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Purpose: Molecular subtyping based on gene expression profiling (i.e., PAM50 assay) aids in determining the prognosis and treatment of breast cancer (BC), particularly in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors, where luminal A and B subtypes have different prognoses and treatments. Several surrogate classifications have been proposed for distinguishing between the luminal A and B subtypes. This study determines the accuracy of local immunohistochemistry (IHC) techniques for classifying HR-positive/HER2-negative (HR+/HER2−) tumors according to intrinsic subtypes using the nCOUNTER PAM50 assay as reference and the HR status definition according the ASCO/CAP recommendations. Methods: Molecular subtypes resulting from nCOUNTER PAM50 performed in our laboratory between 2014 and 2020 were correlated with three different proxy surrogates proposed in the literature based on ER, PR, HER2, and Ki67 expression with different cut-off values. Concordance was measured using the level of agreement and kappa statistics. Results: From 1049 samples with the nCOUNTER test, 679 and 350 were luminal A and B subtypes, respectively. Only a poor-to-fair correlation was observed between the three proxy surrogates and real genomic subtypes as determined by nCOUNTER PAM50. Moreover, 5–11% and 18–36% of the nCOUNTER PAM50 luminal B and A tumors were classified as luminal A and B, respectively, by these surrogates. Conclusion: The concordance between luminal subtypes determined by three different IHC-based classifiers and the nCOUNTER PAM50 assay was suboptimal. Thus, a significant proportion of luminal A and B tumors as determined by the surrogate classifiers could be undertreated or over-treated. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations. [ABSTRACT FROM AUTHOR]

This work presents a new method for assisting in the identification process of missing persons in several contexts, such as enforced disappearances. We apply a Bayesian technique to incorporate non-genetic variables in the construction of prior information. In that way, we can learn from the already-solved cases of a particular mass event of death, and use that information to guide the search among remaining victims. This paper describes a particular application to the proposed method to the identification of human remains of the so-called disappeared during the last dictatorship in Argentina, which lasted from 1976 until 1983. Potential applications of the techniques presented hereby, however, are much wider. The central idea of our work is to take advantage of the already-solved cases within a certain event to use the gathered knowledge to assist in the investigation process, enabling the construction of prioritized rankings of victims that could correspond to each certain unidentified human remains. [ABSTRACT FROM AUTHOR]

The most general Lagrangian describing spin 2 particles in flat spacetime and containing operators up to (mass) dimension 6 is carefully analyzed, determining the precise conditions for it to be invariant under linearized (transverse) diffeomorphisms, linearized Weyl rescalings, and conformal transformations. [ABSTRACT FROM AUTHOR]

A general approach to Bayesian isotonic changepoint problems is developed. Such isotonic changepoint analysis includes trends and other constraint problems and it captures linear, non-smooth as well as abrupt changes. Desired marginal posterior densities are obtained using a Markov chain Monte Carlo method. The methodology is exemplified using one simulated and two real data examples, where it is shown that our proposed Bayesian approach captures the qualitative conclusion about the shape of the trend change. [ABSTRACT FROM AUTHOR]

