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Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7AM1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V. Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology.

The persistence of human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) in the era of effective antiretroviral therapy suggests that modern HIV neuropathogenesis is driven, at least in part, by mechanisms distinct from the viral life cycle. Identifying more subtle mechanisms is complicated by frequent comorbidities in HIV+ populations. One of the common confounds is substance abuse, with cannabis being the most frequently used psychoactive substance among people living with HIV. The psychoactive effects of cannabis use can themselves mimic, and perhaps magnify, the cognitive deficits observed in HAND; however, the neuromodulatory and anti-inflammatory properties of cannabinoids may counter HIV-induced excitotoxicity and neuroinflammation. Here, we review our understanding of the cross talk between HIV and cannabinoids in the central nervous system by exploring both clinical observations and evidence from preclinical in vivo and in vitro models. Additionally, we comment on recent advances in human, multi-cell in vitro systems that allow for more translatable, mechanistic studies of the relationship between cannabinoid pharmacology and this uniquely human virus.

Amyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to ∼97% of ALS cases. Using a Drosophila model of ALS, we show that TDP-43 overexpression (OE) in motor neurons results in decreased expression of the Hsc70-4 chaperone at the neuromuscular junction (NMJ). Mechanistically, mutant TDP-43 sequesters hsc70-4 mRNA and impairs its translation. Expression of the Hsc70-4 ortholog, HSPA8, is also reduced in primary motor neurons and NMJs of mice expressing mutant TDP-43. Electrophysiology, imaging, and genetic interaction experiments reveal TDP-43-dependent defects in synaptic vesicle endocytosis. These deficits can be partially restored by OE of Hsc70-4, cysteine-string protein (Csp), or dynamin. This suggests that TDP-43 toxicity results in part from impaired activity of the synaptic CSP/Hsc70 chaperone complex impacting dynamin function. Finally, Hsc70-4/HSPA8 expression is also post-transcriptionally reduced in fly and human induced pluripotent stem cell (iPSC) C9orf72 models, suggesting a common disease pathomechanism.

The hexanucleotide repeat expansion GGGGCC (G(4)C(2))(n) in the C9orf72 gene is the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings suggest that dysfunction of nuclear-cytoplasmic trafficking could affect the transport of RNA binding proteins in C9orf72 ALS/FTD. Here, we provide evidence that the RNA editing enzyme Adenosine Deaminase Acting on RNA 2 (ADAR2) is mislocalized in C9orf72 repeat expansion mediated ALS/FTD. ADAR2 is responsible for Adenosine (A) to Inosine (I) editing of double stranded RNA, and its function has been shown to be essential for survival. Here we show the mislocalization of ADAR2 in human induced pluripotent stem cell-derived motor neurons (hiPSC-MNs) from C9orf72 patients, in mice expressing (G(4)C(2))(149), and in C9orf72 ALS/FTD patient postmortem tissue. As a consequence of this mislocalization we observe alterations in RNA editing in our model systems and across multiple brain regions. Analysis of editing at 408,580 known RNA editing sites indicates that there are vast RNA A to I editing aberrations in C9orf72-mediated ALS/FTD. These RNA editing aberrations are found in many cellular pathways, such as the ALS pathway and the crucial EIF2 signaling pathway. Our findings suggest that the mislocalization of ADAR2 in C9orf72 mediated ALS/FTD is responsible for the alteration of RNA processing events that may impact vast cellular functions, including the integrated stress response (ISR) and protein translation.

Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic cells into neurons (iNeurons) or glial cells. Distinct differentiation techniques for both models result in a variety of neuronal and glial cell types, which have been successful in displaying unique hallmarks of a variety of neurological diseases. Yield, length of differentiation, ease of genetic manipulation, expression of cell-specific markers, and recapitulation of disease pathogenesis are presented as determining factors in how these methods may be used separately or together to ascertain mechanisms of disease and identify therapeutics for distinct patient populations or for specific individuals in personalized medicine projects.

