Publications by authors named "Javier Suarez"

45 Publications

Usefulness of Self-Expanding Drainage Cannula in Venovenous Extracorporeal Membrane Oxygenation: Tips, Tricks, and Results of an Early Experience.

ASAIO J 2021 Mar 22. Epub 2021 Mar 22.

From the Department of Cardiac Surgery, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Vigo, Spain Department of Anaesthesiology, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Vigo, Spain Department of Critical Care, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Vigo, Spain Department of Cardiology, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Vigo, Spain.

Inadequate venous drainage decreases the efficiency of extracorporeal membrane oxygenation (ECMO). Pump augmentation may even make it worse due to collapse of the venous system under negative pressures. Furthermore, recirculation is a phenomenon that occurs when oxygenated blood supplied through the infusion cannula is withdrawn directly through the drainage cannula without contributing to the oxygenation of the patient and also compromises the efficacy of the therapy. Large drainage cannulas allow for similar flow rates at lower pump speed. But percutaneous insertion of these larger cannulas could be challenging. When using a self-expandable cannula, the diameter of the cannula for the insertion can be reduced, and once inserted, its intravascular diameter maximized, resulting in a large venous cannula due to in situ expansion after mandrel removal (up to 36F). We present a retrospective series of selfexpanding venous cannula 430 or 530 mm in length in six consecutive patients undergoing venovenous (VV) ECMO. No vascular or cardiac iatrogenic injury was caused during implantation. Target flows were reached, and no clinically significant recirculation was described in any case. The use of selfexpanding drainage cannulas was safe, and efficient drainage was achieved with easy and definitive unique positioning during cannulation.
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http://dx.doi.org/10.1097/MAT.0000000000001412DOI Listing
March 2021

Impact of the COVID-19 pandemic during Spain's state of emergency on the diagnosis of colorectal cancer.

J Surg Oncol 2021 Jan 19;123(1):32-36. Epub 2020 Oct 19.

Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain.

Introduction: We evaluate the impact of COVID-epidemic in colorectal cancer (CRC) diagnosis during Spain's state of emergency.

Methods: We compared newly diagnosed patients with patients diagnosed in the same period of 2019.

Results: A new diagnosis of CRC decreased 48% with a higher rate of patients diagnosed in the emergency setting (12.1% vs. 3.6%; p = .048) and a lower rate diagnosed in the screening program (5.2% vs. 33.3%; p = .000).

Conclusions: Fewer patients have been diagnosed with CRC, with a higher rate of patients diagnosed in an emergency setting.
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http://dx.doi.org/10.1002/jso.26263DOI Listing
January 2021

Self-expandable metal stent (SEMS) placement or emergency surgery as palliative treatment for obstructive colorectal cancer: A systematic review and meta-analysis.

Crit Rev Oncol Hematol 2020 Nov 22;155:103110. Epub 2020 Sep 22.

Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Previous meta-analyses on palliative treatment of malignant colorectal obstruction with Self-Expandable Metal Stent (SEMS) or emergency surgery reported contradictory results for morbidity, and frequently included extracolonic obstruction. Therefore, the current meta-analysis aimed to exclusively analyze palliative treatment for primary obstructive colorectal cancer, with early complication rate as a primary outcome. A systematic literature search was performed on studies comparing palliative SEMS and emergency surgery. Corresponding authors were contacted for additional data. Eighteen studies were selected (1518 patients). Early complication rate was 13.6 % for SEMS and 25.5 % for emergency surgery (Odds Ratio (OR) 0.46, 95 % confidence interval (CI) 0.29-0.74). Mortality was 3.9 % and 9.4 % (OR 0.44, 0.28-0.69). Stomas were present in 14.3 % and 51.4 % of patients (OR 0.17, 0.09-0.31). More late complications occurred after SEMS (23.2 % versus 9.8 %, OR 2.55, 1.70-3.83), mostly due to SEMS obstruction. In conclusion, SEMS placement seems the preferred treatment of obstructing colorectal cancer in the palliative setting.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103110DOI Listing
November 2020

"Microbiota, symbiosis and individuality summer school" meeting report.

Microbiome 2020 08 14;8(1):117. Epub 2020 Aug 14.

Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.

How does microbiota research impact our understanding of biological individuality? We summarize the interdisciplinary summer school on "Microbiota, symbiosis and individuality: conceptual and philosophical issues" (July 2019), which was supported by a European Research Council starting grant project "Immunity, DEvelopment, and the Microbiota" (IDEM). The summer school centered around interdisciplinary group work on four facets of microbiota research: holobionts, individuality, causation, and human health. The conceptual discussion of cutting-edge empirical research provided new insights into microbiota and highlights the value of incorporating into meetings experts from other disciplines, such as philosophy and history of science. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00898-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427737PMC
August 2020

Holobionts: Ecological communities, hybrids, or biological individuals? A metaphysical perspective on multispecies systems.

Stud Hist Philos Biol Biomed Sci 2020 Dec 9;84:101323. Epub 2020 Aug 9.

