Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients ...retrieved from lung cancer registries is scarce. This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed. With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or greater than or equal to 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8-10.2 months), with an estimated rate of 70.3% (95% CI 67.2-73.4%), 38.9% (95% CI 35.4-42.4%), and 14.8% (95% CI 11.8-17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1-2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis. This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.
Key message
Strong genetic correlations were observed between Pilodyn measurement and wood density, and between acoustic velocity and MFA. Combination of Pilodyn penetration and acoustic velocity ...measurements from standing trees can provide reliable prediction of stiffness of Norway spruce for breeding selection.
Context
Traditional methods for the estimation of solid wood quality traits of standing tree such as wood density, microfibril angle (MFA), and modulus of elasticity (MOE) are time-consuming and expensive, which render them unsuitable for rapidly screening a large number of trees in tree breeding programs.
Aim
This study aims to evaluate the suitability of using Pilodyn penetration and acoustic velocity (nondestructive evaluation) to assess wood density, MFA, and MOE for Norway spruce.
Methods
Pilodyn penetration and Hitman acoustic velocity, as well as wood density, MFA, and MOE using benchmark SilviScan were measured on 5618 standing trees of 524 open-pollinated families in two 21-year-old Norway spruce (
Picea abies
) progeny trials in southern Sweden.
Results
Strong genetic correlations were observed between Pilodyn measurement and wood density (
r
g
= −0.96), and between acoustic velocity and MFA (
r
g
= −0.94). Combination of Pilodyn penetration and Hitman acoustic velocity measurements (
M
O
E
A
V
2
+
Pilo
) obtained from standing trees showed a genetic correlation with benchmark MOE of 0.99. This combined
M
O
E
A
V
2
+
Pilo
had higher selection efficiency for benchmark MOE (92 %) compared to 58–60 % using acoustic velocity alone and 78 % using Pilodyn penetration alone.
Conclusion
Combination of Pilodyn penetration with Hitman acoustic velocity provided very high selection efficiency for the three most important quality traits for wood mechanical properties in Norway spruce.
Paclitaxel, better known as the anticancer drug Taxol
®
, has been isolated from several plant species and has been shown to be produced by fungi, actinomycetes, and even bacteria isolated from ...marine macroalgae. Given its cytostatic effect, studies conducted in the 1990's showed that paclitaxel was toxic to many pathogenic fungi and oomycetes. Further studies led to the idea that the differences in paclitaxel sensitivity exhibited by different fungi were due to differences in the β-tubulin protein sequence. With the recent isolation of endophytic fungi from the leaves and bark of the Himalayan Yew,
Taxus wallichiana
Zucc., and the availability of genomes from paclitaxel-producing fungi, we decided to further explore the idea that endophytic fungi isolated from Yews should be well-adapted to their environment by encoding β-tubulin proteins that are insensitive to paclitaxel. Our results found evidence of episodic positive/diversifying selection at 10 sites (default
p
-value threshold of 0.1) in the β-tubulin sequences, corresponding to codon positions 33, 55, 172, 218, 279, 335, 359, 362, 379, and 406. Four of these positions (i.e., 172, 279, 359, and 362) have been implicated in the binding of paclitaxel by β-tubulin or formed part of the binding pocket. As expected, all the fungal endophytes grew in different media regardless of the paclitaxel concentration tested. Furthermore, our results also showed that
Taxomyces andreanae
CBS 279.92, the first fungus shown to produce paclitaxel, is a Basidiomycete fungus as the two beta tubulins encoded by the fungus clustered together with other Basidiomycete fungi.
Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing ...number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals. This situation prompted us to investigate two ALK IHC antibodies (using a novel ultrasensitive detection-amplification kit) and an automated ALK FISH scanning system (FDA-cleared) in a series of non-small cell lung cancer tumor samples.
