Intensive rehabilitation programs improve motor and non-motor symptoms in people with Parkinson's disease (PD), however, it is not known whether transfer to daily-living walking occurs. The effects ...of multidisciplinary-intensive-outpatient rehabilitation (MIOR) on gait and balance in the clinic and on everyday walking were examined. Forty-six (46) people with PD were evaluated before and after the intensive program. A 3D accelerometer placed on the lower back measured daily-living walking during the week before and after the intervention. Participants were also stratified into "responders" and "non-responders" based on daily-living-step-counts. After the intervention, gait and balance significantly improved, e.g., MiniBest scores (
< 0.001), dual-task gait speed increased (
= 0.016) and 6-minute walk distance increased (
< 0.001). Many improvements persisted after 3 months. In contrast, daily-living number of steps and gait quality features did not change in response to the intervention (
> 0.1). Only among the "responders", a significant increase in daily-living number of steps was found (
< 0.001). These findings demonstrate that in people with PD improvements in the clinic do not necessarily carry over to daily-living walking. In a select group of people with PD, it is possible to ameliorate daily-living walking quality, potentially also reducing fall risk. Nevertheless, we speculate that self-management in people with PD is relatively poor; therefore, to maintain health and everyday walking abilities, actions such as long-term engaging in physical activity and preserving mobility may be needed.
Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are ...conserved, no specific mutation is correlated with the dissemination of metastases
. Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression. De novo motif analysis of these events detected enrichment of motifs with high similarity to the RBFOX2 motif. Overexpression of RBFOX2 in a patient-derived xenograft (PDX) metastatic PDA cell line drastically reduced the metastatic potential of these cells in vitro and in vivo, whereas depletion of RBFOX2 in primary pancreatic tumour cell lines increased the metastatic potential of these cells. These findings support the role of RBFOX2 as a potent metastatic suppressor in PDA. RNA-sequencing and splicing analysis of RBFOX2 target genes revealed enrichment of genes in the RHO GTPase pathways, suggesting a role of RBFOX2 splicing activity in cytoskeletal organization and focal adhesion formation. Modulation of RBFOX2-regulated splicing events, such as via myosin phosphatase RHO-interacting protein (MPRIP), is associated with PDA metastases, altered cytoskeletal organization and the induction of focal adhesion formation. Our results implicate the splicing-regulatory function of RBFOX2 as a tumour suppressor in PDA and suggest a therapeutic approach for metastatic PDA.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Many older adults walk with a cautious and impaired gait of unknown origin, however, the relationship between fear of falling and the observed gait changes is not well understood. To better ...understand the “cautious” gait of the elderly, we tested the hypothesis that temporal gait variability, putatively a marker of intrinsic walking unsteadiness, is increased among older adults with a cautious gait and a higher-level gait disorder (HLGD), an altered gait that cannot be attributed to a well-defined cause. Twenty-five older adults (mean age: 78 years) with a HLGD were compared to healthy controls of similar age and sex (
n=28). The clinical characteristics (e.g., neurological status, fear of falling), the magnitude of the stride-to-stride variations in gait cycle timing (a measure of temporal gait variability), and a fractal index of gait (a measure of the stride dynamics independent of the magnitude of the variability) were studied in both groups. Gait variability was significantly increased (
P<0.0001) in HLGD subjects (
52±26
ms
) compared to controls (
27±9
ms
). Changes in frontal lobe and extra-pyramidal function were also found in the patient group. Among HLGD subjects, gait variability was not associated (
P>0.05) with age, gender, MMSE score, muscle strength, # of co-morbidities, balance, cerebellar signs, or pyramidal signs, but was significantly associated with scores on the Geriatric Depression Scale (
r=0.46,
P<0.02) and fear of falling (
r=0.69,
P<0.0001). Among HLGD subjects, only a fractal index was significantly different in fallers and non-fallers. These findings underscore the idea that the gait changes in older adults who walk with fear may be an appropriate response to unsteadiness, are likely a marker of underlying pathology, and are not simply a physiological or psychological consequence of normal aging.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
A subset of patients with pancreatic adenocarcinomas (PDAC) harbor mutations that are exploitable in the context of DNA-damage response and repair (DDR) inhibitory strategies. Between 8-18% of PDACs ...harbor specific mutations in the DDR pathway such as BRCA1/2 mutations, and a higher prevalence exists in high-risk populations (e.g., Ashkenazi Jews). Herein, we will review the current trials and data on the treatment of PDAC patients who harbor such mutations and who appear sensitive to platinum and/or poly ADP ribose polymerase inhibitor (PARPi) based therapies due to a concept known as synthetic lethality. Although this current best-in-class precision treatment shows clinical promise, the specter of resistance limits the extent of therapeutic responses. We therefore also evaluate promising pre-clinical and clinical approaches in the pipeline that may either work with existing therapies to break resistance or work separately with combination therapies against this subset of PDACs.
