tbuckley/cabot-search huggingface dataset:
Safety and efficacy of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with newly diagnosed multiple myeloma (MM): A phase I/II study
Authors: P. G. Richardson, S. Lonial, A. Jakubowiak, S. Jagannath, N. Raje, D. Avigan, I. M. Ghobrial, R. Knight, D. Esseltine, K. C. Anderson
Journal: Journal of Clinical Oncology (2008)

8520 Background: Single-agent Bz and Len/Dex are approved for pts with relapsed MM following ≥1 prior therapy. Len/Bz±Dex is active in relapsed/refractory MM, and Len/Dex and Bz/Dex are active in frontline MM. Primary objectives of this phase I/II study were to define the MTD and assess response rate to Len/Bz/Dex in previously untreated MM pts. Methods: Pts received Len 15–25mg on d 1–14, Bz 1.0–1.3mg/m2 on d 1, 4, 8, 11, and Dex 40/20mg (cycles 1–4/5–8) on day of and after Bz for up to eight 21-d cycles, initially at 4 planned dose levels (table). Dose escalation proceeded depending on dose-limiting toxicities (DLTs). Based on safety data, dose level 4M was added with a reduced Dex starting dose (20/10mg). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PN) were excluded. Responses were assessed by modified EBMT and Uniform Criteria. Pts with ≥PR could proceed to ASCT after ≥4 cycles. Results: 66 pts have been enrolled to date. Data are available on 53 pts (median age 58 yrs, 51% men, 68% IgG MM, 49% ISS Stage II/III): 33 in Phase I, including 17 at the maximum planned dose (dose level 4M), and 20 in Phase ll (at max planned dose). Pts have received a median of 6 cycles; 16 (32%) have completed all 8 cycles, 14 have discontinued. Two DLTs of G3 hyperglycemia due to high-dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred for Len in 12 pts, Bz in 11 pts, and Dex in 18 pts, mostly in dose levels 1–4. Toxicities have been manageable, with no unexpected toxicities, no G4 PN, 2 DVTs, and no treatment-related mortality. Response rate (≥PR) to date is 98% in 42 evaluable pts, including 52% CR/nCR/VGPR (table). After median follow-up of 4 months, median TTP, PFS, and OS have not been reached. Median stem cell collection in 7 pts was 11.5 x 106 CD34+ cells/kg. Conclusions: Len/Bz/Dex is very active and well tolerated in newly diagnosed MM pts. Phase II enrollment is almost complete. Updated response data will be presented. Responses by phase/dose level (subject to confirmation) Dose level Len/Bz/Dex starting dose Response-evaluable patients CR nCR VGPR PR RR Phase l 31 8 (26%) 3 (10%) 9 (29%) 10 (32%) 30 (97%) 1 15/1.0/40 3 1 1 1 3 2 15/1.3/40 3 2 1 3 3 20/1.3/40 3 1 2 3 4 25/1.3/40 6 1 3 2 6 4M 25/1.3/20 16 3 2 5 5 15 Phase II 25/1.3/20 11 1 (9%) 1 (9%) 9 (82%) 11 (100%) TOTAL 42 9 (21%) 3 (7%) 10 (24%) 19 (45%) 41 (98%) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene, Millennium Pharmaceuticals Celgene, Millennium, Novartis Celgene, Millennium Celgene, Millennium, Novartis Celgene, Eli Lilly, Millennium, Novartis
Effect of lenalidomide on hypoxia-induced HIF-1α signaling and the invasive phenotype in epithelial solid tumor cells.
Authors: L. Lu, P. Schafer, J. B. Bartlett
Journal: Journal of Clinical Oncology (2010)

