tbuckley/cabot-search huggingface dataset:
The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity
Authors: Yichuan Xiao, Qiang Zou, Xiaoping Xie, Ting Liu, Haiyan S. Li, Zuliang Jie, Jin Jin, Hongbo Hu, Ganiraju Manyam, Li Zhang, Xuhong Cheng, Hui Wang, Isabelle Marie, David E. Levy, Stephanie S. Watowich, Shao-Cong Sun
Journal: The Journal of Experimental Medicine (2017)

Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell-priming activity. We further demonstrate that TBK1 negatively regulates the induction of a subset of genes by type I interferon receptor (IFNAR). Deletion of IFNAR1 could largely prevent aberrant T cell activation and autoimmunity in DC-conditional Tbk1 knockout mice. These findings identify a DC-specific function of TBK1 in the maintenance of immune homeostasis and tolerance.
PRINCIPALES CARACTERÍSTICAS DE LOS PACIENTES SOMETIDOS A ENDOSCOPIA BARIÁTRICA
Authors: E Espinet Coll, C Vila Lolo, JA Gómez Valero, A Juan-Creix Comamala, P Díaz Galán, C Quintana, S Bacchiddu, D Irigoyen, J Nebreda
Journal: Endoscopy (2015)

Desde la SEED se están diseñando Documentos de Consenso para optimizar los tratamientos endoscópicos bariátricos, dado que hasta la fecha está poco protocolizado.
The prognostic factors for advanced gastric cancer with para-aortic nodal involvement after extended gastrectomy.
Authors: Akio Kaito, Takahiro Kinoshita, Hideki Sunagawa, Shizuki Sugita, Masahiro Watanabe, Mitsumi Terada
Journal: Journal of Clinical Oncology (2017)

158 Background: The prognosis of patients with advanced gastric cancer with para-aortic lymph node (PAN) involvement is poor. We retrospectively investigated the prognostic factors for advanced gastric cancer with PAN involvement. Methods: The patients who underwent radical gastrectomy with PAN dissection for advanced gastric cancer between 1992 and 2014 in our institution included in this study. The clinicopathological features and prognostic factors of the patients who identified pathologically PAN involvement after curative gastrectomy were analyzed. Results: In this period, a total of 704 patients underwent gastrectomy with PAN dissection and 65 patients were identified as pathologically PAN positive and eligible for this study. Total gastrectomy and combined resection of other organs were performed for 48 patients and 51 patients, respectively. Complete PAN dissection (a2/b1) was performed for 32 patients. Postoperative abdominal complication was 20% with no hospital deaths. The 3 year and the 5 year overall survival (OS) were 33.8% and 21.2%, respectively. Multivariate cox regression analysis revealed nodal involvement (any of the station No.8a, No.9 and No.11; hazard ratio, 4.04; 95% confidence interval, 1.55-10.5), tumor diameter (over 120mm; HR, 3.37; 95%CI, 1.18-9.63) and total number of PAN involvement (over 2 nodes; HR, 2.24; 95%CI, 1.21-4.15) were poor prognostic factor. The patients without these poor prognostic factors had survived significantly longer than the patient with any of these factors in Kaplan-meier analysis (the 5 year OS: 87.5% vs 9.4%, P &lt;0.001). Conclusions: Tumor size, nodal involvement of the station No.8a, No.9 and No.11 and total number of PAN involvement were poor prognostic factors for advanced gastric cancer with PAN involvement. The candidates for extensive nodal dissection for advanced gastric cancer should carefully be selected.
Exercise prescription and the doctor’s duty of non-maleficence
Authors: Jonathan Pugh, Christopher Pugh, Julian Savulescu
Journal: British Journal of Sports Medicine (2017)

An abundance of data unequivocally demonstrates that exercise can be an effective tool in the fight against obesity and its associated comorbidities.1 Indeed, physical activity can be more effective than widely used pharmaceutical interventions. While metformin reduces the incidence of diabetes by 31% (as compared with a placebo) in both men and women across different racial and ethnic groups, lifestyle intervention (including exercise) reduces the incidence by 58%.2 

