A novel approach for modelling and classifying sit-to-stand kinematics using inertial sensors.

Sit-to-stand transitions are an important part of activities of daily living and play a key role in functional mobility in humans. The sit-to-stand movement is often affected in older adults due to frailty and in patients with motor impairments such as Parkinson's disease leading to falls. Studying kinematics of sit-to-stand transitions can provide insight in assessment, monitoring and developing rehabilitation strategies for the affected populations. We propose a three-segment body model for estimating sit-to-stand kinematics using only two wearable inertial sensors, placed on the shank and back. Reducing the number of sensors to two instead of one per body segment facilitates monitoring and classifying movements over extended periods, making it more comfortable to wear while reducing the power requirements of sensors. We applied this model on 10 younger healthy adults (YH), 12 older healthy adults (OH) and 12 people with Parkinson's disease (PwP). We have achieved this by incorporating unique sit-to-stand classification technique using unsupervised learning in the model based reconstruction of angular kinematics using extended Kalman filter. Our proposed model showed that it was possible to successfully estimate thigh kinematics despite not measuring the thigh motion with inertial sensor. We classified sit-to-stand transitions, sitting and standing states with the accuracies of 98.67%, 94.20% and 91.41% for YH, OH and PwP respectively. We have proposed a novel integrated approach of modelling and classification for estimating the body kinematics during sit-to-stand motion and successfully applied it on YH, OH and PwP groups.

DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because of PDAC's extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, 'cold') tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored. METHODS: We examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy. RESULTS: In both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis. CONCLUSIONS: These findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in 'cold' tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.

The Causes and Impact of Crisis for People with Parkinson's Disease: A Patient and Carer Perspective.

BACKGROUND: The reasons for acute hospital admissions among people with Parkinson's disease are well documented. However, understanding of crises that are managed in the community is comparatively lacking. Most existing literature on the causes of crisis for people with Parkinson's disease (PwP) uses hospital data and excludes the individual's own perspective on the crisis trigger and the impact of the crisis on their care needs. OBJECTIVE: To identify the causes and impact of crises in both community and hospital settings, from a patient and carer perspective. METHODS: A total of 550 UK-based PwP and carers completed a survey on (a) their own personal experiences of crisis, and (b) their general awareness of potential crisis triggers for PwP. RESULTS: In addition to well-recognised causes of crisis such as falls, events less widely associated with crisis were identified, including difficulties with activities of daily living and carer absence. The less-recognised crisis triggers tended to be managed more frequently in the community. Many of these community-based crises had a greater impact on care needs than the better-known causes of crisis that more frequently required hospital care. PwP and carer responses indicated a good general knowledge of potential crisis triggers. PwP were more aware of mental health issues and carers were more aware of cognitive impairment and issues with medications. CONCLUSION: These findings could improve care of Parkinson's by increasing understanding of crisis events from the patient and carer perspective, identifying under-recognised crisis triggers, and informing strategies for best recording symptoms from PwP and carers.

Evaluation of polyherbal ayurvedic formulation 'Peedantak Vati' for anti-inflammatory and analgesic properties.