Department of Philosophy, University of Bielefeld, Bielefeld, Germany. Electronic address:

Holobionts are symbiotic assemblages composed by a macrobe host (animal or plant) plus its symbiotic microbiota. In recent years, the ontological status of holobionts has created a great amount of controversy among philosophers and biologists: are holobionts biological individuals or are they rather ecological communities of independent individuals that interact together? Chiu and Eberl have recently developed an eco-immunity account of the holobiont wherein holobionts are neither biological individuals nor ecological communities, but hybrids between a host and its microbiota. According to their account, the microbiota is not a proper part of the holobiont. Yet, it should be regarded as a set of scaffolds that support the individuality of the host. In this paper, we approach Chiu and Eberl's account from a metaphysical perspective and argue that, contrary to what the authors claim, the eco-immunity account entails that the microorganisms that compose the host's microbiota are proper parts of the holobiont. Second, we argue that by claiming that holobionts are hybrids, and therefore, not biological individuals, the authors seem to be assuming a controversial position about the ontology of hybrids, which are conventionally characterized as a type of biological individual. In doing so, our paper aligns with the contemporary tendency to incorporate metaphysical resources to shed light on current biological debates and builds on that to provide additional support to the consideration of holobionts as biological individuals from an eco-immunity perspective.
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http://dx.doi.org/10.1016/j.shpsc.2020.101323DOI Listing
December 2020

A part-dependent account of biological individuality: why holobionts are individuals and ecosystems simultaneously.

Biol Rev Camb Philos Soc 2020 10 13;95(5):1308-1324. Epub 2020 May 13.

Institute of Philosophy, Jagiellonian University, Kraków, 31-044, Poland.

Given one conception of biological individuality (evolutionary, physiological, etc.), can a holobiont - that is the host + its symbiotic (mutualistic, commensalist and parasitic) microbiome - be simultaneously a biological individual and an ecological community? Herein, we support this possibility by arguing that the notion of biological individuality is part-dependent. In our account, the individuality of a biological ensemble should not only be determined by the conception of biological individuality in use, but also by the biological characteristics of the part of the ensemble under investigation. In the specific case of holobionts, evaluations of their individuality should be made either host-relative or microbe-relative. We support the claim that biological individuality is part-dependent by drawing upon recent empirical evidence regarding the physiology of hosts and microbes, and the recent characterization of the 'demibiont'. Our account shows that contemporary disagreements about the individuality of the holobiont derive from an incorrect understanding of the ontology of biological individuality. We show that collaboration between philosophers and biologists can be very fruitful in attempts to solve some contemporary biological debates.
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http://dx.doi.org/10.1111/brv.12610DOI Listing
October 2020

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer's disease and type 2 diabetes.

Alzheimers Res Ther 2020 04 7;12(1):40. Epub 2020 Apr 7.

Division of Physiology, School of Medicine, Universidad de Cadiz, Plaza Fragela sn, 4 piso 410, Cadiz, Spain.

Background: Both Alzheimer's disease (AD) and type 2 diabetes (T2D) share common pathological features including inflammation, insulin signaling alterations, or vascular damage. AD has no successful treatment, and the close relationship between both diseases supports the study of antidiabetic drugs to limit or slow down brain pathology in AD. Empagliflozin (EMP) is a sodium-glucose co-transporter 2 inhibitor, the newest class of antidiabetic agents. EMP controls hyperglycemia and reduces cardiovascular comorbidities and deaths associated to T2D. Therefore, we have analyzed the role of EMP at the central level in a complex mouse model of AD-T2D.

Methods: We have treated AD-T2D mice (APP/PS1xdb/db mice) with EMP 10 mg/kg for 22 weeks. Glucose, insulin, and body weight were monthly assessed. We analyzed learning and memory in the Morris water maze and the new object discrimination test. Postmortem brain assessment was conducted to measure brain atrophy, senile plaques, and amyloid-β levels. Tau phosphorylation, hemorrhage burden, and microglia were also measured in the brain after EMP treatment.

Results: EMP treatment helped to maintain insulin levels in diabetic mice. At the central level, EMP limited cortical thinning and reduced neuronal loss in treated mice. Hemorrhage and microglia burdens were also reduced in EMP-treated mice. Senile plaque burden was lower, and these effects were accompanied by an amelioration of cognitive deficits in APP/PS1xdb/db mice.

Conclusions: Altogether, our data support a feasible role for EMP to reduce brain complications associated to AD and T2D, including classical pathological features and vascular disease, and supporting further assessment of EMP at the central level.
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http://dx.doi.org/10.1186/s13195-020-00607-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140573PMC
April 2020

Depixelation and enhancement of fiber bundle images by bundle rotation.

Appl Opt 2020 Jan;59(2):536-544

Fiber bundles have become widely adopted for use in endoscopy, live-organism imaging, and other imaging applications. An inherent consequence of imaging with these bundles is the introduction of a honeycomb-like artifact that arises from the inter-fiber spacing, which obscures features of objects in the image. This artifact subsequently limits applicability and can make interpretation of the image-based data difficult. This work presents a method to reduce this artifact by on-axis rotation of the fiber bundle. Fiber bundle images were first low-pass and median filtered to improve image quality. Consecutive filtered images with rotated samples were then co-registered and averaged to generate a final, reconstructed image. The results demonstrate removal of the artifacts, in addition to increased signal contrast and signal-to-noise ratio. This approach combines digital filtering and spatial resampling to reconstruct higher-quality images, enhancing the utility of images acquired using fiber bundles.
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http://dx.doi.org/10.1364/AO.59.000536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286003PMC
January 2020

What Is a Hologenomic Adaptation? Emergent Individuality and Inter-Identity in Multispecies Systems.

