Expression of LRP and MDR1 in locally advanced breast cancer predicts axillary node invasion at the time of rescue mastectomy after induction chemotherapy

BACKGROUND: Axillary node status after induction chemotherapy for locally advanced breast cancer has been shown on multivariate analysis to be an independent predictor of relapse. However, it has been postulated that responders to induction chemotherapy with a clinically negative axilla could be spared the burden of lymphadenectomy, because most of them will not show histological nodal invasion. P-glycoprotein expression in the rescue mastectomy specimen has finally been identified as a significant predictor of patient survival. METHODS: We studied the expression of the genes encoding multidrug resistance associated protein (MDR1) and lung cancer associated resistance protein (LRP) in formalin-fixed, paraffin-embedded tumor samples from 52 patients treated for locally advanced breast cancer by means of induction chemotherapy followed by rescue mastectomy. P-glycoprotein expression was assessed by means of immunohistochemistry before treatment in 23 cases, and by means of reverse-transcriptase-mediated polymerase chain reaction (RT-PCR) after treatment in 46 (6 failed). LRP expression was detected by means of immunohistochemistry, with the LRP-56 monoclonal antibody, in 31 cases before treatment. Immunohistochemistry for detecting the expression of c-erb-B2, p53, Ki67, estrogen receptor and progesterone receptor are routinely performed in our laboratory in every case, and the results obtained were included in the study. All patients had received between two and six cycles of standard 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) chemotherapy, with two exceptions [one patient received four cycles of a docetaxel-adriamycin combination, and the other four cycles of standard cyclophosphamide-methotrexate-5-fluorouracil (CMF) polychemotherapy]. Response was assessed in accordance with the Response Evaluation Criteria In Solid Tumors (RECIST). By these, 2 patients achieved a complete clinical response, 37 a partial response, and the remaining 13 showed stable disease. This makes a total clinical response rate of 75.0%. None achieved a complete pathological response. RESULTS: MDR1 mRNA expression detected by RT-PCR was associated with the presence of invaded axillary nodes at surgery in 18/22 cases (81.8%), compared with 13/24 (54.2%) in the group with undetectable MDR1 expression. This difference was statistically significant (P < 0.05). LRP expression in more than 20% of tumor cells before any treatment was associated with axillary nodal metastasis after chemotherapy and rescue mastectomy in 17/23 cases, compared with 3/8 in nonexpressors. Again, this difference was highly significant (P < 0.01). LRP expression before treatment and MDR1 mRNA expression after treatment were significantly interrelated (P < 0.001), which might reflect the presence of chemoresistant clones liable to metastasize to the regional nodes. Persistence of previously detected MDR1-positivity after treatment (7/9 compared with 0/2 cases) was significantly associated with axillary node metastasis (P < 0.05). Finally, in a logistic regression multivariate model, histology other than ductal, a Ki67 labeling index of at least 20% and the combination of LRP and MDR1 positivity emerged as independent predictors of axillary node invasion at the time of rescue mastectomy. CONCLUSION: The expression of different genes involved in resistance to chemotherapy, both before and after treatment with neoadjuvant, is associated with the presence of axillary node invasion at rescue surgery in locally advanced breast cancer. This might reflect the presence of intrinsically resistant clones before any form of therapy, which persist after it, and could be helpful both for prognosis and for the choice of individual treatment

Serotypes and Stx2 subtyping of Shiga toxin producing Escherichia coli isolates from cattle carcasses and feces

ArticuloShiga toxin E. coli (STEC) is an important pathogen responsible for foodborne illness, this have been related with epidemic outbreaks in the past, mainly because of consumption of bovine meat. The objective of this study was identify the serotypes and Stx2 subtypes and associate them with their possible epidemiology. There were analyzed a total of 65 isolates from the collection of the Centro de Investigación y Estudios Avanzados en Salud Animal, Facultad de Medicina Veterinaria y Zootecnia of the Universidad Autónoma del Estado de México, from carcasses and feces of bovines at three different Municipal slaughterhouses. The identification of Stx2 gene by PCR at final point, sequencing and analyzed with the help of BLAST software. There were found O157:H7, O70:H16, O91:H10, O112ac:H2, O128ac:H26 serotypes, which have been reported to be present at infectious outbreaks previously by foodborne worldwide; 63.07% (41/65) of the Escherichia coli strains got amplified for Stx2 and after BLAS analysis it was confirmed its presence and a hypothetic protein. The presence of this serotypes in combination with different subtype’s, Stx2a, Stx2c, Stx2d, in carcasses and feces of bovine in must be considered as a potential risk for diseases an important problem of the public health

Paraneoplastic Cerebellar Degeneration Secondary to BRAF Mutant Melanoma Metastasis from an Occult Primary Cancer

