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SIERRA J. SEAMAN, MD; JESSICA CHAOUL, MD; ARNOLD P. ADVINCULA, [...]

More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia. Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 106Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high‐resolution respirometry and transmission electron microscopy (TEM). Obese LLC mice experienced significant tumour‐free body weight loss similar to lean (−12.8% vs. −11.8%, P= 0.0001) but had reduced survival (33.3% vs. 6.67%, χ2= 10.04, P= 0.0182). Obese LLC mice had reduced muscle weights (−24%, P< 0.0354) and mCSA (−16%, P= 0.0004) with similar activation of muscle p65 (P= 0.0337), and p38 (P= 0.0008). ADP‐dependent coupled respiration was reduced in both Obese and Obese LLC muscle (−30%, P= 0.0072) consistent with reductions in volitional cage activity (−39%, P< 0.0001) and grip strength (−41%, P< 0.0001). TEM revealed stepwise reductions in intermyofibrillar and subsarcolemmal mitochondrial size with Obese (IMF: −37%, P= 0.0009; SS: −21%, P= 0.0101) and LLC (IMF: −40%, P= 0.0019; SS: −27%, P= 0.0383) mice. Obese LLC mice had increased pAMPK (T172; P= 0.0103) and reduced FIS1 (P= 0.0029) and DRP1 (P< 0.0001) mitochondrial fission proteins, which were each unchanged in Lean LLC. Further, mitochondrial TEM analysis revealed that Obese LLC mice had an accumulation of damaged and dysfunctional mitochondria (IMF: 357%, P= 0.0395; SS: 138%, P= 0.0174) in concert with an accumulation of p62 (P= 0.0328) suggesting impaired autophagy and clearance of damaged mitochondria. Moreover, we observed increases in electron lucent vacuoles only in Obese LLC muscle (IMF: 421%, P= 0.0260; SS: 392%, P= 0.0192), further supporting an accumulation of damaged materials that cannot be properly cleared in the obese cachectic muscle. Taken together, these results demonstrate that obesity is not protective against cachexia and suggest exacerbated impairments to mitochondrial function and quality control with a particular disruption in the removal of damaged mitochondria. Our findings highlight the need for consideration of the severity of obesity and pre‐existing metabolic conditions when determining the impact of weight status on cancer‐induced cachexia and functional mitochondrial deficits.

•Mouse xenograft and allograft models of APL have activated coagulation and fibrinolytic systems, thrombocytopenia, and increased bleeding.•Inhibition of TF decreased the activation of coagulation in both APL models and normalized tail bleeding in the xenograft model.

Uterine leiomyomas affect 70% to 80% of reproductive-age women. Interventions for symptomatic patients include myomectomy, hysterectomy, uterine artery embolization (UAE), and radiofrequency ablation (RFA). Several RFA devices exist on the [...]

ABSTRACTFluorouracil/5-flourouracil (5FU) is a first-line chemotherapy drug for many cancer types; however, its associated toxicities contribute to poor quality of life and reduced dose intensities negatively impacting patient prognosis. While obesity remains a critical risk factor for most cancers, our understanding regarding how obesity may impact chemotherapy’s toxicities is extremely limited. C56BL/6 mice were given high fat (Obese) or standard diets (Lean) for 4 months and then subjected to three cycles of 5FU (5d-40 mg/kg Lean Mass, 9d rest) or PBS vehicle control. Shockingly, only 60% of Obese survived 3 cycles compared to 100% of Lean, and Obese lost significantly more body weight. Dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5FU catabolism, was reduced in obese livers. Total white blood cells, neutrophils, and lymphocytes were reduced in Obese 5FU compared to Lean 5FU and PBS controls. While adipocyte size was not affected by 5FU in Obese, skeletal muscle mass and myofibrillar cross section area were decreased following 5FU in Lean and Obese. Although adipose tissue inflammatory gene expression was not impacted by 5FU, distinct perturbations to skeletal muscle inflammatory gene expression and immune cell populations (CD45+Immune cells, CD45+CD11b+CD68+macrophages and CD45+CD11b+Ly6clo/intmacrophage/monocytes) were observed in Obese only. Our evidence suggests that obesity induced liver pathologies and reduced DPD exacerbated 5FU toxicities. While obesity has been suggested to protect against cancer/chemotherapy-induced cachexia and other toxicities, our results demonstrate that obese mice are not protected, but rather show evidence of increased susceptibility to 5FU-induced cytotoxicity even when dosed for relative lean mass.