e21056 Background: In hematological malignancies lenalidomide (len) exerts tumoricidal and immunomodulatory effects and may also influence the tumor cell microenvironment by blocking proangiogenic and proinvasive effects of growth factors and/or hypoxia. In solid tumor models len is antimetastatic but lacks overt tumoricidal activity. These observations led us to explore the effect of len on hypoxic solid tumor cells, in particular HIF-1α expression and its upstream regulators p53 and HDM-2. Methods: 18 solid tumor cell lines were tested for len's effect on response to hypoxia (1%O2, 5%CO2, 94%N2; Invivo2 400 hypoxic workstation). Cell lysates from 3 cell lines (HCT-15, MDA-MB-231 and SKOV-2) were assessed for HIF-1α, p53 and HDM-2 proteins by immunoblot. The effect of len on HIF-1α mRNA was assessed in transfected Luc-HIF NIH 3T3 cells. Len effects on hypoxia-induced trans-well invasion of 3 cell lines were also assessed. Results: Len (1μM) significantly inhibited hypoxia-induced HIF-1α protein levels dose-dependently in most of the tumor cell lines tested; breast (by 68%, MDA-MB-231; 65%, MCF-7), colorectal (76%, HCT-116; 65%, HCT-15; 82% HT-29), ovarian (71%, OVCAR-3; 66%, SKOV-3), renal (83%, 786-O; 57%, HEK293), prostate (54%, DU-145) and pancreatic (45%, MiaPaca-3) (all p < 0.05). However, len had no effect on HIF-1α in SW480 (colorectal), Panc-1, BxPC3 (pancreatic), SW579 (thyroid), NCI-H446 (SCLC) or Caki-1 (Renal) cell lines. In addition to inhibition of HIF-1α protein, len also inhibited hypoxia-induced HIF- 1α mRNA expression (p < 0.01). Len enhanced p53 levels in hypoxic HCT-15 cells (by 2-fold; p < 0.05), SKOV-3 cells (4-fold; p < 0.01) and MDA-MB-231 cells (∼2-fold; p < 0.05). Len totally inhibited the 2-fold hypoxic induction of HDM-2 levels in HCT-15 (p < 0.05) and SKOV-3 (p < 0.01) cells but had no effect on HDM-2 in p53 mutant MDA-MB-231 cells. Tumor cell invasiveness was enhanced in response to hypoxia by ∼3-fold in all 3 lines, and was blocked by 50-80% in the presence of len (all p < 0.05). Conclusions: These results suggest that len inhibits the proinvasive hypoxic response in multiple tumor lines and may exert antimetastatic effects within the hypoxic solid tumor microenvironment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene
Micro(RNA) management of smooth muscle cell phenotype and response to vascular injury: Figure 1
Authors: Robert A. Mcdonald, Karine Pinel, Andrew H. Baker
Journal: Cardiovascular Research (2015)

This editorial refers to ‘Down-regulation of miR-23b induces phenotypic switching of vascular smooth muscle cells in vitro and in vivo ’ by C. Iaconetti et al. , doi:10.1093/cvr/cvv141. 

Pathological remodelling of the blood vessel wall following vascular injury involves a switch in smooth muscle cell (SMC) phenotype, from a differentiated and contractile phenotype to a proliferative and synthetic state, resulting in adventitial and medial remodelling. Although this process is essential during wound healing, dysregulation of this process is central to the aetiology of a number of vascular proliferative pathologies. A substantial research effort has been attributed to trying to determine the underpinning molecular mechanisms which control this phenotypic switch in order to harness novel approaches to prevent prolonged periods of de-differentiation following vascular injury, thereby potentially improving clinical outcome. Recently, a number of studies have demonstrated that small non-coding RNA molecules, microRNAs (miRNAs), play a prominent role in controlling or modulating vascular differentiation and proliferation.1–5 These miRNAs function by partial or incomplete binding of their so-called seed region to complementary sequences in target genes to cause translational repression or degradation of these genes. This incomplete binding is thought to allow a single miRNA to target multiple mRNAs, which can potentially confer beneficial effects on disease pathogenesis through regulation of multiple genes.

