Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation ...of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.
Systemic Sclerosis in the hand is characteristically evidenced by Raynaud's phenomenon, fibrosis of the skin, tendons, ligaments, and joints as well as digital ulcers with prolonged healing. Current ...medical treatment does not always cure these complications. Local adipose-derived stromal vascular fraction administration into the hands has been proposed as an emerging treatment due to its regenerative properties. The objective of this randomized controlled clinical trial was to evaluate the safety and clinical effects of fat micrografts plus adipose derived-stromal vascular fraction administration into the hands of patients with systemic sclerosis.
This was an open-label, monocentric, randomized controlled study. Twenty patients diagnosed with systemic sclerosis were assigned to the experimental or control group. Fat micrografts plus the adipose derived-stromal vascular fraction were injected into the right hand of experimental group patients. The control group continued to receive only medical treatment. Demographic, serologic data and disease severity were recorded. Digital oximetry, pain, Raynaud phenomenon, digital ulcers number, mobility, thumb opposition, vascular density of the nail bed, skin affection of the hand, serologic antibodies, hand function, and quality of life scores were evaluated in both groups.
The results of the intervention were analyzed with the Wilcoxon rank test, and the differences between the control and experimental groups at 0 days and 168 days were analyzed with the Mann-Whitney U test. Adverse events were not observed in both groups. At the end of the study, statistically significant improvements were observed in pain levels (p<0.05) and number of digital ulcers (p<0.01) in the experimental vs control group.
The injection of adipose derived-stromal vascular fraction plus fat micrografts is a reproducible, and safe technique. Pain and digital ulcers in the hands of patients with systemic sclerosis can be treated with this technique plus conventional medical treatment.
Folliculocystic and collagen hamartoma (FCCH) is a rare entity with only 18 reported cases worldwide. Of them, most are found in patients diagnosed with tuberous sclerosis complex (TSC). FCCH has ...distinctive histopathologic features, including collagen deposition in the dermis, perifollicular fibrosis, and comedones with keratin‐containing cysts lined by infundibular epithelium. We report three patients with a definitive TSC clinical diagnosis in whom clinical, histopathologic, and molecular features were studied to establish if there exists a genotype–phenotype correlation. The molecular results showed different heterozygous pathogenic variants (PV) in TSC2 in each patient: NM_000548.4:c.5024C>T, NG_005895.1:c.1599+1G>T, and NM_000548.4:c.2297_2298dup, to our knowledge; the latter PV has not been reported in public databases. The same PVs were identified as heterozygous in the tumor tissue samples, none of which yielded evidence of a TSC2 second hit. Because all FCCH patients with available molecular diagnosis carry a pathogenic genotype in TSC1 or TSC2, we suggest that FCCH should be considered as a new and uncommon diagnostic manifestation in the TSC consensus international diagnostic criteria. The early recognition of FCCH by clinicians could prompt the identification of new TSC cases. Interestingly, our molecular findings suggest that one of the patients described herein is a probable case of somatic mosaicism.
Objective: Murmurs are abnormal heart sounds, identified by experts through cardiac auscultation. The murmur grade, a quantitative measure of the murmur intensity, is strongly correlated with the ...patient's clinical condition. This work aims to estimate each patient's murmur grade (i.e., absent, soft, loud) from multiple auscultation location phonocardiograms (PCGs) of a large population of pediatric patients from a low-resource rural area. Methods: The Mel spectrogram representation of each PCG recording is given to an ensemble of 15 convolutional residual neural networks with channel-wise attention mechanisms to classify each PCG recording. The final murmur grade for each patient is derived based on the proposed decision rule and considering all estimated labels for available recordings. The proposed method is cross-validated on a dataset consisting of 3456 PCG recordings from 1007 patients using a stratified ten-fold cross-validation. Additionally, the method was tested on a hidden test set comprised of 1538 PCG recordings from 442 patients. Results: The overall cross-validation performances for patient-level murmur gradings are 86.3% and 81.6% in terms of the unweighted average of sensitivities and F1-scores, respectively. The sensitivities (and F1-scores) for absent, soft, and loud murmurs are 90.7% (93.6%), 75.8% (66.8%), and 92.3% (84.2%), respectively. On the test set, the algorithm achieves an unweighted average of sensitivities of 80.4% and an F1-score of 75.8%. Conclusions: This study provides a potential approach for algorithmic pre-screening in low-resource settings with relatively high expert screening costs. Significance: The proposed method represents a significant step beyond detection of murmurs, providing characterization of intensity, which may provide an enhanced classification of clinical outcomes.