Forty-seven ALK FISH-positive and 56 ALK FISH-negative NSCLC samples were studied. All specimens were screened for ALK expression by two IHC antibodies (clone 5A4 from Novocastra and clone D5F3 from Ventana) and for ALK rearrangement by FISH (Vysis ALK FISH break-apart kit), which was automatically captured and scored by using Bioview's automated scanning system.
All positive cases with the IHC antibodies were FISH-positive. There was only one IHC-negative case with both antibodies which showed a FISH-positive result. The overall sensitivity and specificity of the IHC in comparison with FISH were 98% and 100%, respectively.
The specificity of these ultrasensitive IHC assays may obviate the need for FISH confirmation in positive IHC cases. However, the likelihood of false negative IHC results strengthens the case for FISH testing, at least in some situations.
Among animal phyla, some of the least studied nervous systems are those of the phylum Echinodermata. Part of the problem lies in that most of their nervous components are embedded in the body wall ...that has calcareous skeletal components.
We have developed a novel technique for the successful isolation of the radial nerve cords (RNCs) and an in vitro system where the isolated RNCs can be cultured and are amenable to experimental manipulation. Here we use this system to isolate the RNC of the sea cucumber Holothuria glaberrima as a way to extend our studies on its regeneration capabilities.
The RNCs can be isolated from the surrounding tissues by collagenase treatment. The explants obtained following enzymatic dissociation can be kept in culture for up to 2 weeks. Histological and immunohistochemical studies show that the explants maintain a stable number of cells with little proliferation or apoptosis throughout the culture incubation period. The main change observed in RNCs in vitro is a progressive dedifferentiation of radial glia-like cells. This dedifferentiation corresponds to the first step in the regeneration response to injury that has been described in vivo.
There are no existing methods to isolate and culture echinoderm radial nerve cord.
The described protocol provides a unique tool to obtain easily accessible RNC from holothurians to perform cellular, biochemical, and genomic experiments in the echinoderm nervous system without interference of adjacent tissues. The technique provides a unique opportunity to study the dedifferentiation response associated with the regeneration of the nervous system in echinoderms.
•Reliable dissection technique for successful isolation of the radial nerve cord.•In vitro system where isolated radial nerve cords can be cultured.•Cultured RNCs undergo low cell proliferation and cell death in vitro.•Progressive dedifferentiation of radial glia-like cells in the cultured explants.
El artículo surge de la investigación artística “Retrarelatos de un parto olvidado” realizada con 48 madres chilenas que iban relatando sus vivencias del parto y resignificándolas de manera ...relacional y mediada. Este espacio de mediación artística configuró un espacio libre y de reconocimiento, donde pudieron problematizar sus vivencias. Se destaca la categoría de empoderamiento, donde se puede observar el impulso de cuestionar lo vivido desde sus propias necesidades, desnaturalizando la violencia e irrumpiendo las barreras que no les permiten tomar decisiones de sus propios partos. Al problematizar la experiencia desde la creación artística como mediación, se transforman las subjetividades y se superpone al parto en una esfera política para su agenciamiento. La reconfiguración de subjetividades femeninas da lugar a la discusión pública del parto como un espacio necesitado de responsabilidad social desde las artes.
The article arises from the artistic investigation “Portraits of a forgotten childbirth” carried out with 48 Chilean mothers who were recounting their experiences of childbirth and resignifying them in a relational and mediated way. This space of artistic mediation configured a free space and of recognition, where they could problematize their experiences. The empowerment category stands out, where the impulse to question what has been experienced from their own needs can be observed, denaturing violence, and breaking through the barriers that do not allow them to make decisions about their own births. By problematizing the experience from artistic creation as mediation, subjectivities are transformed, and birth is superimposed in a political sphere for its assemblage. The reconfiguration of female subjectivities gives rise to the public discussion of childbirth as a space in need of social responsibility from the arts.