Abstract Introduction The Timed Up and Go (TUG) test is a widely used measure of mobility and fall risk in older adults and in Parkinson's disease (PD). We tested the hypothesis that body-fixed ...accelerometers can provide insight into TUG performance in PD patients. Methods We examined 17 patients with PD (Hoehn and Yahr score: 2.7 ± 0.7; ON state) and 15 age-matched healthy controls; mean ages were 66.8 ± 5.9 years, 67.6 ± 9.6 years, respectively. Subjects wore a 3D-accelerometer (ADXL330, Analog Devices) on the lower back while performing the TUG test. Sit-to-Stand and Stand-to-Sit times were extracted from the anterior–posterior (AP) signal. Parameters included Sit-to-Stand, Stand-to-Sit durations, amplitude range (Range) and slopes (Jerk). Acceleration median and standard deviation (SD) were also calculated. Results Stopwatch-based TUG duration tended to be higher for the PD patients compared to the control group, although not significantly ( p = 0.08). In contrast, the TUG duration that was extracted from the acceleration signal was significantly ( p < 0.02) higher in the PD group compared to the control group. Many acceleration-parameters were also significantly different ( p < 0.05) between groups; most were not correlated with TUG duration. Conclusions Accelerometer-derived parameters are sensitive to group differences, indicating that PD patients have poorer mobility during specific aspects of the TUG. In addition to test duration, these measures may serve as complementary and objective bio-markers of PD to augment the evaluation of disease progression and the response to therapeutic interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than 1 year, underscoring the importance of evaluating novel targets with matched targeted agents. We ...recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR (
). Here, we evaluated PARG as a target in PDAC models using both genetic silencing of PARG and established small-molecule PARG inhibitors (PARGi), PDDX-01/04. Homologous repair-deficient cells compared with homologous repair-proficient cells were more sensitive to PARGi
.
, silencing of PARG significantly decreased tumor growth. PARGi synergized with DNA-damaging agents (i.e., oxaliplatin and 5-fluorouracil), but not with PARPi therapy. Mechanistically, combined PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase-3, and increased γH2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi. SIGNIFICANCE: PARG is a potential target in pancreatic cancer as a single-agent anticancer therapy or in combination with current standard of care.
Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline
or
(g
) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on g
...mutational status alone is associated with heterogeneous responses.
We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were g
mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers.
We found that biallelic inactivation of
/
is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17).
In summary, we propose a predictive and prognostic model of g
-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.
Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified ...based on the spectrum of response to platinum/PARP inhibition: (i) refractory overall survival (OS) <6 months, (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions.
glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer related deaths in the U.S. Recent advances in understanding RNA biology in PDAC have shed light on ...post-transcriptional regulation of genes and pathways through RNA binding proteins (RBP). Our lab has demonstrated that HuR, an RBP, is overexpressed in PDAC cells and stabilizes pro-survival mRNAs. Additionally, our work and others have demonstrated that this level of gene regulation can support drug resistance in PDAC cells. A synthetic lethal strategy employing Poly-ADP ribose polymerase inhibitors (PARPi) in a subset of patients with DNA repair deficient pancreatic cancers has been gaining interest. However, the success of PARPi is often hindered by the emergence of drug resistance in patients who initially respond. We have published that short-term PARPi treatment of PDAC cells causes activation of HuR where it stabilizes a DNA repair enzyme, PAR-glycohydrolase, and mediates acute PARPi resistance. In this study, we generated olaparib acquired resistant pancreatic cancer cells in vitro and acquired pancreatic patient derived xenograft cell lines (pre- and post PARPi) to understand acute versus acquired resistant mechanism(s). In characterising the acquired resistant model of PARPi resistance, we found that these cells are >20 fold more resistant to olaparib and platinums and >5 fold resistant to other PARPi like rucaparib and veliparib, compared to parental cells. No cross resistance was seen with other chemotherapeutics like gemcitabine. Additionally, we also found acquired resistant cells lost PARP-1 protein expression compared to parental cells. Bioinformatic analyses on HuR-RNA immunoprecipitation-microarray (RIP-microarray) data from acutely treated olaparib cells show enrichment of pro-survival mRNAs. Interestingly, these mRNAs are significantly downregulated in acquired resistant cells compared to control cells (i.e., negative log2 fold changes, p<0.001) in differential expression of HuR and HuR established targets. Interestingly, upregulated gene transcripts in these samples belong to pathways that negatively regulate biosynthetic and metabolic processes, and hence may represent pathways to target. Further, in vitro analyses show that parental PDAC cells are sensitive to combined inhibition of PARP and HuR but acquired resistant cells fail to respond to HuR inhibition. In conclusion, HuR mediates acute resistance to PARPi in PDAC cells and HuR inhibitor therapy could enhance PARPi therapy immediately, yet is most likely not useful in the setting of acquired- resistance. Future studies will explore genetic alterations and novel HuR-independent pathways in PARPi acquired resistant cells. Finally, we have begun a line of investigation of combining PARPi therapy with HuR inhibitors in an effort to optimize upfront therapeutic efficacy
Citation Format: Aditi Jain, Matthew McCoy, Lebaron A. Agostini, Yuriy Gusev, Subha Madhavan, Michael Pishvaian, Sankar Addya, Eric Londin, Maria R. Gurevich, Chani Stossel, Talia Golan, Charles J. Yeo, Jonathan R. Brody. A global transcriptome analysis of pancreatic cancer cells distinguishes between acute and acquired PARP inhibitor resistance mechanisms abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4764.
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