In this context, it is notable that a group of prominent medics and exercise scientists recently sent a well-publicised letter to the General Medical Council (GMC) and Medical Schools Council calling for the introduction of evidence-based lifestyle education into all medical curricula.3 The letter warns that there is a lack of understanding of the impact that exercise and nutrition can have on physical health among doctors. In the absence of an educational overhaul, the signatories warn that the government is likely to fail to reach its goal of preventing tens of thousands of premature deaths from heart disease and cancer by 2020.

While we agree with the need to address this apparent lack of understanding, the ethical justification of doing so is not limited to this broadly beneficence-based justification. There is also a justification grounded in the duty of non-maleficence, that is, the duty to avoid unreasonable harm to patients.

Despite the well-established long-term beneficial effects of exercise, the risk of an acute cardiovascular event may be transiently elevated during and just after vigorous physical exertion for susceptible individuals. This is the so-called ‘paradox of exercise’.4 This paradox does not mean doctors should refrain from prescribing exercise; the …
Toward a Rational and Mechanistic Account of Mental Effort
Authors: Amitai Shenhav, Sebastian Musslick, Falk Lieder, Wouter Kool, Thomas L. Griffiths, Jonathan D. Cohen, Matthew M. Botvinick
Journal: Annual Review of Neuroscience (2017)

In spite of its familiar phenomenology, the mechanistic basis for mental effort remains poorly understood. Although most researchers agree that mental effort is aversive and stems from limitations in our capacity to exercise cognitive control, it is unclear what gives rise to those limitations and why they result in an experience of control as costly. The presence of these control costs also raises further questions regarding how best to allocate mental effort to minimize those costs and maximize the attendant benefits. This review explores recent advances in computational modeling and empirical research aimed at addressing these questions at the level of psychological process and neural mechanism, examining both the limitations to mental effort exertion and how we manage those limited cognitive resources. We conclude by identifying remaining challenges for theoretical accounts of mental effort as well as possible applications of the available findings to understanding the causes of and potential solutions for apparent failures to exert the mental effort required of us.
Impact of three and further treatment lines in advanced non-small cell lung cancer patients according to molecular profile: A retrospective analysis.
Authors: Maria de los Llanos GIL Gil Moreno, Teresa Moran, Laia VilÃ Martinez, Max Hardy-Werbin, Laura Angelats, Geovanna Perez, Carmen Centeno, Carol Tudela, Laua Soldevila, Natalia Megadja, Patricia Raya, Felipe Andreo, Carlos Martinez, Samuel Garcia, Marta Mila, Jose Luis Mate, Ignasi Guasch, Victor Margeli, Anna Estival, Enric Carcereny
Journal: Journal of Clinical Oncology (2015)