Electromyographic signals have been used with low-degree-of-freedom prostheses, and recently with multifunctional prostheses. Currently, they are also being used as inputs in the human-computer ...interface that controls interaction through hand gestures. Although there is a gap between academic publications on the control of an upper-limb prosthesis developed in laboratories and its service in the natural environment, there are attempts to achieve easier control using multiple muscle signals. This work contributes to this, using a database and biomechanical simulation software, both open access, to seek simplicity in the classifiers, anticipating their implementation in microcontrollers and their execution in real time. Fifteen predefined finger movements of the hand were identified using classic classifiers such as Bayes, linear and quadratic discriminant analysis. The idealized movements of the database were modeled with Opensim for visualization. Combinations of two preprocessing methods-the forward sequential selection method and the feature normalization method-were evaluated to increase the efficiency of these classifiers. The statistical methods of cross-validation, analysis of variance (ANOVA) and Duncan were used to validate the results. Furthermore, the classifier with the best recognition result was redesigned into a new feature space using the sparse matrix algorithm to improve it, and to determine which features can be eliminated without degrading the classification. The classifiers yielded promising results-the quadratic discriminant being the best, achieving an average recognition rate for each individual considered of 96.16%, and with 78.36% for the total sample group of the eight subjects, in an independent test dataset. The study ends with the visual analysis under Opensim of the classified movements, in which the usefulness of this simulation tool is appreciated by revealing the muscular participation, which can be useful during the design of a multifunctional prosthesis.
Abstract
Social cheating is the exploitation of public goods that are costly metabolites, like exoproteases. Exoprotease exploitation in Pseudomonas aeruginosa has been studied in reference strains. ...Experimental evolution with reference strains during continuous growth in casein has demonstrated that nonexoprotease producers that are lasR mutants are selected while they behave as social cheaters. However, noncanonical quorum-sensing systems exist in P. aeruginosa strains, which are diverse. In this work, the exploitation of exoproteases in the environmental strain ID4365 was evaluated; ID4365 has a nonsense mutation that precludes expression of LasR. ID4365 produces exoproteases under the control of RhlR, and harbors an inducible prophage. As expected, rhlR mutants of ID4365 behave as social cheaters, and exoprotease-deficient individuals accumulate upon continuous growth in casein. Moreover, in all continuous cultures, population collapses occur. However, this also sometimes happens before cheaters dominate. Interestingly, during growth in casein, ID4565’s native prophage is induced, suggesting that the metabolic costs imposed by social cheating may increase its induction, promoting population collapses. Accordingly, lysogenization of the PAO1 lasR mutant with this prophage accelerated its collapse. These findings highlight the influence of temperate phages in social cheating.
The lasR-deficient ID4365 P. aeruginosa strain is subject to exoprotease exploitation, rhlR mutants behave as social cheaters, and the production of temperate phages may accelerate population collapses.
•Cooke’s method scores European rabbit abundance according to the sightings of pellets.•It provides a simple and accurate way to estimate the relative abundance of rabbits.•It is inexpensive and is ...accessible for non-expert land managers worldwide.•It may be used in a wide range of habitats and scales.
