The ability of cells to follow gradients of extracellular matrix stiffness—durotaxis—has been implicated in development, fibrosis, and cancer. Here, we found multicellular clusters that exhibited ...durotaxis even if isolated constituent cells did not. This emergent mode of directed collective cell migration applied to a variety of epithelial cell types, required the action of myosin motors, and originated from supracellular transmission of contractile physical forces. To explain the observed phenomenology, we developed a generalized clutch model in which local stick-slip dynamics of cell-matrix adhesions was integrated to the tissue level through cell-cell junctions. Collective durotaxis is far more efficient than single-cell durotaxis; it thus emerges as a robust mechanism to direct cell migration during development, wound healing, and collective cancer cell invasion.
The primary objective of this study was to analyse the current accuracy of targeted and systematic prostate biopsies in detecting csPCa. A secondary objective was to determine whether there are ...factors predicting the finding of csPCa in targeted biopsies and, if so, to explore the utility of a predictive model for csPCa detection only in targeted biopsies. We analysed 2122 men with suspected PCa, serum PSA > 3 ng/mL, and/or a suspicious digital rectal examination (DRE), who underwent targeted and systematic biopsies between 2021 and 2022. CsPCa (grade group 2 or higher) was detected in 1026 men (48.4%). Discrepancies in csPCa detection in targeted and systematic biopsies were observed in 49.6%, with 13.9% of csPCa cases being detected only in systematic biopsies and 35.7% only in targeted biopsies. A predictive model for csPCa detection only in targeted biopsies was developed from the independent predictors age (years), prostate volume (mL), PI-RADS score (3 to 5), mpMRI Tesla (1.5 vs. 3.0), TRUS-MRI fusion image technique (cognitive vs. software), and prostate biopsy route (transrectal vs. transperineal). The csPCa discrimination ability of targeted biopsies showed an AUC of 0.741 (95% CI 0.721–0.762). The avoidance rate of systematic prostate biopsies went from 0.5% without missing csPCa to 18.3% missing 4.6% of csPCa cases. We conclude that the csPCa diagnostic accuracy of targeted biopsies is higher than that of systematic biopsies. However, a significant rate of csPCa remains detected only in systematic biopsies. A predictive model for the partial omission of systematic biopsies was developed.
Concerns exist regarding the effects of 5-alpha reductase inhibitors (5-ARIs) on multipa-rametric magnetic resonance imaging (mpMRI) and clinically significant prostate cancer (csPCa) detection. Our ...objective is to analyze the effect of 5-ARI on the prostate imaging-reporting and data system (PI-RADS) distribution and csPCa and insignificant PCa (iPCa) detection. Among 2212 men with serum prostate-specific antigen levels of >3.0 ng/mL and/or suspicious digital rectal examinations who underwent mpMRI and targeted and/or systematic biopsies, 120 individuals exposed to 5-ARI treatment for over a year were identified. CsPCa was defined when the grade group (GG) was >2. The overall csPCa and iPCa detection rates were 44.6% and 18.8%, respectively. Since logistic regression revealed independent predictors of PCa, a randomized matched group of 236 individuals was selected for analysis. The PI-RADS distribution was comparable with 5-ARI exposure (
0.685). The CsPCa detection rates in 5-ARI-naïve men and 5-ARI-exposed men were 52.6% and 47.4%, respectively (
0.596). IPCa was detected in 37.6 and 62.5%, respectively (
0.089). The tumor GG distribution based on 5-ARI exposure was similar (
0.149) to the rates of csPCa and iPCa across the PI-RADS categories. We conclude that exposure to 5-ARI in suspected PCa men did not change the PI-RADS distribution and the csPCa and iPCa detection rates.
