Medial prefrontal cortex and anteromedial thalamus interaction regulates goal-directed behavior and dopaminergic neuron activity.

The prefrontal cortex is involved in goal-directed behavior. Here, we investigate circuits of the PFC regulating motivation, reinforcement, and its relationship to dopamine neuron activity. Stimulation of medial PFC (mPFC) neurons in mice activated many downstream regions, as shown by fMRI. Axonal terminal stimulation of mPFC neurons in downstream regions, including the anteromedial thalamic nucleus (AM), reinforced behavior and activated midbrain dopaminergic neurons. The stimulation of AM neurons projecting to the mPFC also reinforced behavior and activated dopamine neurons, and mPFC and AM showed a positive-feedback loop organization. We also found using fMRI in human participants watching reinforcing video clips that there is reciprocal excitatory functional connectivity, as well as co-activation of the two regions. Our results suggest that this cortico-thalamic loop regulates motivation, reinforcement, and dopaminergic neuron activity.

Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.

PURPOSE: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M-negative resistance. EXPERIMENTAL DESIGN: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M-) disease. RESULTS: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M- tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M- tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M- and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. CONCLUSIONS: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Treatment of Laser-Responsive Dermal Pigmentary Conditions in Type III-IV Asian Skin With a 755-nm Picosecond Pulse Duration Laser: A Retrospective Review of Its Efficacy and Safety.

BACKGROUND: Picosecond lasers have become very popular in the treatment of hyperpigmentation. OBJECTIVE: Evaluating the efficacy and safety of picosecond 755-nm laser in treatment of nevi of Ota (NO) and Hori's nevi (HN) in Asians with Fitzpatrick skin Types III/IV. METHODS: A retrospective review of patient records at the National Skin Center, Singapore, from 2015 to 2017. Three independent blinded dermatologists assessed pre-and-post treatment photographs using the physician's global assessment (PGA) score (0-clear, 1-almost clear, 2-mild, 3-moderate, and 4-severe). RESULTS: There were 18 cases of NO and 11 cases of HN. Mean treatment sessions were 2.22 (NO; range 1-6) and 3.82 (HN; range 1-6). In the NO group, mean pre-and-post treatment PGA scores were 3.1 and 1.3, respectively (1.8 point change, p-value 0.0002), and average fluence used was 2.02 J/cm (range: 1.02-2.38). In the HN group, mean pre-and-post treatment PGA scores were 2.6 and 1.1, respectively (1.5 point change, p-value 0.004), and average fluence was 2.08 J/cm (range: 1.98-3.40). Eleven patients (37.9%) experienced postlaser erythema, and 1 (3.4%) patient developed transient postlaser hypopigmentation. No permanent hyper/hypopigmentation was seen. CONCLUSION: The picosecond 755-nm laser is effective in the treatment of dermal pigmentary conditions in Asians with Fitzpatrick skin Types III/IV, with minimal risk of postlaser complications, and compared with the center's past experience with the Q-switched nanosecond 1064-nm laser, results in faster and more effective pigment clearance.

Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 µM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 µM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 µM), hepatotoxicity (up to 30 µM) or cardiotoxicity (up to 30 µM).

An ethnopharmacological approach to the preliminary screening of native Australian herbal medicines for anticancer activity.

BACKGROUND: Five plants used traditionally by Australian Aboriginals and two edible native Australian fruits have been investigated for anticancer activity. The aim was to identify native Australian herbal medicines which displayed anticancer activity, with cytotoxicity to cancer cells but sparing or even proliferating normal immunological cells, and subsequently provide potentially new anticancer drug leads. METHODS: Extracts and derived fractions were assayed for cell viability against a multiple myeloma cell line, RPMI-8226, in comparison to the peripheral blood mononuclear cells (PBMC) representing normal human immunological cells. RESULTS: None of the crude extracts exhibited the desirable differential activity; however, following further fractionation of the Eremophila duttonii F. Muell. (Myoporaceae) extract, one fraction (termed F01) exhibited a greater cytotoxicity to the cancer cell line than to the normal cells. CONCLUSIONS: One fraction may potentially contain valuable compounds which may be useful for further investigation. This may focus on the identification of the bioavailable purified compounds present within these fractions or by detailed delineation of the related mechanisms of action.

Complementary and alternative medicine in diabetes (CALMIND)--a prospective study.