Melanoma metastasis from an unknown primary cancer has an incidence of 3.2% among melanoma patients. Furthermore, paraneoplastic neurological syndromes (PNS) are rare, occurring in 1-3% of patients with malignancies. Paraneoplastic cerebellar degeneration (PCD) is one of the classic PNS and is characterized by acute or subacute onset of ataxia and/or presence of onconeural antibodies. A 61-year-old male with ataxia, vertigo, and headache later developed dysarthria, multidirectional nystagmus, hyperactive delirium, auditory hallucinations, psychomotor agitation, and myoclonus. Toxicological, metabolic, infectious, and autoimmune etiologies were assessed and reported negative. An osteolytic lesion was observed in the right iliac crest via computed tomography (CT). A positron emission tomography-CT reported increased fluorodeoxyglucose uptake of a right iliac and right inguinal ganglion. After biopsy of the right inguinal ganglion, a BRAF mutation-positive melanoma metastasis from an occult primary cancer was diagnosed. Dermatologic, ophthalmologic, and endoscopic gastrointestinal assessment did not reveal a primary malignant melanoma. The patient's movement disorders and neuropsychiatric symptoms improved with quetiapine, prednisone, azathioprine, and cyclophosphamide. Oncological management was conducted with MAPK pathway inhibitors (i.e., dabrafenib and trametinib). Movement disorders associated with neuropsychiatric symptoms are complex to diagnose. PNS are rare and often associated with antibodies against neural antigens expressed by the tumor. The case presented above describes a patient with a BRAF-positive malignant melanoma metastasis from an occult primary associated with PCD - to the best of our knowledge, the first reported in the literature.</p

Mercury in archaeological human bone: biogenic or diagenetic?

We investigated mercury (Hg) in human bone from archaeological sites in the Iberian Peninsula where the cultural use of cinnabar (HgS) as a pigment, offering or preservative in burial practices has been documented from the 4th to 2nd millennia cal B.C. (Late Neolithic, Copper Age and Bronze Age). Previous analyses have shown high levels of total mercury (THg) in human bone at numerous Neolithic and Chalcolithic sites in this region, but the question remains if this mercury entered the bones via diagenetic processes in the soil, especially where cinnabar powder and paint was found associated with the burials, or if it entered the bone via biogenic pathways from exposure to mercury from using cinnabar in life. We analyzed the humerus, femur, and tibia from a total of 30 individual burials from four Neolithic to Bronze Age sites in Iberia and found low to high values of THg in these bones, with the humerus showing significantly more THg concentrations than other skeletal elements when the THg was greater than 1 ppm. This pattern of Hg deposition in skeletal material from different sites and ages strongly suggests a biogenic origin for the mercury. In addition, absence of detectable Hg in bones with high to low values of THg using SEM EDS analysis further discounts diagenetic intrusion of Hg or cinnabar particles into the bone from the soil. It is likely that greater stress and bone remodeling rates from use of heavy tools and other activities in life are responsible for higher THg in the humerus than other skeletal elements, but additional research is needed to verify this.National Science FoundationNational Science Foundation (NSF) [ECCS-1542174]Spanish GovernmentSpanish Government [HAR2016-78036-P, HAR2016-74846-P, HAR2017-82755-P, HAR2017-83004-P, I + D HAR2017-87324-P]CIAS [PEst-OE/SADG/UI0283/2019]FCTPortuguese Foundation for Science and Technology [PTDC/EPH-ARQ/0798/2014]info:eu-repo/semantics/publishedVersio

Covariation between the shape and mineralized tissues of the rib cross section in Homo sapiens, Pan troglodytes and Sts 14

DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.OBJECTIVES : Studying rib torsion is crucial for understanding the evolution of the hominid ribcage. Interestingly, there are variables of the rib cross section that could be associated with rib torsion and, consequently, with the morphology of the thorax. The aim of this research is to conduct a comparative study of the shape and mineralized tissues of the rib cross section in different hominids to test for significant differences and, if possible, associate them to different thoracic morphotypes. MATERIALS AND METHODS : The sample consists of the rib cross sections at the midshaft taken from 10 Homo sapiens and 10 Pan troglodytes adult individuals, as well as from A. africanus Sts 14. The shape of these rib cross sections was quantified using geometric morphometrics, while the mineralized tissues were evaluated using the compartmentalization index. Subsequently, covariation between both parameters was tested by a Spearman's ρ test, a permutation test and a linear regression. RESULTS : Generally, P. troglodytes individuals exhibit rib cross sections that are rounder and more mineralized compared to those of H. sapiens. However, the covariation between both parameters was only observed in typical ribs (levels 3–10). Although covariation was not found in the rib cross sections of Sts 14, their parameters are closer to P. troglodytes. DISCUSSION : On the one hand, the differences observed in the rib cross sections between H. sapiens and P. troglodytes might be related to different degrees of rib torsion and, consequently, to different thoracic 3D configurations. These findings can be functionally explained by considering their distinct modes of breathing and locomotion. On the other hand, although the rib cross sections belonging to Sts 14 are more similar to those of P. troglodytes, previous publications determined that their overall morphology is closer to modern humans. This discrepancy could reflect a diversity of post-cranial adaptations in Australopithecus.Consejo Superior de Investigaciones Científicas; DST-NRF; Leakey Foundation; Spanish Ministry of Economy, Industry and Competitivity; Spanish Ministry of Science and Innovation.http://wileyonlinelibrary.com/journal/ajpahj2024AnatomySDG-03:Good heatlh and well-bein