Iaconetti et al. 6 provided further evidence that miRNAs play a prominent role in controlling phenotypic modulation of SMCs. The current study demonstrates that miR-23b is down-regulated following vascular injury in a rat model, and that adenovirus-mediated overexpression of miR-23b attenuates neointimal formation following balloon injury. The authors also utilize loss- and gain-of-function approaches to demonstrate that elevation of miR-23b levels reduces SMC proliferation and …
Expression of HER2 in gastric cancer: Comparison between protein expression and gene amplification using a new commercial kit
Authors: T. Yano, A. Ochiai, T. Doi, K. Hashizume, M. Nakanishi, K. Ouchi, Y. Tanaka, A. Ohtsu
Journal: Journal of Clinical Oncology (2004)

4053 Background: Trastuzumab, a monoclonal antibody to HER2 protein, is widely used in patients with HER2-overexpressing breast cancer. Trastuzumab has also shown antitumor activity in human gastric cancer (GC) xenograft models with HER2 overexpression, however, the concordance of protein expression and gene amplification of HER2 in GC cells and the feasibility of using biopsy specimens has not been clarified Aim: The purpose of this study was to evaluate the frequency of HER2 overexpression and the concordance between protein expression and gene amplification in surgical and endoscopic biopsy GC specimens using two commercial immunohistochemical(IHC) kits and fluorescence in situ hybridization (FISH). Materials and Methods: The specimens consisted of formalin-fixed, paraffin-embedded sections of biopsy specimens and surgically resected tumors in 200 cases with invasive GCs who underwent surgery at the National Cancer Center Hospital East. The IHC analysis was performed using the Hercep Test kit (DAKO Corp, Carpinteria, CA), and the expression grading was estimated using an FDA-approved grading system. HER2/neu gene amplification was evaluated using the PathVysion erb2 DNA probe kit (Vysis, Stuttgart-Fasanenhof, Germany). Results: Among these 200 cases, 46 (23%) of the patients were found to exhibit HER2 protein overexpression. The following IHC scores were obtained: 0,126(63%);1+, 28(14%);2+,12(6%);and 3+,34(17%). The FISH assay was technically successful in 199 cases (99.5%).Gene amplification was observed in 54 cases (27.1%). The concordance rate between IHC and FISH in the Her2-protein-overexpression cases was 86.7% (58.5% for 2+, 88.2% for 3+). Among the 200 biopsy specimens, Her2 protein overexpression was observed in 21.5% of the specimens (2+,7.5%; and 3+,14%). The concordance rate between the surgically resected materials and the biopsy specimens was 88.7%. Conclusion: HER2 expression can be assessed in GC tissue as previously reported for breast cancer tissue, using the with Hercep Test and Pathvysion. Furthermore, small biopsy specimens are suitable for evaluating Her2 overexpression in GC cells. No significant financial relationships to disclose.
The proximate-ultimate confusion in teaching and cooperation
Authors: Alex Thornton, Nichola J. Raihani
Journal: Behavioral and Brain Sciences (2015)

Abstract Kline does an admirable job of extending the functionalist framework developed by comparative researchers to help understand the function and form of human teaching. Functionalist approaches consider the adaptive value and underlying mechanisms of behaviour as separate but complementary questions, avoiding the conflation of ultimate and proximate explanations that has long hindered research on teaching and other forms of cooperation.
Phase II study of primary systemic therapy (PST) with doxorubicin (D) and docetaxel (T), then surgery (S), and radiation (RT), followed by use of non-cross-resistant adjuvant chemotherapy (Adj CT) with CMF based on pathologic response, in patients (pts) with locally advanced breast cancer (LABC): Long-term results from study ID97–099, M. D. Anderson Cancer Center
Authors: R. H. Alvarez, S. Kau, E. A. Strom, A. A. Sahin, S. E. Singletary, D. J. Booser, M. Cristofanilli, F. J. Esteva, G. N. Hortobagyi, V. Valero
Journal: Journal of Clinical Oncology (2008)