Front Psychol 2020 4;11:187. Epub 2020 Mar 4.

Department of History of Science, Rey Juan Carlos University, Madrid, Spain.

Contemporary biological research has suggested that some host-microbiome multispecies systems (referred to as "holobionts") can in certain circumstances evolve as unique biological individual, thus being a unit of selection in evolution. If this is so, then it is arguably the case that some biological adaptations have evolved at the level of the multispecies system, what we call . However, no research has yet been devoted to investigating their nature, or how these adaptations can be distinguished from adaptations at the species-level (genomic adaptations). In this paper, we cover this gap by investigating the nature of hologenomic adaptations. By drawing on the case of the evolution of sanguivory diet in vampire bats, we argue that a trait constitutes a hologenomic adaptation when its evolution can only be explained if the holobiont is considered the biological individual that manifests this adaptation, while the bacterial taxa that bear the trait are only opportunistic beneficiaries of it. We then use the philosophical notions of and to explain the nature of this form of individuality and argue why it is special of holobionts. Overall, our paper illustrates how the use of philosophical concepts can illuminate scientific discussions, in the trend of what has recently been called metaphysics of biology.
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http://dx.doi.org/10.3389/fpsyg.2020.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064717PMC
March 2020

The stability of traits conception of the hologenome: An evolutionary account of holobiont individuality.

Authors:
Javier Suárez

Hist Philos Life Sci 2020 Feb 26;42(1):11. Epub 2020 Feb 26.

Logos - Barcelona Institute for Analytic Philosophy, University of Barcelona, Barcelona, Spain.

Bourrat and Griffiths (Hist Philos Life Sci 40(2):33, 2018) have recently argued that most of the evidence presented by holobiont defenders to support the thesis that holobionts are evolutionary individuals is not to the point and is not even adequate to discriminate multispecies evolutionary individuals from other multispecies assemblages that would not be considered evolutionary individuals by most holobiont defenders. They further argue that an adequate criterion to distinguish the two categories is fitness alignment, presenting the notion of fitness boundedness as a criterion that allows divorcing true multispecies evolutionary individuals from other multispecies assemblages and provides an adequate criterion to single out genuine evolutionary multispecies assemblages. A consequence of their criterion is that holobionts, as conventionally defined by hologenome defenders, are not evolutionary individuals except in very rare cases, and for very specific host-symbiont associations. This paper is a critical response to Bourrat and Griffiths' arguments and a defence of the arguments presented by holobiont defenders. Drawing upon the case of the hologenomic basis of the evolution of sanguivory in vampire bats (Nat Ecol Evol 2:659-668, 2018), I argue that Bourrat and Griffiths overlook some aspects of the biological nature of the microbiome that justifies the thesis that holobionts are evolutionarily different to other multispecies assemblages. I argue that the hologenome theory of evolution should not define the hologenome as a collection of genomes, but as the sum of the host genome plus some traits of the microbiome which together constitute an evolutionary individual, a conception I refer to as the stability of traits conception of the hologenome. Based on that conception I argue that the evidence presented by holobiont defenders is to the point, and supports the thesis that holobionts are evolutionary individuals. In this sense, the paper offers an account of the holobiont that aims to foster a dialogue between hologenome advocates and hologenome critics.
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http://dx.doi.org/10.1007/s40656-020-00305-2DOI Listing
February 2020

"Whole" vs. "fragmented" approach to EAACI pollen season definitions: A multicenter study in six Southern European cities.

Allergy 2020 07 11;75(7):1659-1671. Epub 2020 May 11.

Department of Allergy and Immunology, Koç University Hospital, Istanbul, Turkey.

Background: The adequate definition of pollen seasons is essential to facilitate a correct diagnosis, treatment choice, and outcome assessment in patients with seasonal allergic rhinitis. A position paper by the European Academy of Allergy and Clinical Immunology (EAACI) proposed season definitions for Northern and Middle Europe.

Objective: To test the pollen season definitions proposed by EAACI in six Mediterranean cities for seven pollen taxa.

Methods: As part of the @IT.2020 multi-center study, pollen counts for Poaceae, Oleaceae, Fagales, Cupressaceae, Urticaceae (Parietaria spp.), and Compositae (Ambrosia spp., Artemisia spp.) were collected from January 1 to December 31, 2018. Based on these data, pollen seasons were identified according to EAACI criteria. A unified monitoring period for patients in AIT trials was created and assessed for feasibility.

Results: The analysis revealed a great heterogeneity between the different locations in terms of pattern and length of the examined pollen seasons. Further, we found a fragmentation of pollen seasons in several segments (max. 8) separated by periods of low pollen counts (intercurrent periods). Potential monitoring periods included often many recording days with low pollen exposure (max. 341 days).

Conclusion: The Mediterranean climate leads to challenging pollen exposure times. Monitoring periods for AIT trials based on existing definitions may include many intermittent days with low pollen concentrations. Therefore, it is necessary to find an adapted pollen season definition as individual solution for each pollen and geographical area.
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http://dx.doi.org/10.1111/all.14153DOI Listing
July 2020

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

J Pharmacol Exp Ther 2020 03 9;372(3):339-353. Epub 2019 Dec 9.