Physical rehabilitation plays a crucial role in restoring motor function following injuries or surgeries. However, the challenge of overcrowded waiting lists often hampers doctors’ ability to monitor ...patients’ recovery progress in person. Deep Learning methods offer a solution by enabling doctors to optimize their time with each patient and distinguish between those requiring specific attention and those making positive progress. Doctors use the flexion angle of limbs as a cue to assess a patient’s mobility level during rehabilitation. From a Computer Vision perspective, this task can be framed as automatically estimating the pose of the target body limbs in an image. The objectives of this study can be summarized as follows: (i) evaluating and comparing multiple pose estimation methods; (ii) analyzing how the subject’s position and camera viewpoint impact the estimation; and (iii) determining whether 3D estimation methods are necessary or if 2D estimation suffices for this purpose. To conduct this technical study, and due to the limited availability of public datasets related to physical rehabilitation exercises, we introduced a new dataset featuring 27 individuals performing eight diverse physical rehabilitation exercises focusing on various limbs and body positions. Each exercise was recorded using five RGB cameras capturing different viewpoints of the person. An infrared tracking system named OptiTrack was utilized to establish the ground truth positions of the joints in the limbs under study. The results, supported by statistical tests, show that not all state-of-the-art pose estimators perform equally in the presented situations (e.g., patient lying on the stretcher vs. standing). Statistical differences exist between camera viewpoints, with the frontal view being the most convenient. Additionally, the study concludes that 2D pose estimators are adequate for estimating joint angles given the selected camera viewpoints.
Prochlorococcus is responsible for a significant part of CO ₂ fixation in the ocean. Although it was long considered an autotrophic cyanobacterium, the uptake of organic compounds has been reported, ...assuming they were sources of limited biogenic elements. We have shown in laboratory experiments that Prochlorococcus can take up glucose. However, the mechanisms of glucose uptake and its occurrence in the ocean have not been shown. Here, we report that the gene Pro1404 confers capability for glucose uptake in Prochlorococcus marinus SS120. We used a cyanobacterium unable to take up glucose to engineer strains that express the Pro1404 gene. These recombinant strains were capable of specific glucose uptake over a wide range of glucose concentrations, showing multiphasic transport kinetics. The K ₛ constant of the high affinity phase was in the nanomolar range, consistent with the average concentration of glucose in the ocean. Furthermore, we were able to observe glucose uptake by Prochlorococcus in the central Atlantic Ocean, where glucose concentrations were 0.5–2.7 nM. Our results suggest that Prochlorococcus are primary producers capable of tuning their metabolism to energetically benefit from environmental conditions, taking up not only organic compounds with key limiting elements in the ocean, but also molecules devoid of such elements, like glucose.
Colorectal cancer is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die ...from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide (NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors.
Ectopic overexpression of nicotinamide phosphoribosil transferase (
) and shRNAs in colorectal cancer cell lines, tumorigenic and stemness properties and transcription measurement in culture and
Transcriptional analysis in public databases. Therapeutic approaches.
NAMPT, the rate-limiting enzyme responsible for the highest source of physiologic NAD biosynthesis, increases tumorigenic properties and induces cancer stem cell-like properties through pathways that control stem cell signaling, thus enriching the cancer-initiating cell (CIC) population. Furthermore,
expression correlated with high levels of CIC-like cells in colon tumors directly extracted from patients, and transcription meta-analysis revealed that NAMPT is also a key factor that induces cancer stem pathways in colorectal cancer tumors. This effect is mediated by PARP and SIRT1. In addition, we report a novel
-driven signature that stratifies prognosis from high to low expression groups. The NAMPT signature contained SIRT1 and PARP1 levels as well as other cancer stem cell-related genes. Finally, NAMPT inhibition increased the sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres.
NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers.
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Background
Alemtuzumab is a high-efficacy treatment approved for relapsing-remitting multiple sclerosis (RRMS). Although clinical trials and observational studies are consistent in showing its ...efficacy and manageable safety profile, further studies under clinical practice conditions are needed to further support its clinical use.
Objective
The aim of this observational retrospective study was to evaluate the effectiveness and safety of alemtuzumab to add to the current real-world evidence on the drug.
Methods
A cohort of 115 adult patients with RRMS treated with alemtuzumab between 2014 and 2020 was retrospectively followed up in five centers in Spain. Analysis included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW), 6-month confirmed disability improvement (CDI), radiological activity, no evidence of disease activity (NEDA-3), and safety signals. Given the different follow-up periods among participants, ARR was calculated using the person-years method. CDI was defined as a ≥ 1.0-point decrease in Expanded Disability Status Scale (EDSS) score assessed in patients with a baseline EDSS score ≥ 2.0 confirmed 6 months apart. CDW was defined as a ≥ 1.0-point increase in EDSS score assessed in patients with a baseline EDSS score ≥ 1.0 (≥ 1.5 if baseline EDSS = 0), confirmed 6 months apart.