To investigate the pharmacological properties of the CR011-vcMMAE fully human antibody–drug conjugate (ADC), such as dose titrations, quantitation of the time (days) to complete regression, pharmacokinetics, and schedule dependency. Our prior study characterized a fully human antibody to GPNMB covalently linked to monomethylauristatin E, CR011-vcMMAE, and further demonstrated cell surface staining of melanoma lines susceptible to the immunoconjugate’s cytotoxicity (Clin Cancer Res 2005; 12(4): 1373–1382). The human SK-MEL-2 and SK-MEL-5 melanoma xenografts were used in athymic mice to assess anti-tumor efficacy. After s.c. implantation, tumors became established (60–100 mg), and treatment commenced by i.v. injection of the immunoconjugate or vinblastine or paclitaxel. Short-term anti-tumor effects (inhibition of tumor growth) and long-term effects (complete regression) were observed. CR011-vcMMAE induced regression of established human SK-MEL-2 and SK-MEL-5 xenografts at doses from 1.25 to 80 mg/kg treatment when administered intravenously every 4 days (4 treatments); strikingly, regressions were not associated with re-growth during the observation period (200 days). The disappearance rate of implants was dose dependent (minimum time, 18.5 days). Detectable serum CR011-vcMMAE ≥1 μg/mL (∼0.01 μM) was observed for >30 days post-dose; CR011-vcMMAE showed an elimination half-life of 10.3 days. A low volume of distribution suggested that CR011-vcMMAE was confined to blood and interstitial fluid. CR011-vcMMAE could be delivered by either a single bolus dose or by intermittent dosing (i.e., every 1, 2, 4, 8, or 16 days) with no discernible differences in the proportion of tumor-free survivors, indicating a lack of schedule dependency. The antibody–drug conjugate produced complete regressions, but the equivalent doses of free monomethylauristatin E or unconjugated antibody did not show anti-tumor effects. In addition, decreases in plasma tumor-derived human interleukin-8 coincided with tumor nodule disappearance. Short-term anti-tumor effects and long-term effects (complete regression) were observed with CR011-vcMMAE, but not with the reference agents. These results suggest that CR011-vcMMAE may provide therapeutic benefit in malignant melanoma. [ABSTRACT FROM AUTHOR]

Consider a process in which different events occur, with random inter-occurrence times. In Markov renewal processes as well as in semi-Markov processes, the sequence of events is a Markov chain and the waiting distributions depend only on the types of the last and the next event. Suppose that the state-space is finite and that the process started far in the past, achieving stationary. Weibull distributions are proposed for the waiting times and their parameters are estimated jointly with the transition probabilities through maximum likelihood, when one or several realizations of the process are observed over finite windows. The model is illustrated with data of earthquakes of three types of severity that occurred in Turkey during the 20th century. [ABSTRACT FROM AUTHOR]

Marigold flowers are the main natural source of xanthophylls, and marigold saponified extract is used as an additive in several food and pharmaceutical industries. In this work, the use of a solid-state fermentation (ensilage) process for increasing the yield of xanthophylls extracted from fermented marigold flowers was examined. The process consisted of a mixed culture of three microorganisms (Flavobacterium IIb,Acinetobacter anitratus, andRhizopus nigricans), part of the normal microbiota associated with the marigold flower. These microorganisms had been previously isolated, and were identified as relevant for the ensilage process due to their capacity to produce cellulolytic enzymes. Based on experimental design strategies, optimum operation values were determined for aeration, moisture, agitation, and marigold-to-inoculum ratio in the proposed solid-state fermentation equipment, leading to a xanthophylls yield of 17.8-g/kg dry weight. The optimum achieved represents a 65% increase with respect to the control. HPLC analysis indicated conservation of extracted oleoresin. Based on the experimental results, interactions were identified that could be associated with the heat and mass-transfer reactions taking place within the bioreactor. The insight gained allows conditions that limit growth and metabolic activity to be avoided. [ABSTRACT FROM AUTHOR]

Ornithine decarboxylase from respiratory fungal pathogen, Coccidioides immitis, cloned in the pETCiODC plasmid under control of T7lac promoter, was produced in E. coli BL21(DE3), BL21(DE3)pLysS, BLR(DE3) and EWH319 transformant strains. E. coli BL21(DE3)pLysS-pETCiODC expressed the highest specific activity of ODC, suggesting that this strain could be successfully used for protein structure and drug testing studies. [ABSTRACT FROM AUTHOR]