BACKGROUND: This study aims to further elucidate the demographic and diabetes characteristics of diabetic patients in Australia who use complementary and alternative medicines (CAM). METHODS: This was a prospective, cross-sectional questionnaire-based study of 149 patients with diabetes attending a general endocrine clinic in a tertiary referral hospital in Sydney, Australia. RESULTS: Thirty-seven patients (25%) stated they had used CAM therapies within the past 5 years. Vitamins (53%) were the most common CAM therapy used. A greater number of CAM nonusers reported calf pain whilst walking (21% vs. 9%, p=0.051), and HbA1c values were lower for CAM nonusers (7.7% vs. 8.1%, p=0.057). Amongst CAM users, a majority of patients (85%) did not consult with their specialist or general practitioner prior to starting CAM therapy. CONCLUSIONS: With the increasing burden of diabetes, health practitioners will need to be more vigilant and understanding of the potential impact of CAM use on diabetes management.

Application of OctaAmmonium-POSS functionalized single walled carbon nanotubes for thermal treatment of cancer.

INTRODUCTION: Single walled carbon nanotubes (SWCNTs) have distinctive physical and chemical properties. Additionally, innovative properties can be established to match the clinical need by attachment of functional groups to the SWCNT. In this experiment SWCNT was functionalized with OctaAmmonium-POSS. Evidence suggests that functionalization of SWCNT with OctaAmmonium-POSS would augment the dispersion of SWCNT. We further postulate that functionalization of SWCNT with OctaAmmonium-POSS would enhance the temperature increase of SWCNT upon exposure to NIR laser irradiation. METHODS: Functionalization of SWCNT was conferred by refluxing with acid and OctaAmmonium-POSS. Fourier Transform Infrared (FTIR) test UV-visible spectroscopy and morphology analysis using Transmission Electron Microscopy (TEM) confirmed successful functionalization of SWCNT. NIR irradiation of samples was conducted using an 808 nm laser at 1 watt. Temperature changes were documented using a thermal camera. A HT-29 colorectal cancer cell line was used as a model for photothermal ablation. Cell viability test was performed using trypan blue and fluorescence activated cell sorting (FACS) technique. Graph plotting and statistical analysis was conducted using Graph Pad Prism. RESULTS: Following the functionalization process, TEM images showed a layer on the surface of the SWCNT. In the FTIR experiment, results illustrated the presence of the -COOH group on the functionalized SWCNTs. Upon further functionalization of SWCNT with OctaAmmonium-POSS, various peaks determined the formation of amide bond between the POSS molecule and functionalized SWCNT. The UV-visible spectra also determine the successful functionalization of the SWCNT following its treatment with acid and OctaAmmonium-POSS. Upon exposure to NIR, OctaAmmonium-POSS-SWCNT was the only treatment group that illustrated significantly higher temperature increase than the other treatment groups. Additionally cell death of NIR irradiated OctaAmmonium-POSS-SWCNT was statistically significant compared to other treatment groups. CONCLUSION: OctaAmmonium-POSS was used to render SWCNT biocompatible and water dispersible. Observation from this study determines that functionalization with OctaAmmonium-POSS show greater temperature increase compared to pristine SWCNTs upon its exposure NIR. This significant temperature increase is due to increasing the solubility of SWCNT following its functionalization with OctaAmmonium-POSS.

A new era of cancer treatment: carbon nanotubes as drug delivery tools.

Cancer is a generic term that encompasses a group of diseases characterized by an uncontrolled proliferation of cells. There are over 200 different types of cancer, each of which gains its nomenclature according to the type of tissue the cell originates in. Many patients who succumb to cancer do not die as a result of the primary tumor, but because of the systemic effects of metastases on other regions away from the original site. One of the aims of cancer therapy is to prevent the metastatic process as early as possible. There are currently many therapies in clinical use, and recent advances in biotechnology lend credence to the potential of nanotechnology in the fight against cancer. Nanomaterials such as carbon nanotubes (CNTs), quantum dots, and dendrimers have unique properties that can be exploited for diagnostic purposes, thermal ablation, and drug delivery in cancer. CNTs are tubular materials with nanometer-sized diameters and axial symmetry, giving them unique properties that can be exploited in the diagnosis and treatment of cancer. In addition, CNTs have the potential to deliver drugs directly to targeted cells and tissues. Alongside the rapid advances in the development of nanotechnology-based materials, elucidating the toxicity of nanoparticles is also imperative. Hence, in this review, we seek to explore the biomedical applications of CNTs, with particular emphasis on their use as therapeutic platforms in oncology.