Haemodialysis centres have conventionally provided maintenance haemodialysis using a standard dialysate temperature (eg, 36·5°C) for all patients. Many centres now use cooler dialysate (eg, 36·0°C or lower) for potential cardiovascular benefits. We aimed to assess whether personalised cooler dialysate, implemented as centre-wide policy, reduced the risk of cardiovascular-related death or hospital admission compared with standard temperature dialysate.

The biocarbon (SKPH) was obtained from Sargassumspp., and it was evaluated electrochemically as support for the CO2reduction. The biocarbon was synthesized and activated with KOH, obtaining a high surface area (1600 m2g−1) due to the activation process. Graphitic carbon formation after pyrolysis was confirmed by Raman spectroscopy. The XRD results show that SKPH has an amorphous structure with peaks corresponding to typical amorphous carbonaceous materials. FTIR was used to determine the chemical structure of SKPH. The bands at 3426, 2981, 2851, and 1604 cm−1correspond to O–H, C-H, and C-O stretching vibrations, respectively. Then, it compares SKPH films with different carbon films using two electrolytic systems with and without charge transfer. The SKPH film showed a capacitive behavior in the KOH, H2SO4, and, KCl systems; in the acid medium, the presence of a redox couple associated with carbon functional groups was shown. Likewise, in the [Fe(CN)6]−3and Cu(II) systems, the charge transfer process coupled with a capacitive behavior was described, and this effect is more noticeable in the [Fe(CN)6]−3system. Electrodeposition of copper on SKPH film showed two stages Cu(NH3)42+/Cu(NH3)2+and Cu(NH3)2+/Cuin ammonia media. Hydrogen formation and the activity of CO2are observed on SKPH film and are favored by the carbon’s surface chemistry. Cu/SKPH electrocatalyst has a catalytic effect on electrochemical reduction of CO2and inhibition of hydrogen formation. This study showed that the SKPH film electrode responds as a capacitive material that can be used as an electrode for energy storage or as metal support.

An isthmocele is a pouch-like anterior uterine wall defect at the site of a previous cesarean scar. The incidence is not well known, but it is estimated in the literature [...]

The distal gut is home to the dynamic and influential gut microbiome, which is intimately linked to mammalian health by promoting and facilitating countless physiological functions. In a time of increased anthropogenic pressures on wildlife due to widespread habitat destruction, loss of natural prey/foods, and rapid urbanization, the study of wildlife gut microbiomes could prove to be a valuable tool in wildlife management and conservation. Diet is one of the most influential determinants of a host’s gut microbiome; yet many wildlife agencies allow baiting to facilitate wildlife harvest, although the impact of human-provisioned foods on wildlife gut health is largely unknown. We used stable isotope analysis derived from carbon (δ 13C) to index the use of human-provisioned foods by 35 legally harvested American black bears (Ursus americanus), and16S rRNA gene amplicon sequencing to examine the impact of human-provisioned foods on the gut microbial diversity of black bears. We found that greater long-term consumption of human-provisioned foods was associated with significantly reduced microbial species richness and phylogenetic diversity. Our results indicate that consumption of anthropogenic foods through baiting significantly alters the mammalian gut microbiome.

Gut microbiomes encode myriad metabolic functions critical to mammalian ecology and evolution. While fresh fecal samples provide an efficient, noninvasive method of sampling gut microbiomes, collecting fresh feces from elusive species is logistically challenging. Nonfresh feces, however, may not accurately represent the gut microbiome of the host due to succession of gut microbial consortia postdefecation as well as colonization by microbes from the surrounding environment. Using American mink (Neovison vison) as a model species, we examined postdefecation microbial community succession to learn how ambient temperature and temporal sampling constraints influence the reliability of nonfresh feces to represent host gut microbiomes. To achieve our goal, we analyzed fresh mink feces (n= 5 females; n= 5 males) collected at the time of defecation from captive mink at a farm in the Upper Peninsula of Michigan and we subsequently subsampled each fecal specimen to investigate microbial community succession over five days, under both warm (21°C) and cold (–17°C to –1°C) temperature treatments. We found that both temperature and time influenced fecal microbiome composition; and we also detected significant sexual dimorphism in microbial community structures, with female mink microbiomes exhibiting significantly greater variation than males’ when exposed to the warm temperature treatment. Our results demonstrate that feces from unknown individuals can be a powerful tool for examining carnivore gut microbiomes, though rigorous study design is required because sex, ambient temperature, and time since defecation drive significant microbial variation and the sample size requirements necessary for detecting statistically significant differences between target populations is an important consideration for future ecologically meaningful research.