e19131 Background: Little evidence support the efficacy of third-line systemic therapy in NSCLC patients(p) with advanced(a) disease.Nonetheless, further-line chemotherapy(CT) is frequently offered in daily clinical practice. We retrospectively analyzed the clinical, pathological characteristics and outcomes of p with aNSCLC who received > 3CT regimens to identify subsets of patients more likely to benefit.The presence of underlying molecular alterations has also been evaluated Methods: The study included data from all consecutive p diagnosed with aNSCLC in our Institution from January 2008 to December 2013. Median overall survival(OS) and progression free survival(PFS) were evaluated with Kaplan-Meier curves and groups were compared using the Log-rank test. Variables analyzed included p, tumor and treatment characteristics. Results: A total of 486p were included .175p(36%) received > 3 lines. Group 3+included more female (35.4%vs22.8%; p = 0.0041),younger (58.9vs61.9;p = 0.0016), never-smoker p(26.9%vs18%;p = 0.015),less lung(10.9%vs22.2%;p = 0.0020)and heart (4%vs11.6%;p = 0.0020) comorbidities,a higher proportion of molecular alterations(EGFR/ALK)(25.7%vs12.9%; p = 0.0005),adenocarcinoma histology(68.6%vs55%;p = 0.0045)and less brain metastasis (14.3%vs23.5%;p = 0.018). ORR to first line was higher in group 3+ (45.8%vs 29%;p = 0.0009). 82.3% non-squamous NSCLC were tested for at least one molecular alteration.The mOS of p in group 3+ was longer [24.3 m vs. 7.7 m, p < 0.0001)], including p with EGFR/ALK/ROS1 wild-type or unknown [21.6m vs.7.4 m,p < 0.0001) ].In the univariate analysis molecular alteration were related to longer PFS. In univariate analysis > 3 lines, females, age < 65 and molecular alterations were associated with longer OS. In the multivariate analysis > 3 therapeutic lines and the presence of molecular alterations were related to longer OS. Conclusions: P treated with > 3 systemic treatments were more likely to respond better, progress later and live longer. This better prognosis could be related to the presence of molecular alteration. However p without or unknown molecular alteration could benefit from subsequent lines.
Results from a phase II trial (NTC01902680) of ultrafocal brachytherapy for low/intermediate risk prostate cancer.
Authors: Pierre Graff-Cailleaud, Bernard Malavaud, Daniel Portalez, Thomas Brun, Richard Aziza, Amellie Lusque, Jonathan Khalifa, Thomas Filleron, Jean-Marc Bachaud
Journal: Journal of Clinical Oncology (2017)

124 Background: Biology suggests that the most significant focus drives the natural history of prostate cancer. We assessed the feasibility of ultrafocal brachytherapy (BT) of the index tumor. Methods: In a 2-step Simon’s design (&amp;=0.1, ß=0.1), 17 patients were needed to assess that 100% of clinical target volume (CTV) - gross tumor volume on T2-MRI plus 2mm margin - received ≥95% of the prescribed dose (primary objective: D100≥152Gy). Pre-inclusion:EAU guidelines for Surveillance [PSA &lt;10ng/mL, cT1c-cT2a, Gleason sum on referring biopsies ≤6(3+3), ≤3 positive biopsies, ≤50% of cancer] and for BT [IPSS &lt;10, no TURP, prostate &lt;60mL, &gt;10yr life expectancy]. Inclusion:when mpMRI detected a PIRADS≥3 focal lesion, confirmed as Gleason sum ≤7a (3+4) cancer on elastic fusion registration (EFR) biopsies (Koelis). Procedure:EFR was used to insert trans-rectally a US-visible marker (Bard SourceLink) within CTV before biplanar TRUS for BT. Dose distribution was optimized by inverse planning (Variseed v7.2) before ultrafocal implantation of I-125 seeds (Bard Pro-Link). 1 ary objective:Doses delivered within the first 30d to CTV were assessed by Variseed rigid registration between pre-implant MRI and d30 CT-Scan. 2 ary objectives: GI, GU CTCAE toxicity &amp; QoL (IPSS, IIEF5, QLQc30) were prospectively accrued. Protocol biopsies of GTV and rest of the gland were obtained by EFR 1yr post-implantation. Results: 27 patients failed confirmatory biopsies (multifocal n=10; aggressive 11; no cancer 6). Of 17 included (10/2013-8/2016), only 3 did not meet the primary objective (D100: 76, 105, 132 Gy) and the trial was deemed successful. Mean CTV was 0.74±0.31mL that is 1.9±1.1% of the gland. Prescribed dose was delivered to 14.5±6.4% of the gland, in line with the ultrafocal nature of the treatment. To date 11 patients, including the previous 3, received 1yr biopsies. No in-field recurrences (GTV) were observed, 5 non-clinically significant cancers were found in the contralateral lobe. No grade&gt;2 toxicity was observed. QoL evaluation is in process. Conclusions: As shown by optimal dosimetry in 14/17(82.4%), minimal toxicity in all, and no in-field recurrences (0/11), ultrafocal BT is a promising avenue in focal treatment. Clinical trial information: NCT01902680.
Targeted treatment of RAI-resistant metastatic thyroid cancer postcomprehensive genomic profiling.
Authors: Kim M. Hirshfield, Joseph Aisner, Siraj M. Ali, Philip J. Stephens, Vincent A. Miller, Lorna Rodriguez, Shridar Ganesan
Journal: Journal of Clinical Oncology (2014)

