tbuckley/cabot-search huggingface dataset:
Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology
Authors: Michael C. Pace, Guilian Xu, Susan Fromholt, John Howard, Benoit I. Giasson, Jada Lewis, David R. Borchelt
Journal: Molecular Neurodegeneration (2018)

Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins.Mice expressing high levels of mutant forms of tau and α-synuclein (αSyn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation.Mice expressing low levels of G85R-SOD1:YFP, alone, lived normal lifespans and were free of evidence of inclusion pathology, setting the stage to use this protein as a reporter of proteostatic function. We observed robust induction of G85R-SOD1:YFP inclusion pathology in the neuropil of spinal cord and brainstem of bigenic mice that co-express high levels of mutant tau in the spinal axis and develop robust spinal tau pathology (JNPL3 mice). In contrast, in crosses of the G85R-SOD1:YFP mice with mice that model spinal α-synucleinopathy (the M83 model of αSyn pathology), we observed no G85R-SOD1:YFP inclusion formation. Similarly, in crosses of the G85R-SOD1:YFP mice to mice that model cortical tau pathology (rTg4510 mice), we did not observe induction of G85R-SOD1:YFP inclusions.Despite robust burdens of neurodegenerative pathology in M83 and rTg4510 mice, the introduction of the G85R-SOD1:YFP protein was induced to aggregate only in the context of spinal tau pathology present in the JNPL3 model. These findings suggest unexpected specificity, mediated by both the primary protein pathology and cellular context, in the induced "secondary aggregation" of a mutant form of SOD1 that could be viewed as a reporter of proteostatic function.
Cancer survivorship and diet: Is there a consensus? A narrative review.
Authors: Kalyani Murthy, Dana Kamenetsky, Krishna Soujanya Gunturu
Journal: Journal of Clinical Oncology (2018)

100 Background: Diet and nutrition play a key role in the maintenance of health-related quality of life. Studies indicate cancer survivors evince a great interest in learning about nutrition and are willing to initiate life-style changes at the time of diagnosis. However recent survivor data indicates a lack of professional advice on nutrition. Given current guidelines by the American Cancer Society on increasing healthy eating awareness, we present a narrative review of published literature and discuss options for information dissemination. Methods: PubMed search from 2012-2017 was conducted. Studies on outcomes related to diet and nutrition in cancer survivors were included. We excluded general reviews, case reports, pediatric and complementary medicine abstracts. Results: Our initial search yielded 355 abstracts. We focused our review on 33 studies in breast, prostate and colo-rectal cancer care. Diet rich in saturated and trans-fats was detrimental in survivors (≈24%). Low-fat diet improved recurrence rates and overall mortality in 18% studies. Despite this high fat and dairy rich diet were noted in ≈18% studies. Data from studies (18%) incorporating fruits and vegetables indicated improvement in cognitive scores, post-cancer related fatigue and survival benefit. Adherence rates based on healthy-eating-index scores were low in survivors in a recent national survey. Vitamin D repletion is an area of debate. Studies have shown improvement in survival and mortality rates in breast and prostate cancer survivors. Conclusions: Data on survivor dietary preferences, changes and subsequent results are heterogeneous. Evidence suggests improvement in diet quality is positively associated with cancer and unrelated mortality. It is crucial to enforce the importance of healthy dietary changes to cancer survivors. Enabling access to key nutritional information to providers caring for survivors forms a major crux in this endeavor to empower survivors towards better health. Tools such as e-learning could be harnessed for this purpose. Ultimately recognition of optimal strategies and guidelines to assist, educate and motivate survivor adherence to such changes long-term needs further evaluation.
Abstract 12663: Ankle-brachial Index For Prognosis of Cardiovascular Disease in Patients With Mild Renal Insufficiency
Authors: Hitoshi Nishimura, Takashi Miura, Masatoshi Minamisawa, Yasushi Ueki, Naoyuki Abe, Naoto Hashizume, Tomoaki Mochidome, Mikiko Harada, Kunihiko Shimizu, Wataru Shoin, Koji Yoshie, Yasutaka Oguchi, Soichiro Ebisawa, Hirohiko Motoki, Atsushi Izawa, Jun Koyama, Uichi Ikeda
Journal: Circulation (2016)