In cell culture, the compound317615.2HCl, a potent inhibitor ofVEGF-stimulated HUVEC proliferation, wasnot very effective against MX-1 breastcancer cells (IC50 = 8.1 μM) orSKOV-3 ovarian carcinoma cells (IC50 =9.5 μM). Exposure to combinations ofpaclitaxel or carboplatin and317615.2HCl with MX-1 cells in cultureresulted in cell survival that reflectedprimarily additivity of the two agents.Exposure of SKOV-3 cells to paclitaxel orcarboplatin along with 317615.2HClresulted in cell survivals that reflectedadditivity of 317615.2HCl withpaclitaxel and greater-than-additivecytotoxicity with carboplatin.Administration of 317615.2HCl orallytwice daily to nude mice bearingsubcutaneous MX-1 tumors or SKOV-3 tumorsresulted in a decreased number ofintratumoral vessels as determined by CD31and CD105 staining with decreases of 35%and 43% in MX-1 tumors and 60% and 75%in SKOV-3 tumors, respectively.317615.2HCl was an active antitumoragent against the MX-1 xenograft andincreased the tumor growth delay producedby paclitaxel by 1.7-fold and the tumorgrowth delay produced by carboplatin by3.8-fold. Administration of317615.2HCl also increased the tumorgrowth delay produced by fractionatedradiation therapy in the MX-1 tumor.Treatment with 317615.2HCl aloneincreased the lifespan of animals bearingintraperitoneal SKOV-3 xenografts by 1.9fold compared with untreated controlanimals. The combination of paclitaxel and317615.2HCl resulted in 100% 120-daysurvival of SKOV-3 bearing animals.Administration of 317615.2HCl alongwith carboplatin to animals bearing theSKOV-3 tumor produced a 1.8-fold increasein lifespan compared with carboplatinalone. 317615.2HCl is a promising newantiangiogenic agent that is in early phaseclinical testing. [ABSTRACT FROM AUTHOR]

Background: Protein kinase C frequently plays a central role in the intracellular signal transduction of growth factors and cytokines.Methods: The acyclic bisindolylmaleimide 317615 x 2HCl was identified as a potent selective inhibitor of protein kinase Cbeta. The compound 317615 x 2HCl was tested in culture and in vivo in the rat corneal micropocket and in the SW2 small-cell lung carcinoma human tumor xenograft.Results: In cell culture, 317615 x 2HCl was a more potent inhibitor of VEGF-stimulated HUVEC proliferation (IC50 150 nM, 72 h) than of human SW2 small-cell lung carcinoma cell proliferation (IC50 3.5 microM, 72 h). When administered orally twice daily for 10 days, the compound 317615 x 2HCl markedly decreased the neoangiogenesis induced by VEGF or bFGF in the rat corneal micropocket assay. To assess antitumor efficacy, 317615 x 2HCl was administered orally twice daily to nude mice bearing SW2 xenograft tumors on days 14 through 30 after tumor implantation. The number of countable intratumoral vessels was decreased in a dose-dependent manner reaching as low as one-quarter the number in the control tumors. The decrease in intratumoral vessels was paralleled by increases in tumor growth delay. Treatment of the tumor-bearing animals with paclitaxel or carboplatin followed by treatment with 317615 x 2HCl resulted in a 2.5- to 3.0-fold increase in tumor growth delay compared with the standard chemotherapeutic agents alone.Conclusions: 317615 x 2HCl represents a new approach to antiangiogenic therapy in cancer-blocking multiple growth factor signaling pathways in endothelial cells with a single agent. 317615 x HCl is in early clinical testing. [ABSTRACT FROM AUTHOR]

In cell culture, the compound 317615.2HCl, a potent inhibitor of VEGF-stimulated HUVEC proliferation, was not very effective against Calu-6 non-small-cell lung carcinoma cells (IC50 26 microM). Exposure to combinations of paclitaxel or carboplatin and 317615.2HCl with Calu-6 cells in culture resulted in cell survival that reflected less-than-additivity to additivity of the two agents. Administration of 317615.2HCl orally twice daily to nude mice bearing subcutaneous Calu-6 tumors resulted in a decreased number of intratumoral vessels as determined by CD31 and CD105 staining to 50% of the number in control tumors. 317615.2HCl showed antitumor activity against the Lewis lung carcinoma and increased the tumor growth delay produced by paclitaxel by 5-fold, that produced by gemcitabine by 2-fold and that produced by carboplatin by 1.7-fold. There was a decrease in the number of lung metastases in the Lewis lung carcinoma that paralleled the increased response of the primary tumor with each treatment combination. Administration of 317615.2HCl also increased the tumor growth delay produced by fractionated radiation therapy in the Lewis lung tumor. Treatment with 317615.2HCl was an effective therapy in the Calu-6 non-small-cell lung carcinoma xenograft when the compound was administered early (days 4-18) or later (days 14-30). Combination treatment regimens in which 317615.2HCl was administered along with or sequentially with paclitaxel or carboplatin were much more effective than the chemotherapeutic agents administered alone. 317615.2HCl is in early clinical testing. [ABSTRACT FROM AUTHOR]