While California is widely known for its hostility to restrictive covenants, the California Supreme Court recently clarified that this hostility does not extend to every agreement involving competitive restrictions. The court's decision also offers further guidance for businesses seeking to pursue claims for interference with at-will contracts, as the court expressly predicated liability on pleading (and proving) some independent wrongfulness. However, the court acknowledged that whether interference with an at-will contract "more closely resembles" a claim for interference with contractual relations or one for interference with prospective economic advantage remains a separate question, which the court had partially addressed in Reeves v. Hanlon, 33 Cal. 4th 1140, 1145 (2004). [Extracted from the article]

A minilaparotomy is loosely defined as a laparotomy measuring between 4 cm and 6 cm. For the appropriate surgical candidate, a minilaparotomy is a useful alternative to laparotomy or laparoscopy, [...]

A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking that is goal-directed but not habit-like. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry in rats trained to self-administer cocaine paired with an audiovisual cue to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habit-like cue-induced cocaine seeking and how it is impacted by cue extinction. After minimal fixed-ratio training, rats showed enhanced DMS and DLS calcium responses to cue-reinforced compared to unreinforced lever presses. After rats were trained on goal-promoting fixed ratio schedules or habit-promoting second-order schedules of reinforcement, different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses emerged. Rats trained on habit-promoting second-order schedules showed reduced DMS calcium responses and enhanced DLS dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habit-like behavior and the DLS are unaffected.

Bioluminescence imaging with luciferase–luciferin pairs is routinely used to monitor cellular functions. Multiple targets can be visualized in tandem using luciferases that process unique substrates, but only a handful of such orthogonal probes are known. Multiplexed studies require additional robust, light-emitting molecules. In this work, we report new luciferins for orthogonal imaging that comprise disubstituted cores. These probes were found to be bright emitters with various engineered luciferases. The unique patterns of light output also provided insight into enzyme–substrate interactions necessary for productive emission. Screening studies identified mutant luciferases that could preferentially process the disubstituted analogues, enabling orthogonal imaging with existing bioluminescent reporters. Further mutational analyses revealed the origins of substrate selectivity. Collectively, this work provides insights into luciferase–luciferin features relevant to bioluminescence and expands the number of probes for multicomponent tracking.

Porous electrodes are widely used in the industry because of their high surface area to volume ratio. However, the stochastic morphology of most commercially available porous electrodes results in poor electrical connections in the solid phase and inefficient mass transport through the pore phase. This can be especially detrimental for gas-evolving processes such as water electrolysis for hydrogen and oxygen generation. Bicontinuous interfacially jammed emulsion gels (bijels) offer templates from which to create porous electrodes with robust solid-state interconnectivity and a uniform pore structure that facilitate improved electron and mass transport. In this study, gas release rates and electrochemical experiments are utilized to study the effects of powder- and bijel-derived microstructures on hydrogen generation by water electrolysis. The bijel-derived electrodes are shown to expel product gas faster and require up to 25% less overpotential to drive water electrolysis over the range of current densities tested (−5 to −40 mA/cm2) than their powder-derived analogs. Our findings suggest that the uniform and bicontinuous domains of bijel-derived porous electrodes can mitigate the limited current distribution and deleterious bubble effect found in stochastic electrodes, in turn improving the overall performance of electrolytic processes requiring transport of gaseous species.

Little is known about the prognosis of patients with massive pulmonary embolism (PE) and its risk of recurrent venous thromboembolism (VTE) compared with non‐massive PE, which may inform clinical decisions. Our aim was to compare the risk of recurrent VTE, bleeding, and mortality after massive and non‐massive PE during anticoagulation and after its discontinuation. We included all participants in the RIETE registry who suffered a symptomatic, objectively confirmed segmental or more central PE. Massive PE was defined by a systolic hypotension at clinical presentation (<90 mm Hg). We compared the risks of recurrent VTE, major bleeding, and mortality using time‐to‐event multivariable competing risk modeling. There were 3.5% of massive PE among 38 996 patients with PE. During the anticoagulation period, massive PE was associated with a greater risk of major bleeding (subhazard ratio [sHR] 1.72, 95% confidence interval [CI] 1.28–2.32), but not of recurrent VTE (sHR 1.15, 95% CI 0.75–1.74) than non‐massive PE. An increased risk of mortality was only observed in the first month after PE. After discontinuation of anticoagulation, among 11 579 patients, massive PE and non‐massive PE had similar risks of mortality, bleeding, and recurrent VTE (sHR 0.85, 95% CI 0.51–1.40), but with different case fatality of recurrent PE (11.1% versus 2.4%, P= .03) and possibly different risk of recurrent fatal PE (sHR 3.65, 95% CI 0.82–16.24). In this large prospective registry, the baseline hemodynamic status of the incident PE did not influence the risk of recurrent VTE, during and after the anticoagulation periods, but was possibly associated with recurrent PE of greater severity.