Background: Low ankle-brachial index (ABI) is a known predictor for future cardiovascular events and mortality in patients with advanced stage chronic kidney disease (CKD) or undergoing hemodialysis. While most prior studies defined CKD as an estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73 m 2 , recent reports have demonstrated that cardiovascular risk may increase even in earlier stages of renal insufficiency. We hypothesized that low ABI may predict future cardiovascular morbidity and mortality in patients with mild impairment of renal function. Methods: The IMPACT-ABI study was a retrospective, single-center, cohort study that enrolled and obtained ABI measurements for 3131 patients hospitalized for cardiovascular disease between January 2005 and December 2012. From this cohort, we identified 1511 patients with mild renal insufficiency (eGFR = 60-89 ml/min/1.73 m 2 ), and stratified them into two groups: ABI ≤ 0.9 (low ABI group; 9.3%) and ABI &gt; 0.9 (90.6%). The primary outcome measured was the cumulative incidence of major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, and stroke). Results: Over a mean follow-up of 5.1 years, 101 MACE occurred. The incidence of MACE was significantly higher in patients with low ABI than in those with ABI &gt; 0.9 (29.7% vs. 14.3%, log rank P &lt; 0.001). In multivariate Cox proportional hazard analysis adjusted for traditional cardiovascular risk factors, low ABI was an independent predictor of MACE (hazard ratio: 1.79; 95% confidence interval: 1.03-3.08; P = 0.036). Conclusions: Low ABI was an independent predictor for MACE in patients with mild renal insufficiency.
Managing childhood cancer survivors at risk for stroke: Practice norms and areas of controversy.
Authors: Lisa Brazzamano Kenney, Bethany Ames, Alexis L. Michaud, David Williams, Nicole A. Ullrich, Peter Manley
Journal: Journal of Clinical Oncology (2018)

124 Background: Childhood cancer survivors (CCS) treated with cranial radiation (CR) are at increased risk for stroke. There is no evidence to guide stroke prevention strategies for CSS. We aimed to describe regional practice norms for managing survivors at risk for stroke and to define areas where management is controversial. Methods: We conducted a Delphi panel of 30 physicians from the New England region who care for CCS, including primary care and specialists. Panelists anonymously answered 3 rounds of open ended questionnaires querying their management approach to a childhood brain tumor survivor treated with CR formatted as 5 clinical scenarios (asymptomatic, large and small vessel cerebral vascular disease (CVD), TIA, stroke), covering 5 categories of management (imaging, lab testing, medication, counseling, referrals). Consensus was defined as ≥ 90% of panelist agreeing with management option. Results: There was a 100% response rate for all 3 rounds of questionnaires. Of the 25 management questions related to 5 clinical scenarios, consensus was reached on 18 while 7 remained controversial. In the scenario of acute stroke symptoms, consensus was reached in all 5 categories of management. In the scenarios of large vessel CVD with symptoms of a TIA, large-vessel CVD without symptoms, and small-vessel CVD without symptoms panelists did not reach consensus on medication, specifically, aspirin use. The primary reasons for disagreement were no evidence for benefit/risk and beyond area of expertise. In the scenario of an asymptomatic survivor with no history of CVD panelists did not reach consensus on indication for MRI surveillance imaging, the primary reasons for disagreement were no clear benefit and risk of findings with uncertain clinical significance. Consensus was not reached on specialty referral patterns in any scenario except acute stroke. Conclusions: Despite lack of evidence to guide stroke prevention in childhood cancer survivors treated with CR, a panel of regional physicians reached consensus on managing most clinical scenarios. Controversial areas requiring further study are follow-up imaging for asymptomatic survivors, aspirin for stroke prophylaxis, and indications for sub-specialty referral.
Impact of PIK3CA mutation status on immune marker response and pCR in the WSG-ADAPT HER2+/HR+ phase II trial.
Authors: Nadia Harbeck, Ulrike Nitz, Matthias Christgen, Ronald E. Kates, Michael Wilhelm Braun, Sherko Kummel, Claudia Schumacher, Jochem Potenberg, Wolfram Malter, Doris Augustin, Bahriye Aktas, Helmut Forstbauer, Joke Tio, Anke Kleine-Tebbe, Cornelia Liedtke, Sanne de Haas, Regula Deurloo, Rachel Wuerstlein, Hans Heinrich Kreipe, Oleg Gluz
Journal: Journal of Clinical Oncology (2018)