611 Background: PST is the principal component of a multidisciplinary treatment of LABC. One of the aims of this study was to evaluate if an improvement in survival could be achieved if pts were given an alternate non-cross resistant CT regimen, based on their pathologic response to anthracycline and taxane. Methods: After multidisciplinary evaluation pts had PST: D 60 mg/m2 IV and T 60 mg/m2 IV, with GM-CSF support. Pts received q3-week DT x4. Pts with inoperable disease after DT x4 received CMF chemotherapy x4 (C: 600 mg/m2, M: 40 mg/m2, F: 600 mg/m2) day 1 and 8 q 28 days, followed by S. Pts received adjuvant CT as follows: Pts with pathologic complete response (pCR) received adjuvant DT x2; Pts with pathologic partial response (pPR) and < 3+ nodes (+LN) received DT x 2 by CMF x6 cycles; Pts with lack of response and/or > 4+ LN after DT received CMF x 6. All pts received adjuvant RT and hormonotherapy (HT) if ER+ and/or PR+. Results: 88 pts were enrolled from 1/1998 to 6/2000: 86 with LABC, 2 with inflammatory breast cancer. Median age: 51 yrs (r: 28–73). Clinical stage: IIB, 1% IIIa, 28% IIIb, 47% IIIc, 24%. Nuclear grade III, 81%, ER (-), 41%; HER2+, 28%; HER2 (-), 52%; HER2 unk, 20%; Triple receptor (-), 18%. All pts were evaluable for response, toxicity, and survival. Median follow-up is 8 yrs. 79 pts had clinical response with 11 (14%) pCRs. 74 pts had S, 13% had BCS, and 85% had mastectomy. 14 pts crossed-over to CMF prior to S, 1 pt had pCR. 72 of the 88 pts received Adj CT: 9 pts DT (10%), 21 DT followed by CMF (24%), 41 CMF only (46%), 16 none (18%), 1 paclitaxel (1%). Grade 3/4 toxicity: neutropenic fever 27%, no CHF or AML. Survival analysis: 5-yr progression-free survival: 60% (standard error 5.3%), and 5-yr overall survival (OS): 73% (standard error 4.8%). Conclusions: In this group of pts with LABC and poor prognostic factors, the use of non-cross-resistant CMF CT did not improve pCR rate, median PFS or OS. Newer, potentially more effective therapies, including antiangiogenic therapies, should be further studied to improve OS of women with LABC. No significant financial relationships to disclose.
Nitric oxide inhibits sodium reabsorption in the isolated perfused cortical collecting duct.
Authors: B A Stoos, N H Garcia, J L Garvin
Journal: Journal of the American Society of Nephrology (1995)