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.NIHR HTA Programm

La vid silvestre en México. Actualidades y potencial

En ocho capítulos se aborda el estado del arte de la vid silvestre en MéxicoEl estudio de las especies vegetales nativas de México representa un reto que cada día más investigadores mexicanos asumen. Durante muchos años, el apoyo a la investigación pública ha sido mínimo; desde el punto de vista agronómico es insuficiente para avanzar a la velocidad que requiere nuestro país para afrontar problemas de producción y distribución de alimentos. Por esa razón, entre otras, me es grato presentar esta obra que compila parte de los trabajos de la Red de Vid Silvestre patrocinada por el Sistema Nacional de Recursos Fitogenéticos (sinarefi) dependiente de la sagarpa; trabajos apuntalados por investigadores que sin pertenecer a la red han colaborado en el estudio de las plantas del género Vitis. En este libro se muestra el potencial del país para aprovechar el recurso vid, empleado desde antes de la conquista española por nativos mexicanos que conocían sus bondades. Es necesario continuar el avance en el conocimiento de este recurso, por ello el presente libro pretende invitar a toda persona interesada en contribuir con el rescate y conservación de las vides mexicanas. Los autores y editores, así como las instituciones en donde laboramos y aquellas que patrocinan estas investigaciones, esperamos se cumpla este objetivo y que el lector, alumno, profesor, investigador, público en general, disfrute esta lectura y, sobre todo, se interese en el recurso VitisSEP, SINAREFI, UAEME

Modulation of KV4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2

The transient outward potassium current (Itof) is generated by the activation of KV4 chan- nels assembled with KChIP2 and other accessory subunits (DPP6 and KCNE2). To test the hypothesis that these subunits modify the channel pharmacology, we analyzed the electrophysiological effects of (3-(2-(3-phenoxyphenyl)acetamido)-2-naphthoic acid) (IQM-266), a new KChIP2 ligand, on the currents generated by KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (KV4.3/KChIP2, KV4.3/KChIP2/DPP6 or KV4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 currents, slowing their time course of inactivation in a concentration-, voltage-, time- and use-dependent manner. IQM-266 produced an increase in the charge in KV4.3/KChIP2 channels that was intensified when DPP6 was present and abolished in the presence of KCNE2. IQM-266 induced an activation unblocking effect during the applica- tion of trains of pulses to cells expressing KV4.3/KChIP2 and KV4.3/KChIP2/KCNE2, but not in KV4.3/KChIP2/DPP6 channels. Overall, all these results are consistent with a preferential IQM-266 binding to an active closed state of Kv4.3/KChIP2 and Kv4.3/KChIP2/KCNE2 channels, whereas in the presence of DPP6, IQM-266 binds preferentially to an inactivated state. In conclusion, DPP6 and KCNE2 modify the pharmacological response of KV4.3/KChIP2 channels to IQM-266.This publication is the results of the: Grants SAF2016-75021-R (to C.V.), RTI2018-097189-B- C22 (to M.M.-M.) and BIO2017-89523-R (to A.A.) funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”; Grants PID2019-104366RB-C21 (to C.V.), PID2019-104366RB- C22 (to M.G.-R.), PID2020-114256RB-I00 (to A.O. and J.A.G.-V.), PID2020-119805RB-I00 (to A.A.) funded by MCIN/AEI/10.13039/501100011033; Grant A-FQM-386-UGR20 funded by FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento (to J.A.G.-V.); Grant CB/11/00222 funded by Instituto de Salud Carlos III CIBERCV (to C.V.); Grants PIE202180E073 (to M.M.-M. and M.G.-R.), PIE201820E104 and 2019AEP148 (to C.V.) funded by Consejo Superior de Investigaciones Científicas. Grants BES-2017-080184 (to A.d.B.-B.), BES-2010-036573 (to P.C.), PRE2018- 083280 (to M.D.-M.) and RYC2018-023837-I (to A.P.-L.) funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”; Grant FPU17/02731 (to P.G.S.) funded by Ministerio de Ciencia e Innovación.Peer reviewe

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN