Serpins promote cancer cell survival and vascular co-option in brain metastasis.

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy.

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.

CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma.

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.

Polo-like kinase 4 inhibitor CFI-400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity.

BACKGROUND AND AIMS: Prognosis of HCC remains poor due to lack of effective therapies. Immune checkpoint inhibitors (ICIs) have delayed response and are only effective in a subset of patients. Treatments that could effectively shrink the tumors within a short period of time are idealistic to be employed together with ICIs for durable tumor suppressive effects. HCC acquires increased tolerance to aneuploidy. The rapid division of HCC cells relies on centrosome duplication. In this study, we found that polo-like kinase 4 (PLK4), a centrosome duplication regulator, represents a therapeutic vulnerability in HCC. APPROACH AND RESULTS: An orally available PLK4 inhibitor, CFI-400945, potently suppressed proliferating HCC cells by perturbing centrosome duplication. CFI-400945 induced endoreplication without stopping DNA replication, causing severe aneuploidy, DNA damage, micronuclei formation, cytosolic DNA accumulation, and senescence. The cytosolic DNA accumulation elicited the DEAD box helicase 41-stimulator of interferon genes-interferon regulatory factor 3/7-NF-κß cytosolic DNA sensing pathway, thereby driving the transcription of senescence-associated secretory phenotypes, which recruit immune cells. CFI-400945 was evaluated in liver-specific p53/phosphatase and tensin homolog knockout mouse HCC models established by hydrodynamic tail vein injection. Tumor-infiltrated immune cells were analyzed. CFI-400945 significantly impeded HCC growth and increased infiltration of cluster of differentiation 4-positive (CD4 + ), CD8 + T cells, macrophages, and natural killer cells. Combination therapy of CFI-400945 with anti-programmed death-1 showed a tendency to improve HCC survival. CONCLUSIONS: We show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing-mediated immune response, CFI-400945 effectively restrained tumor progression through cell cycle inhibition and inducing antitumor immunity to achieve a durable suppressive effect even in late-stage mouse HCC.

Augmented-reality-assisted intraoral scanning: A proof-of-concept study.

PURPOSE: The aims of the present study were (a) to compare the scanning time and image count to complete optical scans of a typodont between augmented-reality-assisted intraoral scanning (ARIOS) and intraoral scanning (IOS); (b) to compare the accuracy of the digital casts derived from ARIOS and IOS; (c) to compare participant-related outcomes between ARIOS and IOS. MATERIALS AND METHODS: A multi-session within-subject experiment was conducted to compare ARIOS and IOS. Thirty-one dental students participated in the study. Following a trial session, each participant obtained optical scans under ARIOS and IOS conditions. The time required to complete the scan, and the number of images taken were recorded. Participant feedback was collected using entry, exit, and NASA-Task Load Index (TLX) surveys. The accuracy of the digital casts derived from the optical scans was measured in root mean square error (RMSE). RESULTS: The present study found a 6.8% increase in preference for ARIOS from entry to exit survey. Slightly more participants favored the ARIOS setup compared to IOS; 54.8% of participants favored ARIOS, 9.7% were indifferent, and 35.5% favored IOS. NASA-TLX subscale ratings were higher for IOS in general apart from mental demand. The accuracy of the digital casts between ARIOS and IOS was comparable in RMSE. CONCLUSION: ARIOS was advantageous compared to IOS in ergonomics, improved scanner tracking, and ease of scanner orientation. However additional trials, increased field of view, and better superimposition of scanning status to the target site were improvements desired by the study participants.

Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses.