Indirect evidence suggests that nitric oxide inhibits sodium reabsorption by the collecting duct; however, direct evidence is lacking. It was hypothesized that endothelium-derived nitric oxide inhibits sodium flux in the cortical collecting duct by blocking amiloride-sensitive sodium channels. Tubules were obtained from Sprague-Dawley rats pretreated with deoxycorticosterone acetate (5 mg/rat i.m.) 5 to 9 days before the experiment. Nitric oxide was added to the system by either the addition of endothelial cells and the induction of the release of nitric oxide via acetylcholine (10(-7) M) or by the addition of nitric oxide donors. Acetylcholine-induced nitric oxide release from endothelial cells decreased lumen-to-bath sodium flux by 24 +/- 7% (N = 3; P < 0.05). The addition of the nitric oxide donor, spermine NONOate (10(-5) M), decreased net sodium flux 68% from 10.1 +/- 2.0 to 3.6 +/- 2 pmol/mm.min (N = 5; P < 0.025). To assure that the inhibition of sodium flux was due to nitric oxide, another donor, nitroglycerin (2 x 10(-5) M), was used, which decreased sodium flux by 43%. Luminal amiloride (10 microM) decreased net sodium flux by 83% (from 14.8 +/- 1.2 to 2.4 +/- 0.7 pmol/mm.min; N = 5; P < 0.025). The addition of nitric oxide via spermine NONOate to tubules decreased intracellular sodium levels by 26% (N = 6; P < 0.005). The Na(+)-K+ATPase activity of spermine NONOate-treated tubules was 14.7 +/- 3.2 pmol/mm.min compared with the control value of 10.2 +/- 2.0 pmol/mm.min. Nitroglycerin did not significantly affect pump activity either.(ABSTRACT TRUNCATED AT 250 WORDS)
Health-Related Quality of Life in Patients with Primary Immune Thrombocytopenia Compared with the General Population
Authors: Fabio Efficace, Paola Fazi, Francesco Rodeghiero, Gianluca Gaidano, Piercarla Schinco, Monica Carpenedo, Alessandro Rambaldi, Maria Pina Simula, Paolo De Fabritiis, Paolo Ditonno, Giovanni Caocci, Salvatore Soldati, Alessandra Borchiellini, Erminia Baldacci, Julia Daragjati, Franco Mandelli, Maria Gabriella Mazzucconi
Journal: Blood (2012)
Outpatient autologous stem cell transplants for selected patients with myeloma: Morbidity, mortality, and duration of hospitalization
Authors: S. Liu, D. T. Vogl, E. A. Chong, S. M. Luger, D. L. Porter, S. J. Schuster, D. E. Tsai, C. Andreadis, S. D. Nasta, P. A. Mangan, E. A. Stadtmauer
Journal: Journal of Clinical Oncology (2007)

7104 Background: High-dose melphalan with autologous stem cell support improves survival for patients with myeloma but often requires prolonged inpatient hospitalization. Short hospitalization with close follow-up may reduce complications, cost, and duration of total hospitalization for selected patients with good performance status and social support. Methods: We reviewed all initial autologous transplants for myeloma from 1/03–4/06, categorized by length of initial hospitalization as brief stay (≤4 days) or prolonged stay (≥5 days). Clinical selection for a brief stay had been based on a combination of age; cardiac, pulmonary, and renal function; performance status; availability of caregivers at home; distance from our medical center; and patient preference. We reviewed the post-transplant course to 100 days and calculated cumulative hospitalization by adding length of initial hospitalization to that of subsequent readmissions within 100 days. Results: 148 patients received an initial transplant for myeloma: 64 were selected for brief stay and 84 for prolonged stay. There were no significant differences in age or in renal function, Durie-Salmon stage, or B 2 -microglobulin at diagnosis. Brief stay patients were discharged home after stem cell reinfusion, with first follow-up scheduled 3–14 days later. Care at home included a nurse visit after discharge, intravenous fluids and ondansetron, and oral antibiotics, with blood work twice weekly. 46% of brief stay patients required readmission during the first 100 days and had a median of 8.5 cumulative hospital days post-transplant, as compared to 18 days for prolonged stay patients (p=0.0001). There were fewer documented infections among brief stay patients (29.7% vs 50.0%, p=0.01) and fewer admissions to intensive care units (0 vs 6.0%, p=0.047). The groups had similar rates of bleeding (1.6% vs 4.8%, p=0.3) and thrombosis (3.1% vs 8.3%, p=0.2). No patients in the brief stay group died within 100 days, while mortality in the prolonged stay group was 4.8% (p=0.08). Conclusion: Selected patients receiving an autologous stem cell transplant for treatment of myeloma can be managed with brief initial hospitalization and outpatient follow-up, with low morbidity and mortality. No significant financial relationships to disclose.
Association of Resting Metabolism in the Fear Neural Network With Extinction Recall Activations and Clinical Measures in Trauma-Exposed Individuals
Authors: Marie-France Marin, Huijin Song, Michael B. VanElzakker, Lindsay K. Staples-Bradley, Clas Linnman, Edward F. Pace-Schott, Natasha B. Lasko, Lisa M. Shin, Mohammed R. Milad
Journal: American Journal of Psychiatry (2016)