Background & Aims Accumulating evidence indicates that microRNAs play a role in a number of disease processes including the pathogenesis of liver fibrosis in hepatitis C infection. Our goal is to add to the accruing information regarding microRNA deregulation in liver fibrosis to increase our understanding of the underlying mechanisms of pathology and progression. Methods We used next generation sequencing to profile all detectable microRNAs in liver tissue and serum from patients with hepatitis C, stages F1–F4 of fibrosis. Results We found altered expression of several microRNAs, in particular, miR-182, miR199a-5p, miR-200a-5p and miR-183 were found to be significantly upregulated in tissue from liver biopsies of hepatitis C patients with advanced fibrosis, stage F3 and F4, when compared with liver biopsies from patients with early fibrosis, stages F1 and F2. We also found miR-148-5p, miR-1260b, miR-122-3p and miR-378i among the microRNAs most significantly down-regulated from early to advanced fibrosis of the liver. We also sequenced the serum microRNAs; however, we were not able to detect significant changes in circulating microRNAs associated with fibrosis stage after adjusting for multiple tests. Conclusions Adding measurements of tissue microRNAs acquired during routine biopsies will continue to increase our knowledge of underlying mechanisms of fibrosis. Our goal is that these data, in combination with studies from other researchers and future long-term studies, could be used to enhance the staging accuracy of liver biopsies and expand the surveillance of patients at increased risk for cancer and progression to advanced fibrosis.

Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping putative toxic mechanisms causing disease pathogenesis have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients.

Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic cells into neurons (iNeurons) or glial cells. Distinct differentiation techniques for both models result in a variety of neuronal and glial cell types, which have been successful in displaying unique hallmarks of a variety of neurological diseases. Yield, length of differentiation, ease of genetic manipulation, expression of cell-specific markers, and recapitulation of disease pathogenesis are presented as determining factors in how these methods may be used separately or together to ascertain mechanisms of disease and identify therapeutics for distinct patient populations or for specific individuals in personalized medicine projects.

Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)–negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m2 i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m2 orally twice daily, days 1–14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45–0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44–0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71−1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand–foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. Clin Cancer Res; 19(10); 2745–54. ©2013 AACR.

Introduction Accurate assessment of HER2 status is critical in determining appropriate therapy for breast cancer patients but the best HER2 testing methodology has yet to be defined. In this study, we compared quantitative HER2 expression by the HERmark™ Breast Cancer Assay (HERmark) with routine HER2 testing by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and correlated HER2 results with overall survival (OS) of breast cancer patients in a multicenter Collaborative Biomarker Study (CBS). Methods Two hundred and thirty-two formalin-fixed, paraffin-embedded breast cancer tissues and local laboratory HER2 testing results were provided by 11 CBS sites. HERmark assay and central laboratory HER2 IHC retesting were retrospectively performed in a blinded fashion. HER2 results by all testing methods were obtained in 192 cases. Results HERmark yielded a continuum of total HER2 expression (H2T) ranging from 0.3 to 403 RF/mm2 (approximately 3 logs). The distribution of H2T levels correlated significantly (P

BACKGROUND Doxorubicin plus ketoconazole has exhibited significant activity in patients with advanced prostate cancer. However, overall and cardiac-specific toxicity was reported to be high. Mitoxantrone has activity similar to that of doxorubicin, is less cardiotoxic, and is widely used to treat prostate cancer. The current study sought to evaluate the toxicity and activity of mitoxantrone plus ketoconazole in a cohort of patients with hormone-refractory prostate cancer. METHODS Progression after medical or surgical castration and, for those patients receiving antiandrogens, progression after withdrawal was required, as was objective evidence of metastasis, castrate levels of testosterone, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and intact cardiac function. After enrollment onto a multicenter local consortium study, subjects were treated with mitoxantrone at a dose of 12 mg/m2 intravenously every 3 weeks plus continuous oral ketoconazole at a dose of 400 mg 3 times daily and ascorbic acid at a dose of 250 mg. Replacement doses of hydrocortisone were given. RESULTS For 40 enrolled subjects, the median prostate-specific antigen and ECOG performance status were 68 and 1, respectively, 53% had Gleason scores of 8 to 10, and all had metastasis. Predominant Grade 3/4 toxicities were: neutropenia in 13%, neutropenic fever in 10%, and anemia in 13%. Of 37 evaluable patients, 8% achieved a complete remission (CR) and 62% achieved a partial remission (PR), for a CR plus PR rate of 70%. For soft tissue and bone disease, overall response rates were 13% and 8%, respectively. The median progression-free survival and overall survival were 10 months and 18 months, respectively. CONCLUSIONS Mitoxantrone plus ketoconazole is well tolerated, is active in hormone-refractory prostate cancer, and should be studied further. Cancer 2006. © 2006 American Cancer Society.