Posttransplant high-dose cyclophosphamide (PTCy) effectively prevents GvHD after haploidentical SCT. However, its use in HLA-matched SCT has been less explored. Fifty-six consecutive patients who underwent allo-SCT for hematological malignancies have been included in this prospective single-center protocol. Donors have been HLA-identical siblings, fully-matched unrelated or 1-allele-mismatched unrelated donors in 30%, 32%, and 37% of cases, respectively. Nine patients have received a TBI-containing MAC regimen, while the remaining (84%) received RIC platforms based on Fludarabine plus Busulfan/Melphalan. Due to the high graft failure (GF) rate (21%) in a preliminary analysis in the allo-RIC cohort (n= 29), protocol amendments have been implemented, with no further cases of GF after the introduction of mini-thiotepa (0/18). The overall incidence of grade II–IV acute GvHD is 24% (95% CI: 17–31%) with four steroid-refractory cases. Severe chronic GvHD has occurred in only 1 of 43 evaluable cases. The 1-year NRM and relapse are 18% (95% CI: 12–26%) and 30% (18–42%) and the OS and DFS are 78% and 64%, respectively. These outcomes support the feasibility of using PTCy as a SOC outside the haplo-setting, albeit mini-thiotepa (3 mg/kg) was incorporated in the standard allo-RIC platforms to prevent GF. Despite the limitations of a single-center experience and the short follow-up, these protocols show promising results with particular benefit in reducing the occurrence of moderate-to-severe GvHD.

Polyamine and polyammonium ion conjugates are often used to direct reagents to nucleic acids based on their strong electrostatic attraction to the phosphoribose backbone. Such nonspecific interactions do not typically alter the specificity of the attached reagent, but polyammonium ions dramatically redirected the specificity of a series of quinone methide precursors. Replacement of a relatively nonspecific intercalator based on acridine with a series of polyammonium ions resulted in a surprising change of DNA products. Piperidine stable adducts were generated in duplex DNA that lacked the ability to support a dynamic cross-linking observed previously with acridine conjugates. Minor reaction at guanine N7, the site of reversible reaction, was retained by a monofunctional quinone methide-polyammonium ion conjugate, but a bisfunctional analogue designed for tandem quinone methide formation modified guanine N7 in only single-stranded DNA. The resulting intrastrand cross-links were sufficiently dynamic to rearrange to interstrand cross-links. However, no further transfer of adducts was observed in duplex DNA. An alternative design that spatially and temporally decoupled the two quinone methide equivalents neither restored the dynamic reaction nor cross-linked DNA efficiently. While di- and triammonium ion conjugates successfully enhanced the yields of cross-linking by a bisquinone methide relative to a monoammonium equivalent, alternative ligands will be necessary to facilitate the migration of cross-linking and its potential application to disrupt DNA repair.

Estudiar la influencia del cateterismo vesical intermitente (CVI) sobre la función del tracto urinario inferior (TUI) en pacientes con retención urinaria (RU) por insuficiencia contráctil (IC) del detrusor.

Two-dimensional (2D) quantum materials offer a unique platform to explore mesoscopic phenomena driven by interfacial and topological effects. Their tunable electric properties and bidimensional nature enable their integration into sophisticated heterostructures with engineered properties, resulting in the emergence of new exotic phenomena not accessible in other platforms. This has fostered many studies on 2D ferromagnetism, proximity-induced effects, and quantum transport, demonstrating their relevance for fundamental research and future device applications. Here, we review ongoing progress in this lively research field with special emphasis on spin-related phenomena.

El objetivo de este estudio es evaluar las características generales y los resultados oncológicos en una cohorte de 408 casos de prostatectomía radical asistida por robot da Vinci Standard de 4 brazos, realizadas entre octubre del 2006 y febrero del 2015. El análisis estadístico se realizó con el programa SPSS 20.0. Las variables cualitativas se presentan con su distribución de frecuencias y las cuantitativas con su media y desviación estándar o mediana y rango intercuartil. La asociación entre variables cualitativas se analizó con el test de la χ2. La variable de resultado de la supervivencia libre de enfermedad se evaluó con un análisis de curvas de Kaplan-Meier y se contrastaron las diferencias con el test de Breslow. Se ajustó un modelo de regresión de Cox. Entre los resultados destacamos un seguimiento 47 meses (32-68,75 meses), supervivencia libre de recurrencia 90 meses (IC del 95%, 86-94), mediana de tiempo a recurrencia de 23 meses (10,5-37 meses), recurrencia del 16,6% (68/408), recidiva bioquímica (62/498, 15,2%) y un 22% de complicaciones, la mayoría Clavien I-II. Los resultados se resumen en las tablas 1 a 7 y en la figura 1. Conclusiones: 1)la prostatectomía radical robótica es una técnica segura con un porcentaje asumible de complicaciones, en su mayoría menores (grados iy iide Clavien); 2)encontramos mayor probabilidad de permanecer libre de recidiva en los grados más bajos de la clasificación de ISUP y mayor probabilidad de recidiva en casos de alto riesgo, y 3)en el modelo multivariante comprobamos que el grado ISUP se relacionó de forma significativa con la supervivencia y fueron variables pronosticas independientes los grados de la clasificación ISUP y los márgenes quirúrgicos positivos.