Exposure-based therapy, an effective treatment for posttraumatic stress disorder (PTSD), relies on extinction learning principles. In PTSD patients, dysfunctional patterns in the neural circuitry underlying fear extinction have been observed using resting-state or functional activation measures. It remains undetermined whether resting activity predicts activations during extinction recall or PTSD symptom severity. Moreover, it remains unclear whether trauma exposure per se affects resting activity in this circuitry. The authors employed a multimodal approach to examine the relationships among resting metabolism, clinical symptoms, and activations during extinction recall.Three cohorts were recruited: PTSD patients (N=24), trauma-exposed individuals with no PTSD (TENP) (N=20), and trauma-unexposed healthy comparison subjects (N=21). Participants underwent a resting positron emission tomography scan 4 days before a functional MRI fear conditioning and extinction paradigm.Amygdala resting metabolism negatively correlated with clinical functioning (as measured by the Global Assessment of Functioning Scale) in the TENP group, and hippocampal resting metabolism negatively correlated with clinical functioning in the PTSD group. In the PTSD group, dorsal anterior cingulate cortex (dACC) resting metabolism positively correlated with PTSD symptom severity, and it predicted increased dACC activations but decreased hippocampal and ventromedial prefrontal cortex activations during extinction recall. The TENP group had lower amygdala resting metabolism compared with the PTSD and healthy comparison groups, and it exhibited lower hippocampus resting metabolism relative to the healthy comparison group.Resting metabolism in the fear circuitry correlated with functioning, PTSD symptoms, and extinction recall activations, further supporting the relevance of this network to the pathophysiology of PTSD. The study findings also highlight the fact that chronic dysfunction in the amygdala and hippocampus is demonstrable in PTSD and other trauma-exposed individuals, even without exposure to an evocative stimulus.
Feasibility study of neurocognitive assessment of melanoma patients treated with adjuvant interferon
Authors: D. Combs, A. Baker, J. Fu, A. Herring, J. Jeter, L. Cranmer
Journal: Journal of Clinical Oncology (2009)

e20567 Background: Interferon α-2b (IFN) is the only approved adjuvant therapy for patients diagnosed with high-risk melanoma. Cognitive and mood alterations have been consistently reported during IFN therapy. Rigorous documentation of the magnitude and duration of these changes is lacking. Here, we assess the feasibility of conducting a quantitative study of such effects. Methods: We enrolled patients with at least stage 2B melanoma who were eligible to receive adjuvant IFN. Controls were those IFN-eligible, but not receiving it or those with unresectable melanoma eligible to receive dacarbazine-based chemotherapy (DTIC). Six cognitive function tests were administered: mini-mental status exam (MMSE), Hopkins Verbal Learning Test-Revised (HVLT), controlled oral word association, Ruff 2 and 7 (R27), Trail Making Tests A and B, and the Profile of Mood States-Short Form (POMS). Test results were compared at baseline and after the high-dose phase of IFN, 1–3 months of observation, or first cycle of chemotherapy. Results: A supervising neuropsychologist trained personnel in study instrument administration. Fourteen patients (4 IFN, 8 Obs., 2 DTIC) were seen for a total of 26 testing visits. Study visits lasted 30–40 minutes, and were coordinated with patient clinic schedules. Interpretable test results were obtained in 98% of 144 instrument administrations. Three unrelated administration errors occurred. Differences between observation and IFN patients were seen in the MMSE, HVLT, R27 and POMS, but were not statistically significant. Based on our HVLT data, a total of 17 subjects per arm are required to demonstrate a statistically significant difference (alpha=0.05, beta=0.10). Conclusions: Our pilot results indicate that administration of this test battery is feasible in this population and is a promising tool to quantify adverse cognitive effects of IFN therapy. Such baseline data will allow development of measures to mitigate such effects. [Table: see text]