Janssen Research & Development, LLC, San Diego, California.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.
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http://dx.doi.org/10.1124/jpet.119.262139DOI Listing
March 2020

Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis.

Sci Adv 2019 06 19;5(6):eaav4275. Epub 2019 Jun 19.

Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.

Carcinoma cells undergo epithelial-mesenchymal transition (EMT); however, contributions of EMT heterogeneity to disease progression remain a matter of debate. Here, we addressed the EMT status of ex vivo cultured circulating and disseminated tumor cells (CTCs/DTCs) in a syngeneic mouse model of metastatic breast cancer (MBC). Epithelial-type CTCs with a restricted mesenchymal transition had the strongest lung metastases formation ability, whereas mesenchymal-type CTCs showed limited metastatic ability. EpCAM expression served as a surrogate marker to evaluate the EMT heterogeneity of clinical samples from MBC, including metastases, CTCs, and DTCs. The proportion of epithelial-type CTCs, and especially DTCs, correlated with distant metastases and poorer outcome of patients with MBC. This study fosters our understanding of EMT in metastasis and underpins heterogeneous EMT phenotypes as important parameters for tumor prognosis and treatment. We further suggest that EpCAM-dependent CTC isolation systems will underestimate CTC numbers but will quantify clinically relevant metastatic cells.
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http://dx.doi.org/10.1126/sciadv.aav4275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584608PMC
June 2019

Circulating Tumor Cells in Patients Undergoing Resection of Colorectal Cancer Liver Metastases. Clinical Utility for Long-Term Outcome: A Prospective Trial.

Ann Surg Oncol 2019 Sep 17;26(9):2805-2811. Epub 2019 Jun 17.

Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain.

Background: Patients with resected colorectal cancer liver metastases display heterogeneous clinical behavior. The identification of new prognostic factors would help in making more accurate decisions.

Objective: The aim of this study was to evaluate the survival impact of circulating tumor cells (CTCs) in this setting.

Methods: We conducted a prospective study of patients with resected liver metastases of colorectal cancer. Patients were included in the study from February 2009 to January 2013. The CellSearch System™ was employed for the detection of pre- and postsurgery CTCs. A positive test was defined as two or more CTCs/7.5 mL of blood. Recurrence rate, disease-free survival, and overall survival were calculated, and univariate and multivariate analyses were performed.

Results: Forty-four patients were included in our study. After a median follow-up of 60 months (range 28-74), 32 patients experienced recurrence (72.7%). The CTCs number was determined and the test was positive in 8 patients (18.6%) before surgery and 13 patients (29.5%) after surgery. The postoperative detection of CTCs was not related to any clinical outcome; however, the preoperative detection of CTCs was significantly related to behavior. All patients in the preoperative CTC-positive group relapsed, versus 65% in the CTC-negative group (p = 0.051). Disease-free survival was 19 months in the preoperative CTC-negative group versus 7 months in the CTC-positive group (p = 0.01). Additionally, overall survival was 69 months in the preoperative CTC-negative group versus 17 months in the CTC-positive group (p = 0.004). Preoperative CTC count remained significant in multivariate analysis.

Conclusions: In this cohort of colorectal cancer liver metastases patients, the presence of two or more preoperative CTCs was associated with disease progression and poor survival despite complete resection.
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http://dx.doi.org/10.1245/s10434-019-07503-8DOI Listing
September 2019

Sensory prediction errors in the human midbrain signal identity violations independent of perceptual distance.

Elife 2019 04 5;8. Epub 2019 Apr 5.

Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States.

The firing of dopaminergic midbrain neurons is thought to reflect prediction errors (PE) that depend on the difference between the value of expected and received rewards. However, recent work has demonstrated that unexpected changes in value-neutral outcome features, such as identity, can evoke similar responses. It remains unclear whether the magnitude of these identity PEs scales with the perceptual dissimilarity of expected and received rewards, or whether they are independent of perceptual similarity. We used a Pavlovian transreinforcer reversal task to elicit identity PEs for value-matched food odor rewards, drawn from two perceptual categories (sweet, savory). Replicating previous findings, identity PEs were correlated with fMRI activity in midbrain, OFC, piriform cortex, and amygdala. However, the magnitude of identity PE responses was independent of the perceptual distance between expected and received outcomes, suggesting that identity comparisons underlying sensory PEs may occur in an abstract state space independent of straightforward sensory percepts.
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http://dx.doi.org/10.7554/eLife.43962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450666PMC
April 2019

Impact of specific modes of circumferential resection margin involvement in rectal cancer local recurrence: A retrospective study.

J Surg Oncol 2018 Dec 27;118(7):1122-1128. Epub 2018 Sep 27.

Department of General Surgery, Colorrectal Surgery Unit, Complejo Hospitalario de Navarra, Pamplona, Spain.

Purpose: To compare the local recurrence rate and overall survival between patients with circumferential resection margin (CRM) involvement by direct tumor spread and by a tumor within a lymph node.

Methods: A total of 776 patients diagnosed with rectal cancer underwent rectal resection. Patients with CRM involvement by direct tumor spread were named group A. CRM involvement by tumor within a lymph node formed group B. Patient data, including sex, age, pT, pN, stage I-III versus IV, neoadjuvant radiotherapy, adjuvant chemotherapy, carcinoembryonic antigen, primary tumor location, lymph node retrieval, and need for abdominoperineal resection, were compared between both groups.