BACKGROUND & AIMS: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are the only two classes of FDA-approved drugs for individuals with advanced hepatocellular carcinoma (HCC). While TKIs confer only modest survival benefits, ICIs have been associated with remarkable outcomes but only in the minority of patients who respond. Understanding the mechanisms that determine the efficacy of ICIs in HCC will help to stratify patients likely to respond to ICIs. This study aims to elucidate how genetic composition and specific oncogenic pathways regulate the immune composition of HCC, which directly affects response to ICIs. METHODS: A collection of mouse HCCs with genotypes that closely simulate the genetic composition found in human HCCs were established using genome-editing approaches involving the delivery of transposon and CRISPR-Cas9 systems by hydrodynamic tail vein injection. Mouse HCC tumors were analyzed by RNA-sequencing while tumor-infiltrating T cells were analyzed by flow cytometry and single-cell RNA-sequencing. RESULTS: Based on the CD8+ T cell-infiltration level, we characterized tumors with different genotypes into cold and hot tumors. Anti-PD-1 treatment had no effect in cold tumors but was greatly effective in hot tumors. As proof-of-concept, a cold tumor (Trp53KO/MYCOE) and a hot tumor (Keap1KO/MYCOE) were further characterized. Tumor-infiltrating CD8+ T cells from Keap1KO/MYCOE HCCs expressed higher levels of proinflammatory chemokines and exhibited enrichment of a progenitor exhausted CD8+ T-cell phenotype compared to those in Trp53KO/MYCOE HCCs. The TKI sorafenib sensitized Trp53KO/MYCOE HCCs to anti-PD-1 treatment. CONCLUSION: Single anti-PD-1 treatment appears to be effective in HCCs with genetic mutations driving hot tumors, while combined anti-PD-1 and sorafenib treatment may be more appropriate in HCCs with genetic mutations driving cold tumors. IMPACT AND IMPLICATIONS: Genetic alterations of different driver genes in mouse liver cancers are associated with tumor-infiltrating CD8+ T cells and anti-PD-1 response. Mouse HCCs with different genetic compositions can be grouped into hot and cold tumors based on the level of tumor-infiltrating CD8+ T cells. This study provides proof-of-concept evidence to show that hot tumors are responsive to anti-PD-1 treatment while cold tumors are more suitable for combined treatment with anti-PD-1 and sorafenib. Our study might help to guide the design of patient stratification systems for single or combined treatments involving anti-PD-1.

Extinction risks and mitigation for a megaherbivore, the giraffe, in a human-influenced landscape under climate change.

Megaherbivores play "outsized" roles in ecosystem functioning but are vulnerable to human impacts such as overhunting, land-use changes, and climate extremes. However, such impacts-and combinations of these impacts-on population dynamics are rarely examined using empirical data. To guide effective conservation actions under increasing global-change pressures, we developed a socially structured individual-based model (IBM) using long-term demographic data from female giraffes (Giraffa camelopardalis) in a human-influenced landscape in northern Tanzania, the Tarangire Ecosystem. This unfenced system includes savanna habitats with a wide gradient of anthropogenic pressures, from national parks, a wildlife ranch and community conservation areas, to unprotected village lands. We then simulated and projected over 50 years how realistic environmental and land-use management changes might affect this metapopulation of female giraffes. Scenarios included: (1) anthropogenic land-use changes including roads and agricultural/urban expansion; (2) reduction or improvement in wildlife law enforcement measures; (3) changes in populations of natural predators and migratory alternative prey; and (4) increases in rainfall as predicted for East Africa. The factor causing the greatest risk of rapid declines in female giraffe abundance in our simulations was a reduction in law enforcement leading to more poaching. Other threats decreased abundances of giraffes, but improving law enforcement in both of the study area's protected areas mitigated these impacts: a 0.01 increase in giraffe survival probability from improved law enforcement mitigated a 25% rise in heavy rainfall events by increasing abundance 19%, and mitigated the expansion of towns and blockage of dispersal movements by increasing abundance 22%. Our IBM enabled us to further quantify fine-scale abundance changes among female giraffe social communities, revealing potential source-sink interactions within the metapopulation. This flexible methodology can be adapted to test additional ecological questions in this landscape, or to model populations of giraffes or other species in different ecosystems.

Effect of Ketogenic Diets on Cardio-Metabolic Outcomes in Cancer Patients: A Systematic Review and Meta-Analysis of Controlled Clinical Trials.

In this systematic review and meta-analysis of clinical controlled trials (CCTs) we aimed to investigate the efficacy of KDs as an adjuvant therapy on cardiometabolic outcomes in patient with cancer compared to conventional non-ketogenic diets. Only CCTs involving cancer patients that were assigned to either a KD or a standard diet control group were selected. Two reviewers independently extracted the data, and a meta-analysis was performed using a random effects model to estimate weighted mean differences (WMDs) and confidence intervals (CIs) in body composition, metabolite, lipid profile, liver and kidney function parameters and quality of life. This meta-analysis showed a significant reduction in body weight (WMD= -2.99 kg; 95% CI: -4.67, -1.31; and P < 0.001), BMI (WMD= -1.08 kg/m2; 95% CI: -1.81, -0.34; P ≤ 0.002) and fat mass (WMD= -1.48 kg; 95% CI: -2.56, -0.40; and P = 0.007) by a KD. KDs significantly decreased glucose (WMD= -5.22 mg/dl; 95% CI: -9.0, -1.44; and P = 0.007), IGF-1 (WMD= -17.52 ng/ml; 95% CI: -20.24, -14.8; and P ˂0.001) and triglyceride (WMD= -24.46 mg/dl; 95% CI: -43.96, -4.95; and P = 0.014) levels. Furthermore, KDs induced ketosis by increasing ß-hydroxybutyrate (WMD= 0.56 mmol/l; 95% CI: 0.37, 0.75; and P < 0.001). There were non-significant pooled effects of KDs on improving insulin, C-reactive protein and cholesterol levels and kidney and liver function. Emotional functioning was even increased significantly in the KD compared to the SD groups. In summary we found that KDs result in a greater reduction in glucose, IGF-1, triglycerides, body weight, BMI, and fat mass in cancer patients compared to traditional non-ketogenic diets and improved emotional functioning. The quality of evidence in the meta-analysis was moderate according to the Nutrigrade assessment.