e22070 Background: Metastatic papillary thyroid cancer (PTC) can be managed effectively for prolonged periods with intermittent use of radioactive iodine (RAI) therapy. However when PTC loses RAI uptake capacity and becomes RAI-refractory, there are few effective treatments. The majority of well-differentiated thyroid cancers (e.g. PTC) have clinically meaningful alterations in the RAS-RAF pathway, with BRAFV600E being the most common alteration reported. To examine the prevalence of these alterations in metastatic RAI-refractory thyroid carcinoma, we initiated genomic profiling on formalin-fixed, paraffin-embedded clinical tumor specimens. We report on the first seven completed. Methods: A clinical next generation sequencing (NGS)-based assay was performed on hybridization-captured, adaptor ligation–based libraries to high, uniform coverage for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Results: All but one of the patients with PTC had extensive pulmonary metastases and RAI-refractory disease. Five of the seven patients had tumors with the BRAF V600E mutation and one had NRAS Q61R. The seventh had regional recurrence only and the tumor had no detectable mutations. Treatment with the vemurafenib, targeted therapy highly specific to BRAF V600E, was initiated in one patient, resulting in marked clinical and radiographic responses that were complicated by the development of severe keratoacanthosis and HRASQ61L skin cancer. Three other patients have been enrolled on clinical protocols for MEK-targeted therapy, with clinical responses noted, and one is pending enrollment. Conclusions: In this clinical series of RAI-resistant metastatic papillary thyroid cancers, the majority have clinically meaningful alterations that can potentially guide targeted treatment decisions, particularly in the MEK pathway including BRAF V600E. Therapeutic interventions targeting BRAF activation may be effective in these cancers, and these patients should be enrolled in clinical trials utilizing BRAF and/or MEK inhibitors.
Role of proliferation in response to neoadjuvant chemotherapy in GEICAM/2006-03 and GEICAM/2006-14 breast cancer patients.
Authors: E. Alba, Joan Albanell, Jose Ignacio Chacon Lopez-Muniz, Lourdes Calvo, Juan De la Haba- Rodriguez, Pedro Sanchez Rovira, Arrate Plazaola, Agust Barnadas, Miguel Angel Seguí-Palmer, Angels Arcusa Lanza, Manuel Ramos Vazquez, Federico Rojo, Octavio Burgues, Bella Pajares, Begoña Bermejo, Alfonso Sanchez-Muñoz, Maria Isabel Casas, Rosalia Caballero, Eva Maria Carrasco, Ana Lluch
Journal: Journal of Clinical Oncology (2012)

