactivity is disease- and stimulus-dependent, adopting either a proinflammatory A1 phenotype or a protective, anti-inflammatory A2 phenotype. Recently, we demonstrated, using cell culture, animal models and human brain samples, that dopaminergic neurons produce and secrete higher levels of the chemokine-like signaling protein Prokineticin-2 (PK2) as a compensatory protective response against neurotoxic stress. As astrocytes express a high level of PK2 receptors, herein, we systematically characterize the role of PK2 in astrocyte structural and functional properties. PK2 treatment greatly induced astrocyte migration, which was accompanied by a shift in mitochondrial energy metabolism, a reduction in proinflammatory factors, and an increase in the antioxidant genes Arginase-1 and Nrf2. Overexpression of PK2 in primary astrocytes or in the in vivo mouse brain induced the A2 astrocytic phenotype with upregulation of key protective genes and A2 reactivity markers including Arginase-1 and Nrf2, PTX3, SPHK1, and TM4SF1. A small-molecule PK2 agonist, IS20, not only mimicked the protective effect of PK2 in primary cultures, but also increased glutamate uptake by upregulating GLAST. Notably, IS20 blocked not only MPTP-induced reductions in the A2 phenotypic markers SPHK1 and SCL10a6 but also elevation of the of A1 marker GBP2. Collectively, our results reveal that PK2 regulates a novel neuron-astrocyte signaling mechanism by promoting an alternative A2 protective phenotype in astrocytes, which could be exploited for development of novel therapeutic strategies for PD and other related chronic neurodegenerative diseases. PK2 signals through its receptors on astrocytes and promotes directed chemotaxis. PK2-induced astrocyte reactivity leads to an increase in antioxidant and anti-inflammatory proteins while increasing glutamate uptake, along with decreased inflammatory factors. © 2018 Wiley Periodicals, Inc.

Authors : Neal Matthew, Luo Jie, Harischandra Dilshan S, Gordon Richard, Sarkar Souvarish, Jin Huajun, Anantharam Vellareddy, Désaubry Laurent, Kanthasamy Anumantha, Kanthasamy Arthi,

(10) Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM.[TOP]

Pubmed ID :30269989
Publication Date : //
Although many reports have revealed dysfunction of endothelial cells in aging, resulting in blood-brain barrier (BBB) breakdown, the underlying mechanism or mechanisms remain to be explored. Here, we find that acid sphingomyelinase (ASM) is a critical factor for regulating brain endothelial barrier integrity. ASM is increased in brain endothelium and/or plasma of aged humans and aged mice, leading to BBB disruption by increasing caveolae-mediated transcytosis. Genetic inhibition and endothelial-specific knockdown of ASM in mice ameliorated BBB breakdown and neurocognitive impairment during aging. Using primary mouse brain endothelial cells, we found that ASM regulated the caveolae-cytoskeleton interaction through protein phosphatase 1-mediated ezrin/radixin/moesin (ERM) dephosphorylation and apoptosis. Moreover, mice with conditional ASM overexpression in brain endothelium accelerated significant BBB impairment and neurodegenerative change. Overall, these results reveal a novel role for ASM in the control of neurovascular function in aging, suggesting that ASM may represent a new therapeutic target for anti-aging.

Authors : Park Min Hee, Lee Ju Youn, Park Kang Ho, Jung In Kyung, Kim Kyoung-Tae, Lee Yong-Seok, Ryu Hyun-Hee, Jeong Yong, Kang Minseok, Schwaninger Markus, Gulbins Erich, Reichel Martin, Kornhuber Johannes, Yamaguchi Tomoyuki, Kim Hee-Jin, Kim Seung Hyun, Schuchman Edward H, Jin Hee Kyung, Bae Jae-Sung,