Results: In total, 10.5% of the patients had CRM involvement. Of these, in 57 cases (7.3%), it was by direct tumor spread and in 19 cases (2.4%) by tumor within a lymph node. Other types of CRM involvement were found in six patients. With a mean follow-up of 32.9 months, 18 patients from group A (31.5%) and one patient from group B (5.2%) suffered a local recurrence. Local recurrence-free survival was significantly higher in patients from group B (P = 0.049). Patients in stage I-III (P = 0.037) and from group B ( P = 0.049) had better overall survival.

Conclusion: Patients with CRM involvement by tumor within a lymph node have a low risk of local recurrence and better overall survival than patients with CRM involvement by direct tumor spread.
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http://dx.doi.org/10.1002/jso.25252DOI Listing
December 2018

Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine.

Nature 2017 06;546(7660):676-680

Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.

Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis. However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma. Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress. Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma. Still, the identities and prognostic value of lymphangiogenic mediators remain unclear. Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches. Injectable lymphatic tracers have been developed, but their limited diffusion precludes whole-body imaging at visceral sites. Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer. Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.
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http://dx.doi.org/10.1038/nature22977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005659PMC
June 2017

Local recurrence after five years is associated with preoperative chemoradiotherapy treatment in patients diagnosed with stage II and III rectal cancer.

Int J Surg 2017 Aug 3;44:15-20. Epub 2017 Jun 3.

Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain.

Aim: To asses the moment of local recurrence and its influence on the appraisal of the results of neoadjuvant chemoradiotherapy (CRT).

Methods: We evaluated 317 patients with a preoperative diagnosis of stage II or III rectal cancer who underwent rectal resection. Gender, age, neoadjuvant treatment, circumferencial resection margin, adjuvant treatment, pretreatment carcinoembryonic antigen level, tumor location, TNM stage, lymph node retrieval, abdominoperineal resection, and lymphatic or vascular infiltration were registered prospectively. Follow-up was performed to detect local or systemic recurrences. Timing of local recurrence (LR) in regard to analyzed variables was performed by using analysis of variance. To evaluate the influence of late local recurrence (LLR) on the results of neoadjuvant CRT, we performed a log-rank test censoring all observations at 60 and at 120 months.

Results: After a mean follow-up of 73.6 months (range, 1-171), 68 patients developed a recurrence. Twenty-three patients developed LRs (6.9%), and 5 developed LLRs. The earliest relapse was diagnosed 4 months after rectal surgery, and the latest was diagnosed 120 months after surgery. Patients who underwent neoadjuvant CRT developed LR significantly later than patients without neoadjuvant CRT (51.8 vs 13.5 months; P = 0.002). LR rates in patients who underwent preoperative CRT and those who did not were 9.2% and 3.5% (difference, 5.7%), respectively, after censoring all observations at 60 months and 9.2% and 6.1% (difference, 3.1%) after censoring all observations at 120 months.

Conclusion: Local recurrence was diagnosed significantly later in patients treated with neoadjuvant CRT. Follow-up longer than 5 years is needed to evaluate definitive results in patients treated with neoadjuvant CRT.
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http://dx.doi.org/10.1016/j.ijsu.2017.05.070DOI Listing
August 2017

Effects of the capping ligands, linkers and oxide surface on the electron injection mechanism of copper sulfide quantum dot-sensitized solar cells.

Phys Chem Chem Phys 2017 Jun;19(22):14580-14587

Departamento de Química Física, Facultad de Química, Universidad de Sevilla, 41012 Sevilla, Spain.

Quantum dot-sensitized solar cells, QDSCs, are a clean and effective alternative to fossil fuels to reduce CO emissions. However, the different components that constitute the QDSCs and the difficulty of isolating experimentally their effects on the performance of the whole system slow down the development of more efficient devices. In this work, DFT calculations are combined with a bottom-up approach to differentiate the effect of each component on the electronic structure and absorption spectra. First, CuS QDs were built including a U parameter to effectively describe the localization of electrons. The effect of capping agents is addressed using ligands with different electron-donating/withdrawing groups. The role of linkers and their adsorption on the oxide surface are also examined. Finally, we propose a main indirect electron injection mechanism based on the position of the peaks of the spectra.
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http://dx.doi.org/10.1039/c7cp01076aDOI Listing
June 2017

Stent placement prior to initiation of chemotherapy in patients with obstructive, nonoperative left sided tumors is associated with fewer stomas.

J Surg Oncol 2017 Jun 15;115(7):856-863. Epub 2017 Feb 15.

Department of General Surgery, Coloproctology Unit, Complejo Hospitalario de Navarra, Pamplona, Spain.

Background And Objetives: Due to the potential risks associated with stent placement, European Society Gastrointestinal Endoscopy does not recommend prophylactic insertion of stents in patients without symptoms. The aim was to compare complication rates, need of surgery, colostomy formation, and survival between stent placement prior to start of chemotherapy (SEMS group) and upfront ChT (ChT group) in patients with endoscopically non-transverable metastatic left-sided colorectal cancer.