The development of evidence-based tools that help to monitor wildlife populations is essential to assess the success of management interventions. Here, we evaluated the reliability of a simple method to estimate the abundance of the European rabbit (Oryctolagus cuniculus), which is likely one of the most managed vertebrate species worldwide. Cooke’s method involves noting the distribution and frequency of sightings of rabbit fecal pellets and accordingly scoring the abundance of rabbits on a scale 0–5. To assess its reliability, we used information collected during 101 rabbit surveys conducted across mainland Spain during the summer of 2022. In each 4-km walked transect, we estimated rabbit abundance using Cooke’s method every 400 m (i.e., 10 indexes), and pellet counts (2 plots per 100 m walked, i.e., 80 counts), which were used as a reference index. Our results revealed a strong correlation between the estimates of rabbit abundance obtained using Cooke’s method and the number of pellets counted per m2 regardless of the statistical approach used. This suggests that Cooke’s method provides a simple and inexpensive way of estimating the abundance of European rabbits, which we believe that can be very useful for non-expert land managers after a very short training period. Importantly, our findings demonstrate that it is reliable to estimate rabbit abundance in different land uses. In addition, Cooke’s method can be used in different seasons, is not affected by circadian activity of rabbits, seems to work well across the whole range of rabbit abundance, and may be useful for estimating rabbit abundance at different spatial scales. As everyday people rather than scientists are generally involved in managing European rabbits, we strongly recommend this simple method that allows rabbit abundance to be quickly estimated so that management decisions can be made. More broadly, we encourage researchers to investigate the usefulness of similar monitoring tools for other mammal species that are often surveyed through counting their pellets.
Relevant to mobile health, the design of a portable electrocardiograph (ECG) device using AD823X microchips as the analog front-end is presented. Starting with the evaluation board of the chip, ...open-source hardware and software components were integrated into a breadboard prototype. This required modifying the microchip with the breadboard-friendly Arduino Nano board in addition to a data logger and a Bluetooth breakout board. The digitized ECG signal can be transmitted by serial cable, via Bluetooth to a PC, or to an Android smartphone system for visualization. The data logging shield provides gigabytes of storage, as the signal is recorded to a microSD card adapter. A menu incorporates the device's several operating modes. Simulation and testing assessed the system stability and performance parameters in terms of not losing any sample data throughout the length of the recording and finding the maximum sampling frequency; and validation determined and resolved problems that arose in open-source development. Ultimately, a custom printed circuit board was produced requiring advanced manufacturing options of 2.5 mils trace widths for the small package components. The fabricated device did not degrade the AD823X noise performance, and an ECG waveform with negligible distortion was obtained. The maximum number of samples/second was 2380 Hz in serial cable transmission, whereas in microSD recording mode, a continuous ECG signal for up to 36 h at 500 Hz was verified. A low-cost, high-quality portable ECG for long-term monitoring prototype that reasonably complies with electrical safety regulations and medical equipment design was realized.
Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis ...(SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL,
< 0.01) and SSc (0.611 ± 0.296 ng/mL,
< 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target.
Autologous blood-derived products such as platelet-rich plasma (PRP) are widely used to treat musculoskeletal conditions, including knee osteoarthritis (OA). However, the clinical outcomes after PRP ...administration are often variable, and there is limited information about the specific characteristics of PRP that impact bioactivity and clinical responses. In this study, we aimed to develop an integrative workflow to evaluate responses to PRP in vitro, and to assess if the in vitro responses to PRP are associated with the PRP composition and clinical outcomes in patients with knee OA. To do this, we used a coculture system of macrophages and fibroblasts paired with transcriptomic analyses to comprehensively characterize the modulation of inflammatory responses by PRP in vitro. Relying on patient-reported outcomes and achievement of minimal clinically important differences in OA patients receiving PRP injections, we identified responders and non-responders to the treatment. Comparisons of PRP from these patient groups allowed us to identify differences in the composition and in vitro activity of PRP. We believe that our integrative workflow may enable the development of targeted approaches that rely on PRP and other orthobiologics to treat musculoskeletal pathologies.
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