•Most common reason for opposing campus gun carrying was reduced safety.•Most common reason to support campus carry was self-protection in emergencies.•Campus carry views not associated with perceived campus safety.•Most respondents opposed campus gun carrying.

Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated.

Over a Century of Bioleaching Copper Sulphides at Andacollo One could say 'there is nothing new about copper being extracted by cementation' and of course one would be right. This [...]

A dopant-free, single-mode optical fiber delivered accurate temperature profiles for many months in a Western Canadian SAGD well, while conventional fiber quickly succumbed to 'hydrogen darkening.' SPECIAL FOCUS: DRILLING AND [...]

Bioluminescence is widely used for real-time imaging in living organisms. This technology features a light-emitting reaction between enzymes (luciferases) and small molecule substrates (luciferins). Photons produced from luciferase–luciferin reactions can penetrate through heterogeneous tissue, enabling readouts of physiological processes. Dozens of bioluminescent probes are now available and many are routinely used to monitor cell proliferation, migration, and gene expression patterns in vivo.

Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11thInternational Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.

This work presents a control strategy for a leader-follower formation distance-based model of two single order kinematic model of robots. It uses feedback linearization techniques to derive the control action on the follower robot to maintain a desired distance and orientation with respect to the leader robot. Besides, it is shown that a suitable selection of the desired parameters make the formation behave as a rigid body. The control strategy is applied in a laboratory environment with two omnidirectional robots to show its performance.

The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assessed before transplant rather than at diagnosis we performed a retrospective analysis of the EBMT database. A total of 579 patients had sufficient information available to calculate IPSS-R at transplant. Median overall survival (OS) from transplant was significantly different according to IPSS-R: very low 23.6 months, low 55.0 months, intermediate 19.7 months, high 13.5 months, very high 7.8 months (P<0.001). In a multivariate Cox model the following parameters were significant risk factors for OS: IPSS-R, graft source, age and prior treatment. Median relapse free survival also showed significant differences according to IPSS-R: very low: 23.6 months, low: 24.8 months, intermediate 10.6 months, high 7.9 months, very high 5.5 months (P<0.001). Multivariate risk factors for relapse-free survival (RFS) were: IPSS-R, reduced intensity conditioning, graft source and prior treatment. A trend for an increased relapse incidence was noted for very high risk IPSS-R. We conclude that the IPSS-R at transplant is a useful prognostic score for predicting OS and RFS after transplantation, capturing both disease evolution and response to prior treatment before transplant.

Eighty-one patients with high-risk hematological malignancies received unmanipulated haploidentical stem cell transplants (haploSCT) using the same protocol at four Spanish institutions. The conditioning regimen was thiotepa, busulfan and fludarabine; following bone marrow or peripheral blood infusion. GvHD prophylaxis with high-dose cyclophosphamide on days +3 and +4, and IV tacrolimus from day +5 was administered. 62% were in complete remission, 17% had received previous allogeneic SCT and 44% had a high-very high refined disease risk index. One patient had primary graft failure and three more died before +21. The median days to neutrophil and platelet recoveries were +18 and +23, respectively, and 93% achieved a full donor chimerism on day +30. At 1 year, cumulative incidences (CumInc) of non-relapse mortality and relapse were 27 and 19%. One-year overall survival and PFS were 61 and 51%. CumInc of grade II−IV and III−IV were 23 and 14%. At 30 months, CumInc of limited and extensive GvHD were 20 and 22%. In conclusion, patients with hematological malignancies who receive an unmanipulated haploSCT with post-transplant cyclophosphamide may benefit from less intense pharmacological prophylaxis for GvHD prophylaxis. Whether this approach potentiates the graft-versus-tumor effect and decreases relapses requires further investigation.

This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1–1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.

Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane–dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfrhad significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfrdeletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfrknockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1and Il10mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2and Il1bmRNA levels and decreased interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-1β protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfrknockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31+blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.