572 Background: The ADAPT HER2+/HR+ phase II trial (NCT01745965) compared for the first time 12 wks. neoadjuvant T-DM1 (+/- endocrine therapy (ET)) with trastuzumab (T)+ET; pCR (ypT0/is ypN0) was > 40% in T-DM1 arms and 15% in T+ET. High CD8 at baseline or cycle 2, as well as increased CD8 expression on treatment, were associated with favorable pCR. In HER2+ mBC, T-DM1 was reported effective in both mutated and wildtype (WT) PIK3CA tumors. Methods: This pre-planned translational analysis aimed to identify potential early predictors for response to neoadjuvant therapy (containing T-DM1 or T) in HER2+/HR+ EBC. PIK3CA mutations were assessed by high-throughput microfluidics qPCR (MUT-MAP 13-gene panel). Immune markers, focusing here on CD8 in tumor center, were assessed by IHC in core biopsies at baseline and cycle 2. CD8 positivity was coded as percentage of positively stained cells; CD8 change was defined as cycle 2 minus baseline value. Associations between pCR and PIK3CA mutation status (mutated vs. WT) or with other variables were characterized by Fisher’s exact test and T-statistics. Results: In 190 patients, PIK3CA mutation status was assessed in baseline biopsies (177/190) or surgical samples (or both). Results were identical in all 8 repeated assays (baseline & surgery). Prevalence of PIK3CA mutations was 31/190 (16.3%). pCR was 37.4% in WT vs 16.7% in PIK3CA mutated tumors (p = .035). Distributions of nodal status, grade, and Ki67 were independent of PIK3CA mutation status, but T1 tumors were less prevalent (25.8% vs. 47.2%) for PIK3CA mutations (p = .03); the unfavorable impact of PIK3CA mutations on pCR was strong within the T2+ patient subgroup (9.1% vs 33.8%; p = .017). While CD8 protein expression generally increased following 3 weeks of therapy, and larger positive CD8 responses were themselves associated with pCR (particularly in the T-DM1 containing arms (p = .009)), CD8 changes in PIK3CA mutated tumors were small and lower than in WT (p = .020). Conclusions: PIK3CA mutations were associated both directly (lower pCR) and indirectly (stagnation of CD8 change) with poorer response to neoadjuvant therapy in HER2+/HR+ EBC. Poor response in PIK3CA mutated cases occurs despite excellent overall pCR with T-DM1. Clinical trial information: NCT01817452.
Ultrasound-guided restaging and localization of axillary lymph nodes after neoadjuvant chemotherapy for guidance of axillary surgery in breast cancer patients: Experience with activated charcoal.
Authors: Soo Jung Lee, In Hee Lee, Yee Soo Chae, Jeeyeon Lee, Jin Hyang Jung, Ho Yong Park, Won Hwa Kim, Hye Jung Kim, Byung Woog Kang
Journal: Journal of Clinical Oncology (2018)