Potential antioxidant, antiinflammatory, and proapoptotic anticancer activities of Kakadu plum and Illawarra plum polyphenolic fractions.

Kakadu plum (Terminalia ferdinandiana Exell, Combretaceae) and Illawarra plum (Podocarpus elatus Endl., Podocarpaceae) extracts were fractionated, using a bioassay-guided approach and screened for antioxidant activity [oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) assays] and antiinflammatory activity (nitrite concentration and prostaglandin E(2) release in lipopolysaccharide (LPS)-activated murine macrophages). Among 8 fractions obtained from KP and 5 fractions obtained from IP, fraction KPF5 from KP exhibited superior activity in all assays, with an ORAC value of 3,776 ± 603 µmol Trolox/g DW and a CAA value of 52.2 ± 8.6 µmol quercetin equivalents/g DW. In addition, KPF5 further demonstrated an upregulation of the Nrf2/Keap1 ratio in Hep G2 cells. KPF5 also inhibited the expression of COX-2 and iNOS in LPS-activated murine macrophages, potentially through the NF-κB, p44/42 mitogen activated protein kinase and Akt pathways. KPF5 also induced apoptosis and DNA damage in HT-29 cells, as determined by the cytokinesis block micronucleus cytome assay.

Molecular pathways for cancer chemoprevention by dietary phytochemicals.

Interest in dietary phytochemicals for potential cancer chemoprevention has increased substantially. Screening dietary compounds for chemopreventive activity however, requires a systematic and wide-ranging approach to encompass the complexity of carcinogenesis. We present some of the molecular pathways that underpin the broad biological processes involved in carcinogenesis. Oxidative stress, inflammation, and the evasion of apoptosis are important biological mechanisms by which carcinogenesis occurs. Subsequently, antioxidant, anti-inflammatory, and pro-apoptotic activity represent important activities for preventing, suppressing, or reversing the development of carcinogenesis. Ultimately, these mechanisms of action may provide a useful basis for screening novel phytochemicals for chemopreventive activity. In this review, we identify the important molecular processes that may be targeted in routine screenings of dietary phytochemicals to ultimately select the most effective potential candidates for cancer chemoprevention.

Native Australian fruit polyphenols inhibit cell viability and induce apoptosis in human cancer cell lines.

Apoptosis is one of the most critical forms of defense against cancer, and the induction of apoptosis by dietary polyphenols represents significant potential for cancer preventive activity. The present study examined polyphenols extracted from selected native Australian fruits--Illawarra plum (Podocarpus elatus Endl., Podocarpaceae), Kakadu plum (Terminalia ferdinandiana Exell, Combretaceae), muntries (Kunzea pomifera F. Muell., Myrtaceae), and native currant (Acrotriche depressa R.Br., Epacridaceae)--for antiproliferative activity against a panel of cancer and normal cell lines. Each fruit selectively inhibited the growth of cancer cell lines in a dose-dependent manner. The mechanism of growth inhibition of the human promyelocytic leukaemia cells (HL-60) was determined to be apoptosis by morphological assessment, DNA fragmentation, flow cytometry, and caspase-3 induction. Furthermore, Kakadu plum was found to activate caspase-7, -9, and poly (ADP-ribose) polymerase (PARP), suggesting it acts via the intrinsic apoptosis pathway. The same fruit also caused direct DNA damage in colon adenocarcinoma cells (HT-29) as detected using the cytokinesis-block micronucleus cytome (CBMN Cyt) assay.

Towards the discovery of novel phytochemicals for disease prevention from native Australian plants: an ethnobotanical approach.

Investigation into phytochemicals from foods for disease prevention has increased substantially in the last few decades. However, a clear strategy on the selection of the most promising foods for research has been lacking. An ethnobotanical approach represents an effective method which may improve the outcomes of phytochemical research. Research on the health properties of native Australian plants is limited. The vast number of edible plants used as foods and medicines by the Australian Aboriginal population creates opportunities for the discovery of novel physiologically active compounds. Within this review, we propose an ethnobotanical approach to accelerate research towards the utilisation of native Australian plants for foods with health-enhancing properties.