O artigo surge da investigação artística “Retratos de um parto esquecido” realizada com 48 mães chilenas que contavam suas experiências de parto e as ressignificavam de forma relacional e mediada. Este espaço de mediação artística configurou um espaço livre e de reconhecimento, onde puderam problematizar suas vivências. Destaca-se a categoria empoderamento, onde se observa o impulso de questionar o que foi vivenciado a partir de suas próprias necessidades, desnaturando a violência e rompendo as barreiras que os impedem de tomar decisões sobre o próprio nascimento. Ao problematizar a experiência da criação artística como mediação, as subjetividades se transformam e o nascimento se sobrepõe em uma esfera política para seu agenciamento. A reconfiguração das subjetividades femininas suscita a discussão pública do parto como um espaço carente de responsabilidade social das artes.
Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable ...oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.
Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK‐Is) ultimately progress due to development of ...resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next‐generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK‐positive NSCLC patients at disease progression to an ALK‐I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first‐ and second‐generation ALK‐Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non‐V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK‐Is. Potential ALK‐I‐resistance mutations were also found in PIK3CA and IDH2. Finally, a c‐MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first‐line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK‐I‐resistance mutations in most cases and could be a valuable approach for therapy decision making.
Despite impressive and durable responses, nonsmall cell lung cancer patients treated with ALK inhibitors (ALK‐Is) ultimately progress due to the development of resistance mechanisms. In this study, we show that next‐generation sequencing (NGS) analysis of liquid biopsies upon disease progression is feasible and informative as it can identify different mechanisms underlying resistance to ALK‐Is by NGS profiling of ctDNA.
Introduction
The immediate breast reconstruction after mastectomy has gained prominence in recent years and is considered one of the main procedures in oncoplastic surgery. In the case of ...reconstruction with prostheses, the use of a mesh to extend the pectoralis major muscle is often required to partially cover the implant. The main objective of this study was to determine the percentage of complications in immediate breast reconstructions with a titanized mesh using a dual-plane approach and establish risk factors for prosthesis complications and extrusion.
Materials and Methods
A retrospective study that included women who received postmastectomy reconstructions from January 2012 to December 2019 in a secondary hospital in Spain.
Results
A total of 57 immediate reconstructions were performed in 47 women. There were complications in 16 mastectomies (28.1%), of which seven (12.3%) were Clavien-Dindo ≤ IIIa and nine (15.7%) were IIIb. A total of three patients presented prosthetic extrusion, and the prosthesis was removed in five. The degree of contracture according to the Baker scale was I–II in 50 mastectomies (87.7%) and III–IV in seven (12.3%).
Conclusion
The immediate breast reconstruction with a titanized mesh using a dual-plane approach is a technique with an acceptable percentage of complications. The need for a Wise pattern and the necrosis of the nipple-areola complex in the postoperative period are risk factors for implant loss. Patients undergoing radiotherapy and/or chemotherapy and with a previous surgery are more likely to present capsular contracture.
Level of Evidence IV
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors.
Genetic control of tree growth and wood formation varies depending on the age of the tree and the time of the year. Single-locus, multi-locus, and multi-trait genome-wide association studies (GWAS) ...were conducted on 34 growth and wood property traits in 1,303 Norway spruce individuals using exome capture to cover ~130K single-nucleotide polymorphisms (SNPs). GWAS identified associations to the different wood traits in a total of 85 gene models, and several of these were validated in a progenitor population. A multi-locus GWAS model identified more SNPs associated with the studied traits than single-locus or multivariate models. Changes in tree age and annual season influenced the genetic architecture of growth and wood properties in unique ways, manifested by non-overlapping SNP loci. In addition to completely novel candidate genes, SNPs were located in genes previously associated with wood formation, such as cellulose synthases and a NAC transcription factor, but that have not been earlier linked to seasonal or age-dependent regulation of wood properties. Interestingly, SNPs associated with the width of the year rings were identified in homologs of
BARELY ANY MERISTEM 1 and rice BIG GRAIN 1, which have been previously shown to control cell division and biomass production. The results provide tools for future Norway spruce breeding and functional studies.
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