Gemtuzumab ozogamicin (GO) may increase the risk of sinusoidal obstruction syndrome (SOS) when used prior to allogeneic stem cell transplantation (HSCT). We assessed SOS incidence and outcomes after HSCT of 146 adults, with a median age of 50 years, previously receiving GO. SOS prophylaxis was used in 69 patients (heparin n=57, ursodeoxycholic acid n=8, defibrotide n=4). Cumulative incidence (CI) of SOS was 8% (n=11), with death in 3 patients. Median interval between last GO dose and HSCT was 130 days. Overall survival (OS) and SOS incidence did not differ for patients receiving GO ⩽3.5 months before HSCT and the others. CI of acute and chronic GVHD was 31% and 25%, respectively. Probability of OS and leukemia-free survival (LFS) at 5 years was 40% and 37%, respectively. Relapse incidence and non-relapse mortality were 42% and 21%, respectively. In multivariate analysis, active disease at HSCT was associated with relapse and worse LFS and OS (P<0.03). Liver abnormalities before HSCT correlated with worse OS (P<0.03). Use of low-dose GO prior to HSCT is associated with an acceptable SOS incidence. Prospective studies investigating the role and the utility of SOS prophylaxis are warranted.

Alcohol use among adolescents is widespread and a growing concern due to long‐term behavioral deficits, including altered Pavlovian behavior, that potentially contribute to addiction vulnerability. We tested the hypothesis that adolescent intermittent ethanol (AIE) exposure alters Pavlovian behavior in males and females as measured by a shift from goal‐tracking to sign‐tracking. Additionally, we investigated GLT‐1, an astrocytic glutamate transporter, as a potential contributor to a sign‐tracking phenotype. Male and female Sprague‐Dawley rats were exposed to AIE(5 g/kg, intragastric) or water intermittently 2 days on and 2 days off from postnatal day (P) 25 to 54. Around P70, animals began 20 daily sessions of Pavlovian conditioned approach (PCA), where they learned that a cue predicted noncontingent reward delivery. Lever pressing indicated interaction with the cue, or sign‐tracking, and receptacle entries indicated approach to the reward delivery location, or goal‐tracking. To test for effects of AIEon nucleus accumbens (NAcc) excitatory signaling, we isolated membrane subfractions and measured protein levels of the glutamate transporter GLT‐1 after animals completed behavior as a measure of glutamate homeostasis. Females exhibited elevated sign‐tracking compared to males with significantly more lever presses, faster latency to first lever press, and greater probability to lever press in a trial. AIEsignificantly increased lever pressing while blunting goal‐tracking, as indicated by fewer cue‐evoked receptacle entries, slower latency to receptacle entry, and lower probability to enter the receptacle in a trial. No significant sex‐by‐exposure interactions were observed in sign‐ or goal‐tracking metrics. Moreover, we found no significant effects of sex or exposure on membrane GLT‐1 expression in the NAcc. Females exhibited enhanced sign‐tracking compared to males, while AIEdecreased goal‐tracking compared to control exposure. Our findings support the hypothesis that adolescent binge ethanol can shift conditioned behavior from goal‐ to cue‐directed in PCA, especially in females. Male and female Sprague–Dawley rats were exposed to adolescent intermittent ethanol (AIE), and then trained on Pavlovian conditioned approach in adulthood. Adolescent binge‐level ethanol (EtOH) produced similar blood EtOH concentration in males and females. Females and AIE exposed rats showed more conditioned lever presses (sign‐tracking), whereas AIE exposure significantly decreased conditioned receptacle entries (goal‐tracking). Collectively, our findings suggest that females are more susceptible to cue sensitivity after repeated consumption of EtOH during adolescence.

This study aimed to characterize the incidence, etiology and outcome of infectious episodes in patients with steroid refractory acute GvHD (SR-GvHD). The cohort included 127 adults treated with inolimomab (77%) or etanercept (23%) owing to acute 2–4 SR-GvHD, with a response rate of 43% on day +30 and a 4-year survival of 15%. The 1-year cumulative incidences of bacterial, CMV and invasive fungal infection were 74%, 65% and 14%, respectively. A high rate (37%) of enterococcal infections was observed. Twenty patients (15.7%) developed BK virus-hemorrhagic cystitis and five percent had an EBV reactivation with only one case of PTLD. One-third of long-term survivors developed pneumonia by a community respiratory virus and/or encapsulated bacteria, mostly associated with chronic GvHD. Infections were an important cause of non-relapse mortality, with a 4-year incidence of 46%. In multivariate analysis, use of rituximab in the 6 months before SCT (hazard ratio; HR 4.2; 95% confidence interval; CI 1.1–16.3), severe infection before SR-GvHD onset (HR 5.8; 95% CI 1.3–26.3) and a baseline C-reactive protein >15 UI/mL (HR 2.9; 95% CI 1.1–8.5) were associated with infection-related mortality. High rates of opportunistic infections with remarkable mortality warrant further efforts to optimize long-term outcomes after SR-GvHD.