Objective To evaluate the efficacy and toxicity of the combination of VRCD (velcade/rituximab/cyclophosphamide/dexamethasone) in chemotherapy-naive low-grade non-Hodgkin lymphoma or patients with transplantation-ineligible mantle cells. Methods The patients were treated with velcade, at 1.6 mg/m 2 , on days 1, 8, 15, and 22 on every 35-day cycle. Rituximab was given at 375 mg/m 2 on the same days as velcade during cycle 1 and then only on day 1 in subsequent cycles. Dexamethasone was given orally at 40 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. Cyclophosphamide was administered orally at 400 mg/m 2 on days 1-4. The patients had to meet criteria to initiate therapy and had to demonstrate adequate performance status and organ function. Results Twelve patients were enrolled, after which the study was closed due to a lack of funding. The median age was 68 years (37-83 years), with 83% having stage III/IV disease. Five patients had marginal zone, 4 had follicular, 2 had small lymphocytic, and 1 had mantle cell histologies. The overall response rate was 90% (complete response, 54%). At a median follow-up of 22 months, 9 (75%) patients remain alive, and the median time to progression has not been reached. A third of the patients required dose reductions after a median of 6.5 cycles. No grade 3 or 4 peripheral neuropathy was witnessed. Conclusions Although the number of studied patients is small, VRCD appears safe and active as front-line therapy for low-grade non-Hodgkin lymphoma. Further studies are justified.

491 Lisa Guzman, RN, APN, CHPN, AOCN®, is an advanced practice nurse at Monroe Medical Oncology Clinic in Harvey and Tinley Park, IL, an instructor in the School of Nursing at Ivy Tech Community College in Gary, IN, and director of Blue Skies Hospice in Hammond, IN; Mark Kozloff, MD, is a doctor of oncology at Monroe Medical Oncology Clinic and an associate professor in the School of Medicine at the University of Chicago in Illinois; and James Wallace, MD, is a doctor of oncology and geriatrics and Alexander Starr, MD, is a doctor of oncology, both at Monroe Medical Oncology Clinic. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society.

ContextProlonged postmenopausal hormone replacement therapy (HRT) is associated with increased incidence of breast cancer and, paradoxically, reduced breast cancer mortality. The biological rationale for this discrepancy has not been explored.ObjectiveTo compare the prognostic characteristics of cancers arising in women who have used HRT with those in women who never have used HRT.DesignProspective cohort study from December 1989 to November 1996.SettingTeaching hospital in a large midwestern metropolitan area.PatientsCohort of 331 postmenopausal women who presented consecutively with 349 invasive breast cancers.Main Outcome MeasuresEstrogen receptor (ER) status (ER positive vs ER negative) and S phase (low vs high) for current HRT users vs never users.ResultsThe frequency of high S-phase fraction among cancers in women who were using HRT was markedly increased compared with that in women who had never used HRT (adjusted odds ratio [OR], 2.82; 95% confidence interval [CI], 1.04-7.66). However, the greater frequency of high S-phase fraction was limited to women with ER-positive cancers (for HRT users vs never users, OR, 5.25; 95% CI, 1.36-20.28; for ER-negative cancers in HRT users vs never users, OR, 1.08; 95% CI, 0.20-5.86).ConclusionsUse of HRT appears to stimulate growth of ER-positive but not ER-negative breast cancer as measured by S-phase fraction. The prognostic significance of high S-phase fraction in current HRT users who have ER-positive tumors is unknown.

By transmitting and receiving several discrete tones, a tactical Navy radar can image a target via ISAR with little EMI on surrounding radar systems. Standard methods of stepped frequency sequentially transmit single frequency information which has the striking drawback of large amounts of contiguous transmit time. For large bandwidths and maneuvering targets, requiring several hundreds of milliseconds per frequency set could produce range smearing. FM-CW has the drawback that again, (in tactical environment) occupying several hundred MHz of contiguous bandwidth could interfere with other uses of the band. The method of ISAR image formation that will be described here utilizes a transmit waveform comprising a discrete set of tones. This waveform has many advantages over waveforms that require tactically significant amounts of either time or bandwidth. The specific system that will be discussed will be an augmented x-band CW tracking radar. A method of selecting the specific frequencies will be discussed along with a method of pairwise mixing the receive tones, known as Delta-K, that can be utilized for range profile sidelobe reduction. A method of calibrating the phase differences between channels will be discussed in detail. Results from simulations and data from a real system will be discussed.