Adaptive and Constitutive Activations of Malic Enzymes Confer Liver Cancer Multilayered Protection Against Reactive Oxygen Species.

BACKGROUND AND AIMS: HCC undergoes active metabolic reprogramming. Reactive oxygen species (ROS) are excessively generated in cancer cells and are neutralized by NADPH. Malic enzymes (MEs) are the less studied NADPH producers in cancer. APPROACH AND RESULTS: We found that ME1, but not ME3, was regulated by the typical oxidative stress response pathway mediated by kelch-like ECH associated protein 1/nuclear factor erythroid 2-related factor (NRF2). Surprisingly, ME3 was constitutively induced by superenhancers. Disruption of any ME regulatory pathways decelerated HCC progression and sensitized HCC to sorafenib. Therapeutically, simultaneous blockade of NRF2 and a superenhancer complex completely impeded HCC growth. We show that superenhancers allow cancer cells to counteract the intrinsically high level of ROS through constitutively activating ME3 expression. When HCC cells encounter further episodes of ROS insult, NRF2 allows cancer cells to adapt by transcriptionally activating ME1. CONCLUSIONS: Our study reveals the complementary regulatory mechanisms which control MEs and provide cancer cells multiple layers of defense against oxidative stress. Targeting both regulatory mechanisms represents a potential therapeutic approach for HCC treatment.

Proximity to humans affects local social structure in a giraffe metapopulation.

Experimental laboratory evidence suggests that animals with disrupted social systems express weakened relationship strengths and have more exclusive social associations, and that these changes have functional consequences. A key question is whether anthropogenic pressures have a similar impact on the social structure of wild animal communities. We addressed this question by constructing a social network from 6 years of systematically collected photographic capture-recapture data spanning 1,139 individual adult female Masai giraffes inhabiting a large, unfenced, heterogeneous landscape in northern Tanzania. We then used the social network to identify distinct social communities, and tested whether social or anthropogenic and other environmental factors predicted differences in social structure among these communities. We reveal that giraffes have a multilevel social structure. Local preferences in associations among individuals scale up to a number of distinct, but spatially overlapping, social communities, that can be viewed as a large interconnected metapopulation. We then find that communities that are closer to traditional compounds of Indigenous Masai people express weaker relationship strengths and the giraffes in these communities are more exclusive in their associations. The patterns we characterize in response to proximity to humans reflect the predictions of disrupted social systems. Near bomas, fuelwood cutting can reduce food resources, and groups of giraffes are more likely to encounter livestock and humans on foot, thus disrupting the social associations among group members. Our results suggest that human presence could potentially be playing an important role in determining the conservation future of this megaherbivore.

Relative Contribution of Genetic and Environmental Factors in CKD.

Chronic kidney disease affects nearly 15 percent of the U.S. population. Onset and rate of progression are influenced by a combination of genetic and non-genetic factors. Because health care systems across the U.S. are beginning to deploy automated decision support to stratify patients at risk, we review the relative impact of genetic factors (e.g., APOL1 gene polymorphisms) and non-genetic factors (e.g., clinical comorbidities and exposure to environmental nephrotoxins) contributing to this common disease. Overall, the impact of non-genetic factors appears to exceed the impact of genetic factors.

Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression.

OBJECTIVE: Facilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC). DESIGN: We obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models. RESULTS: We showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib. CONCLUSION: In conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.

Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant-producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction-oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid-derived 2)-like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacological TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.

Fission-fusion dynamics of a megaherbivore are driven by ecological, anthropogenic, temporal, and social factors.