•Integrated care models based on mHealth are emerging in chronic disease populations.•The MY-Medula application was developed considering the needs of allogeneic stem cell transplantation recipients.•The pilot study showed a high degree of usability and satisfaction.•A randomized trial comparing standard and MY-Medula-based follow-up is in the recruitment phase.

This paper propounds a new algorithm, the Sub-Space Random Search (SSRS) for the problem of single-objective optimization, with the aim of improving the robustness and the precision of classical methods of global optimization. The new algorithm is compared with a genetic algorithm (GA), on a set of four scaleable test functions and with the number of variables changing from 1 to 5. A new test function called Deceptive-bimodal (DB) is proposed. Results indicate that, with the same total number of function evaluations, SSRS is about 50% faster than GA. Moreover, SSRS shows a greater precision and similar ability to find the global optimum than GA with 1, 2 and sometimes 3 variables. But this advantage diminishes when the number of variables increases on multimodal and narrow-flat valley functions. Finally, SSRS is successfully applied to a problem of dynamical synthesis of a mechanism.

Helicobacter pylori(H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pyloriconstituent that augments cancer risk is the strain-specific cagpathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+H. pyloristrains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pyloricancer-associated cagT4SS is required for TLR9 activation and that H. pyloriDNA is actively translocated by the cagT4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cagisland may modify the risk for malignancy within the context of H. pyloriinfection and provide an important framework for future studies investigating the microbial–epithelial interface in gastric carcinogenesis.

Chronic inflammation contributes to the development of various forms of cancer. The polyamine catabolic enzyme spermine oxidase (SMOX) is induced in chronic inflammatory conditions, including Helicobacter pylori-associated gastritis, where its production of hydrogen peroxide contributes to DNA damage and subsequent tumorigenesis. MicroRNA expression levels are also altered in inflammatory conditions; specifically, the tumor suppressor miR-124 becomes silenced by DNA methylation. We sought to determine if this repression of miR-124 is associated with elevated SMOX activity and concluded that miR-124 is indeed a negative regulator of SMOX. In gastric adenocarcinoma cells harboring highly methylated and silenced mir-124gene loci, 5-azacytidine treatment allowed miR-124 re-expression and decreased SMOXexpression. Overexpression of an exogenous miR-124-3p mimic repressed SMOXmRNA and protein expression as well as H2O2production by >50% within 24 h. Reporter assays indicated that direct interaction of miR-124 with the 3′-untranslated region of SMOXmRNA contributes to this negative regulation. Importantly, overexpression of miR-124 before infection with H. pyloriprevented the induction of SMOX believed to contribute to inflammation-associated tumorigenesis. Compelling human in vivodata from H. pylori-positive gastritis tissues indicated that the mir-124gene loci are more heavily methylated in a Colombian population characterized by elevated SMOX expression and a high risk for gastric cancer. Furthermore, the degree of mir-124methylation significantly correlated with SMOX expression throughout the population. These results indicate a protective role for miR-124 through the inhibition of SMOX-mediated DNA damage in the etiology of H. pylori-associated gastric cancer.

Estimar la incidencia del cáncer de vejiga (CAV) en las comunidades autónomas que incluyeron mayor número de casos en el registro nacional hospitalario de CAV (Andalucía, Cataluña y Comunidad de Madrid) y describir las diferencias y similitudes clínicas, patológicas y diagnósticas del CAV en estas regiones.

AbstractAfter more than 20 years implementing the “Recommendations for the management of dredged material in Spanish ports” 1994 and taking into account both technical and scientific advances as well as the entry into force of new legislation in the European and Spanish contexts, in the process of implementation of the Spanish Law 41/2010 on the Protection of the Marine Environment, the Interministerial Commission for Marine Strategies adopted in April 2014 the “Guidelines for the characterization of dredged material and their relocation within waters of the maritime-terrestrial public domain”. These Guidelines should be applied for all the projects developed in the Spanish harbours from them.This article reviews the main contents of this new management framework for dredged material in Spain and emphasizes the main differences with the former framework used in Spain. In the conclusions section, it is highlighted the methodological improvements and the problems solved, according the authors opinion, regarding the previous framework used.

A 41 year old previously healthy woman presented with left sided motor deficit. Nuclear magnetic resonance imaging of the brain showed a recent ischaemic lesion of the right thalamus. Transthoracic [...]