Abstract 1769 Introduction: Rituximab (R) alone or R-based Chemoimmunotherapy programs have become the standard front-line approach for LG-NHL patients requiring therapeutic intervention. Nonetheless, identifying programs that are effective in elderly individuals remains challenging. Previous LG-NHL pivotal front-line studies enrolled patients with a median age of 55–60. Given in-vitro data that support synergy between bortezomib and cyclophosphamide and the safety of combining R with different chemotherapeutic agents, we initiated a phase II trial investigating the VRCD combination schedule as a front-line approach for LG-NHL with the primary objective of identifying overall response rate (OR), time to progression, and toxicity. Methods: Eligible patients were those with LG-NHL requiring treatment as defined by the NCI criteria to initiate therapy with good organ function and an ECOG performance status ≤2. Any histology of LG-NHL as defined in the WHO classification was allowed. In addition, mantle cell NHL patients who were not transplant-eligible and MALToma patients who failed radiotherapy and antibiotic treatment were allowed. Patients with ≥grade 2 neuropathy, known HIV+, or CNS involvement were excluded. Bortezomib was given weekly at 1.6 mg/m2 on days 1, 8, 15, 22 every 35-day cycles. R was given on those same days during the first cycle and only on day 1 of subsequent cycles. Cyclophosphamide was given at 400 mg/m2 orally on days 1 through 4 every 35-days. Dexamethasone was given orally at 40 mg dose on days 1, 2, 8, 9, 15, 16, 22, and 23 (the day before and of bortezomib). Treatment continued until disease progression, unacceptable toxicity, completing 8-cycles, or attaining maximal response before finishing 8-cycles at the investigator's discretion. Response assessment took place every 2 cycles using CT-Scans of involved regions, PET scans when indicated, and bone marrow biopsies if applicable. Toxicity was measured every cycle based on NCICTC-version 3.0 Results: Twelve patients have been enrolled (8males), median age 68 (37-83), 10 patients (83%) in stage III/IV, one patient with extra-nodal disease, and median LDH of 161 (range 127–226). Five patients had marginal zone, 4 follicular, 2 small lymphocytic, and 1 mantle cell hsitologies. Median number of cycles given was 4 (1-8). All patients are evaluable for toxicity and 11 for response. Myelosuppression was the most common toxicity as 8 patients (66%) required dose reduction in bortezomib after cycle # 1 and 4 patients (33%) required dose reduction in both bortezomib and cyclophosphamide after cycle # 1. In addition, 4 patients (33%) required a second dose reduction of bortezomib after cycle # 4 of treatment due to prolonged myelosuppression. No patient developed >grade 2 peripheral neuropathy (PN) although this might have been because of dose reductions. Two patients (16%) had grade 1 or 2 PN. Serious adverse events occurred in 4 patients (33%), but only 3 were possibly related to treatment (1 patient developed CNS vasculitis, one had herpes zoster causing tranverse myelitis, and a third developed interstitial pneumonitis). Ten patients completed therapy (2 remain on treatment after initial response) with an OR of 90% (45% complete response and 45% partial response). One patient (9%) had progressive disease after cycle # 2. None of the CR patients have progressed but 2 of the PR patients progressed at 15 and 16 months respectively at a median follow-up of 19 months. Only 2 patients have died; 1 from progressive disease and the other from unrelated cardiac disease (overall survival is 83%). Median time to disease progression in responding patients have not been reached. The trial was closed prematurely due to slow accrual. Conclusions: While the number of treated patients is small, VRCD provides elderly patients with high response rates. Reversible myelosuppression at the starting dose levels was the most common toxicity. However, at a cyclophosphamide dose of 300 mg/m2 and a weekly bortezomib dose of 1.3 mg/m2, this regimen provides patients with a convenient administration schedule and acceptable safety profile worthy of further studies. Disclosures: Nabhan: genentech: Research Funding, Speakers Bureau. Starr:genentech: Honoraria, Speakers Bureau.