Fission-fusion dynamics hypothetically enable animals to exploit dispersed and ephemeral food resources while minimizing predation risk. Disentangling factors affecting group size and composition of fission-fusion species facilitates their management and conservation. We used a 6-year data set of 2888 group formations of Masai giraffes in Tanzania to investigate determinants of social group size and structure. We tested whether ecological (lion density, vegetation structure, and prevalence of primary forage plants), anthropogenic (proximity to human settlements), temporal (rainy or dry season), and social (local giraffe density, adult sex ratio, and proportion of calves) factors explained variation in group size and sex- and age-class composition. Food availability rather than predation risk mediated grouping dynamics of adult giraffes, while predation risk was the most important factor influencing congregations with calves. Smallest group sizes occurred during the food-limiting dry season. Where predation risk was greatest, groups with calves were in bushlands more than in open grasslands, but the groups were smaller in size, suggesting mothers adopted a strategy of hiding calves rather than a predator-detection-and-dilution strategy. Groups with calves also were farther from towns but closer to traditional human compounds (bomas). This may be due to lower predator densities, and thus reduced calf predation risk, near bomas but higher human disturbance near towns. Sex- and age-based differences in habitat use reflected nursing mothers' need for high-quality forage while also protecting their young from predation. Our results have implications for conservation and management of giraffes and other large-bodied, herd-forming ungulates in heterogeneous environments subject to anthropogenic threats.

In vivo cardiac reprogramming contributes to zebrafish heart regeneration.

Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardiomyocytes to divide and replace ventricular myocardium lost from ischaemia-induced infarct. Hence there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium. Past studies have shown that fish and amphibians and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration. Here we have developed, in the zebrafish (Danio rerio), a combination of fluorescent reporter transgenes, genetic fate-mapping strategies and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-ventricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. We observed that Notch signalling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signalling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.

Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26.

UNLABELLED: A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors. We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor. Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C-C motif) ligand 26 production in cancer cells by the hypoxia-inducible factor inhibitor digoxin or blockade of chemokine (C-X3-C motif) receptor 1 in MDSCs by chemokine (C-X3-C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. CONCLUSION: This study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (Hepatology 2016;64:797-813).

Topological Edge-State Manifestation of Interacting 2D Condensed Boson-Lattice Systems in a Harmonic Trap.

In this Letter, it is shown that interactions can facilitate the emergence of topological edge states of quantum-degenerate bosonic systems in the presence of a harmonic potential. This effect is demonstrated with the concrete model of a hexagonal lattice populated by spin-one bosons under a synthetic gauge field. In fermionic or noninteracting systems, the presence of a harmonic trap can obscure the observation of edge states. For our system with weakly interacting bosons in the Thomas-Fermi regime, we can clearly see a topological band structure with a band gap traversed by edge states. We also find that the number of edge states crossing the gap is increased in the presence of a harmonic trap, and the edge modes experience an energy shift while traversing the first Brillouin zone which is related to the topological properties of the system. We find an analytical expression for the edge-state energies and our comparison with numerical computation shows excellent agreement.

Rutin increases the cytotoxicity of temozolomide in glioblastoma via autophagy inhibition.

The chemotherapeutic agent temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM). Rutin, a citrus flavonoid ecglycoside found in edible plants, has neuroprotective and anticancer activities. This study aimed to investigate the efficacy and the underlying mechanisms of rutin used in combination with TMZ in GBM. In vitro cell viability assay demonstrated that rutin alone had generally low cytotoxic effect, but it enhanced the efficacy of TMZ in a dose-dependent manner. Subcutaneous and orthotopic xenograft studies also showed that tumor volumes were significantly lower in mice receiving combined TMZ/Rutin treatment as compared to TMZ or rutin alone treatment. Moreover, immunoblotting analysis showed that TMZ activated JNK activity to induce protective response autophagy, which was blocked by rutin, resulting in decreased autophagy and increased apoptosis, suggesting that rutin enhances TMZ efficacy both in vitro and in vivo via inhibiting JNK-mediated autophagy in GBM. The combination rutin with TMZ may be a potentially useful therapeutic approach for GBM patient.

Selective Population of Edge States in a 2D Topological Band System.

We consider a system of interacting spin-one atoms in a hexagonal lattice under the presence of a synthetic gauge field. Quenching the quadratic Zeeman field is shown to lead to a dynamical instability of the edge modes. This, in turn, leads to a spin current along the boundary of the system which grows exponentially fast in time following the quench. Tuning the magnitude of the quench can be used to selectively populate edge modes of different momenta. Implications of the intrinsic symmetries of the Hamiltonian on the dynamics are discussed. The results hold for atoms with both antiferromagnetic and ferromagnetic interactions.