10616 Background: Ki67 proliferation biomarker determined by immunohistochemistry (IHC) has been studied as a prognostic and predictive factor in Operable Breast Cancer (OBC). Ki67 modifications after neoadjuvant endocrine therapy have been correlated with long term outcome. However, there is no robust data about its predictive role in Neoadjuvant Chemotherapy (NC). In this study, we investigated Ki67 value as predictor of NC efficacy. Methods: 193 patients (pts) from 2 GEICAM phase II randomized trials (2006-03 and 2006-14) were included: 78 (40%) received epirubicine plus cyclophosphamide followed by docetaxel (EC-D), 41 (21%) EC-D plus carboplatin, and out of the 74 HER2+ pts, 37 (19%) received EC-D plus tratuzumab and 37 (19%) EC-D plus lapatinib. Median age was 49 years. From series, 87% were invasive ductal carcinoma, 58% premenopausal, 50% grade III, 23% luminal , 39% basal and 38% HER2+. Ki67 was centrally assessed by IHC (MIB1 clone) and median score was 40% (range 1-100%). Pathological Complete Response (pCR), defined as absence of invasive cells in breast and lymph nodes, was achieved in 56 pts (29%). Univariate and multivariate logistic regression models were used to study the association of each clinical-pathological variable with pCR. ROC curves were used to determine the most accurate ki67 cut-off for predicting NC response. Results: Ki67≥50% was defined as the most accurate threshold to select patients obtaining benefit from NC. In the univariate analysis, histological grade (p=0.01), treatment (P=0.006), ER (p&lt;0.0001), PR (p&lt;0.0001), HER2 (p=0.01), and Ki67≥50% (p=0.0003) were statistically associated with pCR. A multivariate logistic regression showed that only Ki67≥ 50% (p=0.0003; OR=5.4 CI95% 2.1-13.4), ER (p=0.0001; OR=0.2 CI95% 0.1-0.4), and HER2 status (p&lt;0.0001; OR=8.8 CI95% 3.3-23.6) were predictive for pCR (AUC=0.7812). Conclusions: These results suggest that a high proliferation in breast cancer measured by Ki67 marker is an independent predictive factor for pCR in an unclassified HER2 population of OBC patients treated with NC.
Phase I dose-escalation clinical trial with 5-imino-13-deoxydoxorubicin in cancer patients.
Authors: Raymond J. Hohl, Robert E. Vestal, Sarah Abigail Holstein, Richard D. Olson, Karen Parrott, Gerald M. Walsh
Journal: Journal of Clinical Oncology (2013)

2575 Background: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin (dox) analog modified in two locations to prevent formation of a) cardiotoxic metabolites and b) reactive oxygen species. In a rabbit model comparing the cardiotoxicity of dox vs. DIDOX, chronic doses of each caused similar myelosuppression, but only dox caused cardiotoxicity as assessed by echocardiography and histopathology scoring. In view of the non-cardiotoxic nature of DIDOX along with its anticancer efficacy in preclinical studies, DIDOX was entered into a Phase I, open-label, non-randomized dose-finding study in up to 30 patients with solid tumors. Methods: Inclusion criteria included progressing solid tumors and cardiac ejection fraction (CEF) 110% of lower limit of institutional normal (assessed by MUGA). There are 8 dose cohorts and up to 8 cycles/cohort, dosing (iv) once every 3 weeks with an accelerated titration dosing design at the three lowest cohorts. Cohort A =14, B=28, C=56, D=84, E=112, F=150, G=200, and H=265 mg/m 2 /cycle. Dose was escalated to next dose level if &lt; 1 dose limiting toxicity (DLT) is reported. Maximum tolerated dose (MTD) will be exceeded when 2 or more patients in a cohort elicit DLT; the next lower dose is defined as the MTD. DLT occurs when a decrease in CEF is grade 2 or higher, or grade 4 neutropenia lasts &gt; 5 days. Results: Cohorts A-G have been completed. Number of patients for the cohorts are: A=1, B=1, C=1, D=4 E=3 F=3 G=4, and H = 2 (with 4 more to be enrolled in H). No decrease in CEF occurred in any cohorts. There were no DLTs in cohorts A-G. One patient in H had neutropenia grade 4 for 11 days (a DLT). Another patient in H had neutropenia grade 4 for 4 days. There was no disease progression at the completion of dosing for 6 of the 12 patients in cohorts E-H. In contrast, all 7 patients had disease progression in cohorts A-D. Conclusions: No cardiotoxicity was observed in any patient. No DLT was observed in cohorts A-G. With one DLT in cohort H, one more DLT will define MTD for DIDOX at 200 mg/m 2 . At higher DIDOX doses (E-H), 6 of 12 patients showed no disease progression. (IND No. 77,051). Clinical trial information: NCT00710125.
Phase I and pharmacokinetic (PK) study of oblimersen, a proapoptotic Bcl-2 targeting oligonucleotide, in combination with doxorubicin and docetaxel in metastatic and locally advanced breast cancer (BC)
Authors: F. J. Esteva, T. L. Madden, J. Lammey, W. F. Symmans, D. J. Booser, B. Arun, E. Rivera, A. M. Brewster, V. Valero, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2004)

3117 Background: The anti-apoptotic Bcl-2 protein has been associated with drug resistance in BC cells. Oblimersen sodium (Genasense; G3139; GNS) downregulates bcl-2 expression in target tissues at 2–7 mg/kg/d. Preclinical synergy was reported between GNS and DOX, and between GNS and DOC. This phase I trial was conducted to evaluate the PK and safety of GNS in combination with DOX and DOC in patients (pts) with advanced BC. Methods: GNS was administered as a 5-day continuous infusion. DOX (50 mg/m2) and DOC (75 mg/m2) were given i.v. on day 3. Three dose levels (DL) of GNS were evaluated: DL-I (3mg/kg/d), DL-II (5 mg/kg/d), and DL-III (7 mg/kg/d). Three pts were treated at each DL. During cycle 1 of therapy, serial plasma samples were obtained before and for up to 72 h after the start of each infusion. Plasma doxorubicin and docetaxel concentrations were measured using separate validated HPLC assays (DOX LLQ 1 ng/ml, DOC LLQ 10 ng/ml). Individual PK parameters were calculated using compartmental modeling. Results: Ten pts were enrolled, and 9 pts were evaluable (1 pt withdrew consent). On DL-I, 1 pt developed febrile neutropenia, and 1 pt developed grade (gr) 3 infection. These adverse effects were attributed to DOX/DOC, and not considered dose-limiting toxicity (DLT). Prophylactic G-CSF was added on DL-II and DL-III, and no additional gr 3 hematologic toxicity was noted. Gr 3 fatigue ocurred at all DL in five (55%) pts. No DLT was observed at the highest dose of GNS tested (7 mg/kg/d). PK parameters (mean ± SD) are available for the first 6 pts (DL I-II): DOX plasma Cl 52.2±26.4 L/hr/m2, Vss 1491±740 L/m2, T1/2γ37.4± 18.8 h; DOC plasma Cl 35.8±11.4 L/hr/m2, Vss 378±240 L/m2, T1/2γ11.7± 8.2 h. These PK values are within the range previously reported for each agent administered alone. Conclusions: The combination of GNS, DOX and DOC is safe. Preliminary data suggest the combination of these three agents does not alter the PK profile of either DOX or DOC. Studies are underway to examine the PK of GNS in these pts using mass spectrometry. A phase II trial of GNS/DOX/DOC is ongoing. (Support: NCI) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals
Estradiol effects on hypothalamic AMPK and BAT thermogenesis: A gateway for obesity treatment?
Authors: Miguel López, Manuel Tena-Sempere
Journal: Pharmacology & Therapeutics (2017)

In addition to their prominent roles in the control of reproduction, estrogens are important modulators of energy balance, as evident in conditions of deficiency of estrogens, which are characterized by increased feeding and decreased energy expenditure, leading to obesity. AMP-activated protein kinase (AMPK) is a ubiquitous cellular energy gauge that is activated under conditions of low energy, increasing energy production and reducing energy wasting. Centrally, the AMPK pathway is a canonical route regulating energy homeostasis, by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. As a result of those actions, hypothalamic AMPK modulates feeding, as well as brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). Here, we will review the central actions of estrogens on energy balance, with particular focus on hypothalamic AMPK. The relevance of this interaction is noteworthy, because some agents with known actions on metabolic homeostasis, such as nicotine, metformin, liraglutide, olanzapine and also natural molecules, such as resveratrol and flavonoids, exert their actions by modulating AMPK. This evidence highlights the possibility that hypothalamic AMPK might be a potential target for the treatment of obesity.