Methods: Gender, age, CEA, tumor location, sites of metastatic disease, peritoneal involvement, liver involvement, and angiogenesis inhibitors administration, were recorded. Complication rates, need of surgery, stoma creation, and survival were compared between both groups by univariate and multivariate test. Complications of SEMS placement in both groups were compared.

Results: We studied 75 men and 40 women, with a mean age of 66.3 years. Overall complication and perforation rates were similar but patients in the ChT group had a significant higher need of surgery and subsequent stoma creation. Perforation after SEMS placement rates were higher in patients receiving ChT than in patients without ChT. Survival was related to peritoneal carcinomatosis and administration of biological agents.

Conclusions: SEMS placement prior to ChT administration dismissed the need of subsequent surgery and decreased the rates of permanent stoma formation.
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http://dx.doi.org/10.1002/jso.24588DOI Listing
June 2017

Modulating Enzyme Catalysis through Mutations Designed to Alter Rapid Protein Dynamics.

J Am Chem Soc 2016 Mar 8;138(10):3403-9. Epub 2016 Mar 8.

Department of Chemistry and Biochemistry, University of Arizona , 1306 East University Blvd, Tucson, Arizona 85721, United States.

The relevance of sub-picosecond protein motions to the catalytic event remains a topic of debate. Heavy enzymes (isotopically substituted) provide an experimental tool for bond-vibrational links to enzyme catalysis. A recent transition path sampling study with heavy purine nucleoside phosphorylase (PNP) characterized the experimentally observed mass-dependent slowing of barrier crossing (Antoniou, D.; Ge, X.; Schramm, V. L.; Schwartz, S. D. J. Phys. Chem. Lett. 2012, 3, 3538). Here we computationally identify second-sphere amino acid residues predicted to influence the freedom of the catalytic site vibrational modes linked to heavy enzyme effects in PNP. We mutated heavy and light PNPs to increase the catalytic site vibrational freedom. Enzymatic barrier-crossing rates were converted from mass-dependent to mass-independent as a result of the mutations. The mutagenic uncoupling of femtosecond motions between catalytic site groups and reactants decreased transition state barrier crossing by 2 orders of magnitude, an indication of the femtosecond dynamic contributions to catalysis.
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http://dx.doi.org/10.1021/jacs.5b12551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794390PMC
March 2016

Obesity-driven alterations in adipose-derived stem cells are partially restored by weight loss.

Obesity (Silver Spring) 2016 Mar 1;24(3):661-9. Epub 2016 Feb 1.

Cardiac Development and Repair Department, Centro Nacional De Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Objective: The therapeutic potential of adipose-derived stem cells (ASCs) is reduced by various stress-inducing conditions that affect tissue homeostasis such as diabetes, aging, and obesity. Previous works have provided evidence of negative effects of obesity on ASC populations, but it is unclear whether this persists after a weight loss. This study evaluated whether weight loss can restore the attenuated properties found in ASCs derived from populations with obesity (oASCs).

Methods: In vitro functional analyses were performed to investigate the possible recovery properties in mouse oASCs. Using ASCs isolated from subcutaneous tissue from formerly obese mice (dASCs) and control mice (cASCs), cell proliferation, viability, and some regenerative properties in these cells were analyzed compared with oASCs to evaluate the functional cell state.

Results: Cell proliferation, viability, and some regenerative properties are strengthened in dASCs and cASCs compared with oASCs. Nevertheless, metabolic analysis reveals a mitochondrial load misbalance and function leading to impaired respiration in dASCs.

Conclusions: This study demonstrates that an initial obese environment triggers a detrimental state in ASCs that is not completely recovered after weight loss.
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http://dx.doi.org/10.1002/oby.21405DOI Listing
March 2016

Long-term outcomes after stenting as a "bridge to surgery" for the management of acute obstruction secondary to colorectal cancer.

World J Gastrointest Oncol 2016 Jan;8(1):105-12

Javier Suárez, Department of General Surgery, Coloproctology Unit, Complejo Hospitalario de Navarra, 31008 Pamplona, Spain.

Obstructive symptoms are present in 8% of cases at the time of initial diagnosis in cases of colorectal cancer. Emergency surgery has been classically considered the treatment of choice in these patients. However, in the majority of studies, emergency colorectal surgery is burdened with higher morbidity and mortality rates than elective surgery, and many patients require temporal colostomy which deteriorates their quality of life and becomes permanent in 10%-40% of cases. The aim of stenting by-pass to surgery is to transform emergency surgery into elective surgery in order to improve surgical results, obtain an accurate tumoral staging and detection of synchronous lesions, stabilization of comorbidities and performance of laparoscopic surgery. Immediate results were more favourable in patients who were stented concerning primary anastomosis, permanent stoma, wound infection and overall morbidity, having the higher surgical risk patients the greater benefit. However, some findings laid out the possible implication of stenting in long-term results of oncologic treatment. Perforation after stenting is related to tumoral recurrence. In studies with perforation rates above 8%, higher recurrences rates in young patients and lower disease free survival have been shown. On the other hand, after stenting the number of removed lymph nodes in the surgical specimen is larger, patients can receive adjuvant chemotherapy earlier and in a greater percentage and the number of patients who can be surgically treated with laparoscopic surgery is larger. Finally, there are no consistent studies able to demonstrate that one strategy is superior to the other in terms of oncologic benefits. At present, it would seem wise to assume a higher initial complication rate in young patients without relevant comorbidities and to accept the risk of local recurrence in old patients (> 70 years) or with high surgical risk (ASA III/IV).
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http://dx.doi.org/10.4251/wjgo.v8.i1.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714139PMC
January 2016

Isotope-specific and amino acid-specific heavy atom substitutions alter barrier crossing in human purine nucleoside phosphorylase.