Introduction/Purpose: Cryptophycins are a family of antitubulin antitumor agents. A synthetic cryptophycin derivative (LY355703, CRYPTO 52) is in early clinical evaluation. The effect of infusion time on the antitumor activity of four cryptophycins was assessed in rats bearing the 13762 mammary carcinoma and combination treatment regimens were assessed in nude mice bearing human tumor xenografts. Methods: The cryptophycins were prepared in 2% PEG300/8% cremophor/90% normal saline and delivered by jugular vein catheter on days 7, 9 and 11 post tumor implant to 13762 tumor-bearing rats. The cryptophycins prepared in the same formulation were administered by intravenous bolus injection on an alternate day schedule for five doses to human tumor xenograft bearing nude mice. Results: An infusion time of 2 h in the rats increased the tumor growth delay produced by CRYPTO 52 and CRYPTO 55, while increasing the infusion time to 6 h continued to increase the tumor growth delay for CRYPTO 292 and CRYPTO 296. Administering CRYPTO 292 at a higher dose two times was more effective than administering it at a lower dose three times. The tumor growth delays produced by the cryptophycins in the rat 13762 mammary carcinoma were greater than those with cisplatin, doxorubicin, 5-fluorouracil and 5 × 3 Gray and comparable with cyclophosphamide and gemcitabine. Combination studies were carried out in human tumor xenografts including the MX-1 breast carcinoma, the Calu-6 non-small cell lung carcinoma, the H82 small cell lung carcinoma and the SW-2 small cell lung carcinoma. CRYPTO 52 and CRYPTO 55 combined with doxorubicin, paclitaxel and 5-fluorouracil to form highly effective regimens against the human MX-1 breast carcinoma. CRYPTO 52 and CRYPTO 55 were also highly effective against the three lung carcinoma xenografts when combined with the antitumor platinum complexes, cisplatin, carboplatin or oxaliplatin. Conclusions: Cryptophycins represent a promising new class of antitumor agents that may be optimally administered by intravenous infusion and in combination with doxorubicin, paclitaxel and 5-fluorouracil. [ABSTRACT FROM AUTHOR]

A non zero probability amplitude for the appearance of a multidimensional universe of (1+ d) dimensions is found. This can happen either in a 'symmetric phase', in which all dimensions are in an exponential expansion, or else in a 'broken phase', with d dimensions inflating exponentially and d forming a sphere of constant radius. The value of these amplitude for different total number of dimensions is discussed, and so physical consequences for Kaluza-Klein cosmologies are drawn. [ABSTRACT FROM AUTHOR]

We have recently undergone an analysis of gravitational theories as defined in first order formalism, where the metric and the connection are treated as independent fields. The physical meaning of the connection field has historically been somewhat elusive. In this paper, a complete spin analysis of the torsionless connection field is performed, and its consequences are explored. The main properties of a hypothetical consistent truncation of the theory are discussed as well. [ABSTRACT FROM AUTHOR]

Based on the quasi-local energy definition of Brown and York, we compute the integral of the trace of the extrinsic curvature over a codimension-2 hypersurface. In particular, we study the difference between the uncompactified Minkowski spacetime and the toroidal Kaluza-Klein compactification. For the latter, we find that this quantity interpolates between zero and the value for the uncompactified spacetime, as the size of the compact dimension increases. Thus, the quasi-local energy is able to discriminate between the two spacetimes. [ABSTRACT FROM AUTHOR]

This is the written version of a set of introductory lectures to string theory. The lectures were given at the Universidad Autónoma de Madrid in the semester 1997/98 and at the VI Escuela de Otoño de Física Teórica, held in Santiago de Compostela (10-23 september 1998). [ABSTRACT FROM AUTHOR]