e12615 Background: The aim of this study was to review our experience with ultrasound (US)-guided localization of axillary lymph nodes using activated charcoal for the guidance of axillary surgery after neoadjuvant chemotherapy(NAC) in clinically node-positive breast cancer patients. Methods: Between April 2016 and April 2017, US-guided localization of the most suspicious axillary lymph nodes at restaging US using activated charcoal (CharcotraceTM) was performed in 45 consecutive, clinically node-positive breast cancer patients who had less than two suspicious nodes after NAC and axillary surgery with sentinel node biopsy. Sentinel nodes were defined as radioactive nodes or nodes containing blue dye. The concordance between final pathological results for both the tattooed and sentinel nodes was analyzed. Results: Sentinel node biopsy failed in five patients (11%) in whom axillary surgery was performed under the guidance of the tattooed node. The tattooed nodes were identified in the surgical field in 44 patients (98%). Of the 44 tattooed nodes, 25 (57%) were concordant with the sentinel nodes and 19 (43%) were non-sentinel nodes, including the five nodes with failed sentinel node biopsy. In the final pathological results, 18 patients (40%) had metastatic nodes. The sensitivities for detecting axillary metastasis of the sentinel node biopsy, tattooed node biopsy, and the sentinel and/or tattooed node biopsy were 61% (11/18), 67% (12/18), and 78% (14/18), respectively. Conclusions: US-guided localization of axillary lymph nodes using activated charcoal at restaging after NAC in clinically node-positive breast cancer patients is a useful technique to guide axillary surgery, with a high identification rate.
The role of histology on survival of triple negative breast cancer.
Authors: Carol Parise, Vincent Caggiano
Journal: Journal of Clinical Oncology (2018)

e12590 Background: Triple negative breast cancer (TNBC) has the worst survival. The infiltrating ductal, inflammatory, medullary, and metaplastic subtypes comprise the majority of TNBC cases and also have distinct differences in survival. The purpose of this study was to determine if histologic subtype makes a difference in survival of TNBC. Methods: We identified 25,221 cases of first primary female invasive TNBC and 144,020 with the other ER/PR/HER2 subtypes from the California Cancer Registry 2000-2014. Histology was classified as infiltrating ductal, inflammatory, medullary, and metaplastic. Kaplan-Meier breast cancer specific survival and the Log Rank Test were used to compare the histologic subtypes among TNBC versus non-TNBC cases. Five and and 10 year survival and 95% confidence intervals (CI) were computed. Results: For both TNBC and non-TNBC cases, medullary had the best survival and inflammatory had the worse survival. Infiltrating ductal cases and inflammatory cases that were TNBC had significantly worse survival than the respective non-TNBC cases (p < 0.001). There were no statistically significant differences (p > 0.05) between medullary and metaplastic TNBC and non-TNBC cases. Table 1 shows the 5 and 10 year survival for TNBC versus non-TNBC cases of the same histologic subtype. Conclusions: The TNBC subtype is a significant negative factor for breast cancer survival for the inflammatory and infiltrating ductal histologies. Table 1. Kaplan-Meier 5 and 10 year breast cancer specific survival and 95% confidence intervals for TNBC and non-TNBC cases for four histologic subtypes. 5-year (95% CI) 10-year (95% CI) Medullary Not TNBC (n = 355) 93.5 (90.8, 96.2) 89.8 (85.9, 93.8) TNBC (n = 546) 93.2 (91.1, 95.4) 91.0 (88.4, 93.6) Metaplastic Not TNBC (n = 233) 73.4 (67.7, 76.3) 67.2 (60.0, 70.8) TNBC (n = 536) 69.5 (65.7, 71.4) 64.5 (60.2, 66.7) Inflammatory Not TNBC (n = 521) 49.4 (46.2, 51.0) 34.9 (31.5, 36.6) TNBC (n = 104) 24.4 (19.6, 26.9) 20.2 (15.4, 22.6) Infiltrating ductal Not TNBC(n = 127,347) 91.1 (90.9, 91.2) 84.2 (83.9, 84.5) TNBC (n = 18,376) 77.4 (76.8, 78.0) 72.2 (71.5, 73.0)
Healthcare medical costs among post-menopausal women with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC) managed with systemic therapy following CDK 4/6 inhibitor (CDKi) in the real-world setting.
Authors: Nicole Princic, Derek Tang, Aditya Bardia, David Smith, William M. Johnson, Ayal Aizer
Journal: Journal of Clinical Oncology (2018)

1067 Background: To examine US healthcare costs among HR+/HER2- women with mBC having systemic therapy with chemotherapy, endocrine therapy, or everolimus following CDKi. Methods: This population-based analysis used MarketScan Commercial and Medicare administrative claims data to select post-menopausal women diagnosed with HR+/HER2- mBC between 1/1/2012- 10/31/2017 (index = first evidence of metastatic disease). Eligible patients had ≥1 line of systemic therapy on a chemotherapy, endocrine only, or everolimus-based regimen following a CDK4/6i-based line. All-cause and BC-related medical (excluding pharmacy) costs were measured per-patient per-month (PPPM) during each line of therapy. Generalized linear models were used to compare costs for post-CDKi systemic therapy lines after adjusting for key patient characteristics, including health status and line of therapy. Results: In total, 193 chemotherapy,186 endocrine only, and 70 everolimus-based lines following CDKi-based therapy were included. Patients with everolimus-based therapy had significantly (p < 0.001) lower all-cause (∆ = $6,462 PPPM) and BC-related (∆ = $5,706 PPPM) medical costs compared with chemotherapy and similar medical costs (all-cause and BC-related) compared with endocrine therapy after accounting for BC-related office administered treatment (Table). Results were consistent after adjusting for patient characteristics. Conclusions: Patients with HR+/HER2- mBC on everolimus-based therapies relative to chemotherapy following treatment with a CDKi incurred lower medical costs, after accounting for observable confounders. Chemotherapy Endocrine Everolimus Everolimus vs. Chemotherapy Everolimus vs. Endocrine Total medical $11,505 $6,767 $5,043 < 0.001 0.083 Total medical without BC-related office administered treatment $9,075 $5,254 $4,970 0.005 0.767 Total BC- related medical $8,506 $4,899 $2,800 < 0.001 0.004 Total BC-related medical without office administered treatment $6,076 $3,387 $2,727 < 0.001 0.311
MET alterations detected in blood-derived circulating tumor DNA correlate with bone metastases and poor prognosis
Authors: Sadakatsu Ikeda, Maria Schwaederle, Mandakini Mohindra, Denis L. Fontes Jardim, Razelle Kurzrock
Journal: Journal of Hematology & Oncology (2018)

We analyzed clinical associations of MET alterations in the plasma of patients with diverse malignancies. Digital sequencing of circulating tumor DNA (ctDNA) (54–70 genes) was performed in 438 patients; 263 patients also had tissue sequencing (182–315 genes). The most represented tumor types were gastrointestinal (28.1%), brain (24.9%), and lung (23.2%). Most patients (71.2%) had recurrent/metastatic disease. MET alterations were observed in 31 patients (7.1%) and correlated with bone metastasis (P = 0.007), with TP53 (P = 0.001) and PTEN (P = 0.003) abnormalities, and with an increased number of alterations (median, 4 vs 1, P = 0.001) (all multivariable analyses). Patients with MET alterations demonstrated a significantly shorter median time to metastasis/recurrence (1.0 vs 10.4 months, P = 0.044, multivariable) and a poorer survival (30.6 vs 58.4 months, P = 0.013, univariate only). Of the 31 patients with MET alterations, 18 also had tissue testing; only two also had tissue MET alterations (11.1%); MET alterations were detected at a lower frequency in tissue (1.14%) compared to ctDNA (7.1%), with P = 0.0002. In conclusion, the detection of MET alterations by liquid biopsy is feasible. MET ctDNA alterations were associated with a poorer prognosis, higher numbers of genomic abnormalities, and bone metastases. The correlation with bone metastases may explain the higher frequency of MET alterations in blood ctDNA than in tissue (since bones are rarely biopsied) and the previous observations of bone-predominant responses to MET inhibitors. The high number of co-altered genes suggests that MET inhibitors may need to be combined with other agents to induce/optimize responses.
Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection
Authors: Katarina Tomovic, Jelena Lazarevic, Gordana Kocic, Marina Deljanin‐Ilic, Marko Anderluh, Andrija Smelcerovic
Journal: Medicinal Research Reviews (2018)

Abstract Dipeptidyl peptidase‐4 (DPP‐4) cleaves N‐terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP‐4 expression and activity. Besides the regulation of glucose metabolism, DPP‐4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP‐4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti‐inflammatory activity of clinically used DPP‐4 inhibitors in cardiovascular and renal protection.