Proc Natl Acad Sci U S A 2015 Sep 24;112(36):11247-51. Epub 2015 Aug 24.

Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461

Computational chemistry predicts that atomic motions on the femtosecond timescale are coupled to transition-state formation (barrier-crossing) in human purine nucleoside phosphorylase (PNP). The prediction is experimentally supported by slowed catalytic site chemistry in isotopically labeled PNP (13C, 15N, and 2H). However, other explanations are possible, including altered volume or bond polarization from carbon-deuterium bonds or propagation of the femtosecond bond motions into slower (nanoseconds to milliseconds) motions of the larger protein architecture to alter catalytic site chemistry. We address these possibilities by analysis of chemistry rates in isotope-specific labeled PNPs. Catalytic site chemistry was slowed for both [2H]PNP and [13C, 15N]PNP in proportion to their altered protein masses. Secondary effects emanating from carbon-deuterium bond properties can therefore be eliminated. Heavy-enzyme mass effects were probed for local or global contributions to catalytic site chemistry by generating [15N, 2H]His8-PNP. Of the eight His per subunit, three participate in contacts to the bound reactants and five are remote from the catalytic sites. [15N, 2H]His8-PNP had reduced catalytic site chemistry larger than proportional to the enzymatic mass difference. Altered barrier crossing when only His are heavy supports local catalytic site femtosecond perturbations coupled to transition-state formation. Isotope-specific and amino acid specific labels extend the use of heavy enzyme methods to distinguish global from local isotope effects.
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http://dx.doi.org/10.1073/pnas.1513956112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568649PMC
September 2015

Case-based update: primary intraventricular brain abscess in a 10-year-old child.

Childs Nerv Syst 2015 Dec 18;31(12):2235-8. Epub 2015 Aug 18.

Abteilung für Pädiatrische Neurochirurgie, Asklepios Klinik, Arnold-Janssen-Str. 29, 53757, Sankt Augustin, Germany.

Background: Intraventricular abscesses are very rare and usually result from secondary rupture of a brain abscess. In the few published cases, clinical presentation was subacute and different pathogens were found. The diagnosis might be mistaken as an intraventricular tumor.

Case Report: This is a case of a 10-year-old girl suffering from cyanotic heart disease that was presented with subacute onset of headache, vomiting, and some signs of inflammation. Symptoms lead to early brain imaging (CT/MRI) demonstrating left ventricular horn lesion affecting adjacent brain structures. Neuroradiologists suspected an intraventricular tumor, but cardiac history and signs of inflammation led to lumbar puncture and evidence of CNS infection, and intraventricular abscess was suspected. Navigated aspiration was performed, and multi-sensitive Eikenella corrodens was cultivated. Broad antibiotic treatment and dexamethasone were initiated, and symptoms disappeared. Follow-up imaging demonstrated gradual regression of the intraventricular abscess. The girl underwent regular professional teeth cleaning which was discussed as possible cause of infection.

Conclusions: Although an isolated intraventricular abscess is a very rare event, typical predisposing cardiac history together with central nervous symptoms and an intracranial contrasting mass should always lead to the differential diagnosis of a brain abscess and be biopsied first. E. corrodens is a typical organism of the mouth flora, but a rare cause for a brain abscess. Harmless teeth cleaning procedures may cause hematogenic spread and lead to CNS infections, e.g., in patients with predisposing diseases. To our knowledge, there are only six previous reports of primary intraventricular brain abscess.
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http://dx.doi.org/10.1007/s00381-015-2856-6DOI Listing
December 2015

Tight binding enantiomers of pre-clinical drug candidates.

Bioorg Med Chem 2015 Sep 30;23(17):5326-33. Epub 2015 Jul 30.

Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand.

MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2015.07.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567382PMC
September 2015

Complications from the primary tumour are not related with survival in patients with synchronous stage IV colorectal cancer receiving chemotherapy without primary tumour resection.

Int J Colorectal Dis 2015 Oct 7;30(10):1357-63. Epub 2015 Jul 7.

Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain.

Background: The aim of this study was to evaluate the rate of complications from the primary tumour (CPT) requiring surgical or endoscopic intervention during chemotherapy treatment in patients with incurable synchronous stage IV colorectal cancer, the possibility of predicting such complications and their influence on survival.

Methods: One hundred and twenty-five patients were initially treated with chemotherapy. Patients were grouped on the basis of appearance or not of CPT. We assessed the relation between age, gender, carcinoembryonic antigen (CEA) level, primary tumour location, alkaline phosphatase level, unilobar or bilobar liver involvement, presence of peritoneal carcinomatosis, the number of sites of metastatic disease, the addition of target therapies to chemotherapy, the ability to traverse the tumour with an endoscope and the appearance of complications due to the primary tumour and overall survival.