ETHNOPHARMACOLOGICAL RELEVANCE: Peedantak Vati (PV) is a polyherbal ayurvedic formulation, which is regularly prescribed by the ayurvedic practitioner for the inflammatory disorders and joints pain in India. It is composed of 23 different herbs and minerals, described in ayurvedic text for their anti-inflammatory and analgesic properties. AIM OF THE STUDY: To investigate anti-inflammatory and anti-nociceptive potential of 'Peedantak Vati' using in vitro and in vivo methods. MATERIALS AND METHODS: In-vitro anti-inflammatory activity of PV was studied by estimating nitric oxide (NO) and LPS-induced pro-inflammatory cytokines IL-6 and TNF-α, using murine macrophage RAW264.7 and human monocyte THP-1 cell lines. PV's anti-inflammatory potential was studied in vivo using carrageenan-induced rat paw edema model. Similarly, anti-nociceptive property of PV was evaluated using hot plate, tail flick, formalin and writhing tests on CD-1 mice. Phytochemical profiling of hydro-alcoholic extract of PV was done using HPLC and HPTLC techniques to identify different marker compounds. These identified marker compounds were confirmed using LC-MS/MS analysis. RESULTS: In vitro results strongly suggest that, PV significantly (p < 0.001) inhibited NO release and LPS-stimulated pro-inflammatory cytokines IL-6 and TNF-α, in murine RAW264.7 and human THP-1 cells. Further, PV demonstrated significant (p < 0.05) anti-inflammatory activity at different time points after carrageenan injection with maximum effect at 2 h (40.4 ±â€¯5.2% at 400 mg/kg). Similarly, PV significantly (p < 0.05) decreased nociceptive pain, studied using hot plate, tail flick, formalin and writhing tests. Moreover, HPLC and HPTLC methods were developed for the standardization of PV. Five marker phytocompounds viz. rutin, caffeic acid, colchicine, withaferin A and curcumin were identified and quantified by HPLC and HPTLC methods. The presence of these phytoconstituents was confirmed by LC-MS/MS analysis. CONCLUSION: The findings of the study strongly suggest that, the polyherbal ayurvedic formulation 'Peedantak Vati' possesses remarkable anti-inflammatory and analgesic property, providing potent alternative for currently available allopathic medicines such as non steroidal anti-inflammatory drugs (NSAIDs).

Identifying balance impairments in people with Parkinson's disease using video and wearable sensors.

BACKGROUND: Falls and near falls are common among people with Parkinson's (PwP). To date, most wearable sensor research focussed on fall detection, few studies explored if wearable sensors can detect instability. RESEARCH QUESTION: Can instability (caution or near-falls) be detected using wearable sensors in comparison to video analysis? METHODS: Twenty-four people (aged 60-86) with and without Parkinson's were recruited from community groups. Movements (e.g. walking, turning, transfers and reaching) were observed in the gait laboratory and/or at home; recorded using clinical measures, video and five wearable sensors (attached on the waist, ankles and wrists). After defining 'caution' and 'instability', two researchers evaluated video data and a third the raw wearable sensor data; blinded to each other's evaluations. Agreement between video and sensor data was calculated on stability, timing, step count and strategy. RESULTS: Data was available for 117 performances: 82 (70%) appeared stable on video. Ratings agreed in 86/117 cases (74%). Highest agreement was noted for chair transfer, timed up and go test and 3 m walks. Video analysts noted caution (slow, contained movements, safety-enhancing postures and concentration) and/or instability (saving reactions, stopping after stumbling or veering) in 40/134 performances (30%): raw wearable sensor data identified 16/35 performances rated cautious or unstable (sensitivity 46%) and 70/82 rated stable (specificity 85%). There was a 54% chance that a performance identified from wearable sensors as cautious/unstable was so; rising to 80% for stable movements. SIGNIFICANCE: Agreement between wearable sensor and video data suggested that wearable sensors can detect subtle instability and near-falls. Caution and instability were observed in nearly a third of performances, suggesting that simple, mildly challenging actions, with clearly defined start- and end-points, may be most amenable to monitoring during free-living at home. Using the genuine near-falls recorded, work continues to automatically detect subtle instability using algorithms.

Could In-Home Sensors Surpass Human Observation of People with Parkinson's at High Risk of Falling? An Ethnographic Study.

Self-report underpins our understanding of falls among people with Parkinson's (PwP) as they largely happen unwitnessed at home. In this qualitative study, we used an ethnographic approach to investigate which in-home sensors, in which locations, could gather useful data about fall risk. Over six weeks, we observed five independently mobile PwP at high risk of falling, at home. We made field notes about falls (prior events and concerns) and recorded movement with video, Kinect, and wearable sensors. The three women and two men (aged 71 to 79 years) having moderate or severe Parkinson's were dependent on others and highly sedentary. We most commonly noted balance protection, loss, and restoration during chair transfers, walks across open spaces and through gaps, turns, steps up and down, and tasks in standing (all evident walking between chair and stairs, e.g.). Our unobtrusive sensors were acceptable to participants: they could detect instability during everyday activity at home and potentially guide intervention. Monitoring the route between chair and stairs is likely to give information without invading the privacy of people at high risk of falling, with very limited mobility, who spend most of the day in their sitting rooms.