The mechanics of films undergoing volume expansion on curved substrates plays a key role in a variety of technologies including biomedical implants, thermal and environmental barrier coatings, and electrochemical energy storage systems. Silicon anodes for lithium-ion batteries are an especially challenging case because they can undergo volume variations up to 300% that results in cracking, delamination, and thus significant loss in performance. In this study, we use finite element analysis to model the volume expansion during lithiation for silicon coated on spinodal, inverse opal, gyroid, and Schwartz primitive nickel backbones and compare the distributions of maximum principal stress, strain energy density, and von Mises stress, which we use as indicators for propensity for cracking, delamination, and yielding, in order to explore the effect of backbone morphology on mechanical degradation during expansion. We show that, when compared to the inverse opal, the spinodal morphology reduces and uniformly distributes the maximum principal stress and strain energy density in the silicon layer, and delays the onset of expansion-induced yielding at all silicon layer thicknesses, which we ascribe to the unique interfacial curvature distribution of spinodal structures. This work highlights the importance of morphology on coatings undergoing volume variations and unveils the particular promise of spinodally derived materials for the design of next generation lithium-ion battery electrodes.

Soil organic matter (SOM) quality and carbon (C) availability may be major features influencing the effect of earthworms on the aerobic processes in clayey tropical soils. In this study, we assessed the effect of an anecic (Polypheretima elongata), an endogeic (Pontoscolex corethrurus) and an epigeic (Eudrilus eugeniae) earthworm on the aerobic microbial activity of two tropical soils, a calcic Vertisol and an acid Ferralsol, with clay content >70% and very different organic C content and SOM stability. The soil–earthworm interaction was studied in a 6-month mesocosm experiment in a greenhouse using soils with and without (control soil) earthworm addition. Potential C mineralisation, actual net nitrogen (N) mineralisation and dehydrogenase activity (DHA), as indicators of the aerobic activity of the soils, and phosphorus (P) availability were determined during the trial. DHA was used as an indicator of the global aerobic activity. Earthworms had little effect on potential C mineralisation but significantly increased actual net N mineralisation. The increase in N mineralisation in the Vertisol was twice as great as, and longer (6 v. 3 months) than for the Ferralsol. Differences between soils for N mineralisation were associated with a less recalcitrant SOM in the Vertisol. Available P increased 10% in the earthworm treatments. Earthworm activity improved N and P availability. DHA was 15 times higher for the Vertisol than for the Ferralsol, but the positive effect of earthworms on DHA was greater for the Ferralsol. This effect was greater for E. eugeniae, probably because of surface burrows generated by this epigeic earthworm, which favoured oxygen entry into the soil. Differences between the two soils were greater for DHA than for C and N mineralisation, and this was observed for the control soils as well as for the earthworm treatments. This indicates that earthworm activity modified the rate of the aerobic processes but it did not affect the intrinsic biological properties of these tropical soils, which were controlled mainly by SOM quality and C availability.

The representation of the South American Monsoon System (SAMS) by general circulation models (GCMs) is of key relevance for a better understanding of the physical rationale behind the recent climate changes over South Tropical South America (STSA) and their expected changes in a global warming scenario. During the last four decades, STSA experienced a lengthening of the dry season associated with diverse forcings. In this work, a set of 16 GCMs historical Coupled Model Intercomparison Project Phase 6 coupled simulations were evaluated during 1979–2014 in terms of how well they reproduced the atmospheric circulation over STSA through a circulation‐patterns (CPs) approach. Nine CPs were first identified based on low‐level winds from the ERA5 reanalysis. Focus was put on the representation of CPs during the dry‐to‐wet transition season (July‐October). Model performance depended on the seasonal cycle and spatial structure of the CPs. GCMs adequately reproduced the different CPs, with lower skills in the transition seasons. GCMs tended to go from dry to wet conditions too quickly, evidencing deficiencies in the representation of the SAMS onset, related to a poor representation of the southerly wind intrusions to STSA and the variability of the South American low‐level jet. Some GCMs were able to associate the occurrence of anomalous dry and wet years with specific CPs, suggesting well‐represented physical mechanisms controlling precipitation variability. This study could identify a few GCMs that adequately simulated the CPs in STSA (among them, CESM2, CMCC‐CM2‐HR4 and MPI‐ESM1‐2‐HR), which is relevant for driving high‐resolution models and the analysis of future projections. Some general circulation models (GCMs) adequately represented both the seasonal cycle and spatial structure of circulation patternsGCMs often struggled in representing the monsoon initiation and the variability of the South American low‐level jetGCMs tended to go from dry to wet conditions too quickly Some general circulation models (GCMs) adequately represented both the seasonal cycle and spatial structure of circulation patterns GCMs often struggled in representing the monsoon initiation and the variability of the South American low‐level jet GCMs tended to go from dry to wet conditions too quickly