Results: Mean age was 64.9 years, and 89 patients were men. Over a mean of 234 days, 25 patients (20 %) developed a CPT. Eighteen patients required surgery, and seven were treated exclusively by an endoscopic procedure. Mean survival was 15.8 months. We found a statistically relevant correlation between the inability to traverse the tumour with an endoscope and the occurrence of a CPT. There was no statistical differences in survival between both groups, but patients receiving target therapies had better survival.

Conclusion: Twenty percent of patients will suffer a CPT during chemotherapy treatment. The inability to pass the tumour with an endoscope can predict the CPT. Survival was only related to the addition of target therapies to chemotherapy.
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http://dx.doi.org/10.1007/s00384-015-2305-8DOI Listing
October 2015

Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients.

Int J Cancer 2015 Jul 13;137(1):212-20. Epub 2014 Dec 13.

Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands; Department of Radiology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Recent literature suggests that the benefit of adjuvant chemotherapy (aCT) for rectal cancer patients might depend on the response to neoadjuvant chemoradiation (CRT). Aim was to evaluate whether the effect of aCT in rectal cancer is modified by response to CRT and to identify which patients benefit from aCT after CRT, by means of a pooled analysis of individual patient data from 13 datasets. Patients were categorized into three groups: pCR (ypT0N0), ypT1-2 tumour and ypT3-4 tumour. Hazard ratios (HR) for the effect of aCT were derived from multivariable Cox regression analyses. Primary outcome measure was recurrence-free survival (RFS). One thousand seven hundred and twenty three (1723) (52%) of 3,313 included patients received aCT. Eight hundred and ninety eight (898) patients had a pCR, 966 had a ypT1-2 tumour and 1,302 had a ypT3-4 tumour. For 122 patients response, category was missing and 25 patients had ypT0N+. Median follow-up for all patients was 51 (0-219) months. HR for RFS with 95% CI for patients treated with aCT were 1.25(0.68-2.29), 0.58(0.37-0.89) and 0.83(0.66-1.10) for patients with pCR, ypT1-2 and ypT3-4 tumours, respectively. The effect of aCT in rectal cancer patients treated with CRT differs between subgroups. Patients with a pCR after CRT may not benefit from aCT, whereas patients with residual tumour had superior outcomes when aCT was administered. The test for interaction did not reach statistical significance, but the results support further investigation of a more individualized approach to administer aCT after CRT and surgery based on pathologic staging.
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http://dx.doi.org/10.1002/ijc.29355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957736PMC
July 2015

Quality of life assessment by applying EORTC questionnaires to rectal cancer patients after surgery and neoadjuvant and adjuvant treatment.

Rev Esp Enferm Dig 2013 May-Jun;105(5):255-61

Background: Quality of Life (QoL) is a key element in rectal cancer (RC) patients.

Aims: this study assesses QoL in a sample of RC patients in their treatment follow-up period, and compares surgery modalities.

Patients And Methods: eighty four locally advanced RC patients who had received surgery and neoadjuvant chemoradiotherapy were included in the study. Of these, 70 had adjuvant chemotherapy. All patients completed the EORTC QLQ-C30 and the QLQ-CR29 once at least one year after completion of their treatment. Low anterior resection (LAR) patients also completed a Functional Evaluation questionnaire.

Results: QoL scores in the EORTC questionnaires for the sample as a whole were high in most dimensions, in line with the general population´s QoL values, although moderate limitations (> 30 points)were observed in urinary frequency, flatulence, impotence and sexual function. The scores for the Functional Evaluation were adequate (mean combined bowel function score of 18.2). LAR patients had a higher stool frequency than those with abdominoperineal resection (APR; p < 0.001). No differences in body image were found amongst LAR and APR patients. LAR patients with a lower anastomosis had higher faecal incontinence (p = 0.02), whereas those with a reservoir had better emotional functioning (p = 0.04) and higher faecal incontinence (p = 0.03).

Conclusions: QoL scores and functional evaluation indicated patients had adapted to their disease and treatment. The few differences in QoL found between surgery modalities are in line with other recent studies and in contrast with earlier ones that suggested a lower QoL in APR patients.
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http://dx.doi.org/10.4321/s1130-01082013000500003DOI Listing
July 2015

Catalytic site conformations in human PNP by 19F-NMR and crystallography.

Chem Biol 2013 Feb;20(2):212-22

Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

Purine nucleoside phosphorylase (PNP) is a target for leukemia, gout, and autoimmune disorders. Dynamic motion of catalytic site loops has been implicated in catalysis, but experimental evidence was lacking. We replaced catalytic site groups His257 or His64 with 6-fluoro-tryptophan (6FW) as site-specific NMR probes. Conformational adjustments in the 6FW-His257-helical and His64-6FW-loop regions were characterized in PNP phosphate-bound enzyme and in complexes with catalytic site ligands, including transition state analogs. Chemical shift and line-shape changes associated with these complexes revealed dynamic coexistence of several conformational states in these regions in phosphate-bound enzyme and altered or single conformations in other complexes. These conformations were also characterized by X-ray crystallography. Specific (19)F-Trp labels and X-ray crystallography provide multidimensional characterization of conformational states for free, catalytic, and inhibited complexes of human PNP.
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http://dx.doi.org/10.1016/j.chembiol.2013.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584414PMC
February 2013