Anticancer activity of Ophiobolin A, isolated from the endophytic fungus Bipolaris setariae.

The present work describes the anticancer activity of Ophiobolin A isolated from the endophytic fungus Bipolaris setariae. Ophiobolin A was isolated using preparative HPLC and its structure was confirmed by HRMS, (1)H NMR, (13)C NMR, COSY, DEPT, HSQC and HMBC. It inhibited solid and haematological cancer cell proliferation with IC50 of 0.4-4.3 µM. In comparison, IC50 against normal cells was 20.9 µM. It was found to inhibit the phosphorylation of S6 (IC50 = 1.9 ± 0.2 µM), ERK (IC50 = 0.28 ± 0.02 µM) and RB (IC50 = 1.42 ± 0.1 µM), the effector proteins of PI3K/mTOR, Ras/Raf/ERK and CDK/RB pathways, respectively. It induced apoptosis and inhibited cell cycle progression in MDA-MB-231 cancer cells with concomitant inhibition of signalling proteins. Thus, this study reveals that anticancer activity of Ophiobolin A is associated with simultaneous inhibition of multiple oncogenic signalling pathways namely PI3K/mTOR, Ras/Raf/ERK and CDK/RB.

P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity.

The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFß receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G1-S cell-cycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies.

The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer.

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and anti-estrogen-resistant models of ER+ breast cancer. Estrogen receptor-positive (ER+) breast cancer cells were treated ±P7170. Fresh cores from primary ER+/HER2- tumors from two patients were treated ±P7170 ex vivo. Mice bearing breast cancer xenografts were randomized to treatment with vehicle, fulvestrant, P7170, or combinations, and tumor volumes were measured. Tissues and cells were analyzed for markers of pathway activity, cell viability, and apoptosis. In cell lines, P7170 exhibited IC50 values in the range of 0.9-7 nM and induced apoptosis. P7170 potently inhibited mTOR activity (≤ 25 nM) and inhibited PI3K at higher concentrations (≥ 200 nM). P7170 completely inhibited MCF-7 tumor growth, significantly inhibited growth of fulvestrant-resistant T47D tumors, and suppressed tumor cell proliferation but did not induce apoptosis. While P7170 inhibits PI3K and mTOR in ER+/HER2- human breast cancer cells and tumors ex vivo, in vivo data indicate that the primary mechanism of P7170 anti-tumor action is inhibition of mTOR and cell proliferation. P7170 is a novel agent worthy of further investigation for the treatment of ER+ breast cancer.

P7170, a novel inhibitor of mTORC1/mTORC2 and Activin receptor-like Kinase 1 (ALK1) inhibits the growth of non small cell lung cancer.

BACKGROUND: Lung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Some patients though initially respond, but later develop resistance to erlotinib/gefitinib with no option except for cytotoxic therapy. Therefore, development of novel targeted therapeutics is imperative to provide improved survival benefit for NSCLC patients. The mTOR cell survival pathway is activated in naïve, or in response to targeted therapies in NSCLC. METHODS: We have discovered P7170, a small molecule inhibitor of mTORC1/mTORC2/ALK1 and investigated its antitumor efficacy using various in vitro and in vivo models of human NSCLC. RESULTS: P7170 inhibited the phosphorylation of AKT, S6 and 4EBP1 (substrates for mTORC2 and mTORC1) levels by 80-100% and growth of NSCLC cells. P7170 inhibited anchorage-independent colony formation of NSCLC patient tumor-derived cells subsistent of disease sub-types. The compound also induced apoptosis in NSCLC cell lines. P7170 at a well-tolerated daily dose of 20 mg/kg significantly inhibited the growth of NSCLC xenografts independent of different mutations (EGFR, KRAS, or PIK3CA) or sensitivity to erlotinib. Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed sub-micro molar tumor concentrations along with mTORC1/C2 inhibition. CONCLUSIONS: Our results provide evidence of antitumor activity of P7170 in the erlotinib -sensitive and -insensitive models of NSCLC.