Results
ARR decreased from 1.9 (95% confidence interval 1.60–2.33) in the year prior to alemtuzumab initiation to 0.28 (0.17–0.37) after 1 year of treatment (87% reduction), and to 0.22 (0.13–0.35) after the second year. Over the entire follow-up period, ARR was 0.24 (0.18–0.30). At year 1, 75% of patients showed no signs of magnetic resonance imaging (MRI) activity and 70% at year 5. One percent of patients experienced 6-month CDW at year 1, 2.6% at year 2, 7.4% at year 3, and no patients over years 4 and 5. A total of 7.7% of patients achieved 6-month CDI in year 1, 3.6% in year 2, and maintained it at years 3 and 4. Most patients achieved annual NEDA-3: year 1, 72%; year 2, 79%; year 3, 80%; year 4, 89%; year 5, 75%. Infusion-related reactions were observed in 95% of patients and infections in 74%. Thyroid disorders occurred in 30% of patients, and only three patients developed immune thrombocytopenia. No cases of progressive multifocal leukoencephalopathy were reported.
Conclusions
This study shows that alemtuzumab reduced the relapse rate and disability worsening in real-world clinical practice, with many patients achieving and sustaining NEDA-3 over time. The safety profile of alemtuzumab was consistent with previous findings, and no new or unexpected safety signals were observed. As this was an observational and retrospective study, the main limitation of not having all variables comprehensively available for all patients should be considered when interpreting results.
Objective
To describe the spectrum of neurological complications observed in a hospital‐based cohort of COVID‐19 patients who required a neurological assessment.
Methods
We conducted an ...observational, monocentric, prospective study of patients with a COVID‐19 diagnosis hospitalized during the 3‐month period of the first wave of the COVID‐19 pandemic in a tertiary hospital in Madrid (Spain). We describe the neurological diagnoses that arose after the onset of COVID‐19 symptoms. These diagnoses could be divided into different groups.
Results
Only 71 (2.6%) of 2750 hospitalized patients suffered at least one neurological complication (77 different neurological diagnoses in total) during the timeframe of the study. The most common diagnoses were neuromuscular disorders (33.7%), cerebrovascular diseases (CVDs) (27.3%), acute encephalopathy (19.4%), seizures (7.8%), and miscellanea (11.6%) comprising hiccups, myoclonic tremor, Horner syndrome and transverse myelitis. CVDs and encephalopathy were common in the early phase of the COVID‐19 pandemic compared to neuromuscular disorders, which usually appeared later on (p = 0.005). Cerebrospinal fluid severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) polymerase chain reaction was negative in 15/15 samples. The mortality was higher in the CVD group (38.1% vs. 8.9%; p = 0.05).
Conclusions
The prevalence of neurological complications is low in patients hospitalized for COVID‐19. Different mechanisms appear to be involved in these complications, and there was no evidence of direct invasion of the nervous system in our cohort. Some of the neurological complications can be classified into early and late neurological complications of COVID‐19, as they occurred at different times following the onset of COVID‐19 symptoms.
Description of the spectrum of neurological complications observed in a hospital‐based cohort of COVID‐19 patients during the first wave of the pandemic in a tertiary hospital in Madrid (Spain). The prevalence of neurological complications was low. Different mechanisms appear to be involved; however, there was no evidence of direct invasion of the nervous system. Some of the neurological complications can be classified into early and late neurological complications of COVID‐19.
This article studies the cycle of Carthusian saints that Pedro Duque
Cornejo painted in 1741 for the prior cell of the Carthusian monastery of Santa
María de las Cuevas in Seville, thanks to the ...discovery of two new canvases of this
series, in the sevillian convent of Santa Isabel. Their analysis allows us to reconstruct the iconographic program of the cycle and to deepen our knowledge of the
creative process of the artist, whose pictorial facet is little known. The paintings are
also contextualized in relation to their patrons and the circumstances that led to
their dispersion in the 19th century are reconstructed
El artículo estudia el ciclo de santos cartujos que Pedro Duque Cornejo pintó en 1741 para la celda prioral de la Cartuja de Santa María de las Cuevas de Sevilla, gracias al hallazgo de dos nuevos lienzos de esta serie en el convento sevillano de Santa Isabel. Su análisis permite reconstruir el programa iconográfico del ciclo y profundizar en el conocimiento del proceso creativo del artista, cuya faceta pictórica es poco conocida. Las pinturas son igualmente contextualizada relación con sus patrocinadores y se reconstruyen las circunstancias que llevaron a su dispersión en el siglo XIX.
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