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We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ . By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere. Synopsis A novel drug‐screening platform compatible with patient‐derived samples identifies effective therapies to prevent brain metastasis. METPlatform is a novel drug‐screening strategy to identify vulnerabilities of metastasis while colonizing organs ex vivo . METPlatform identified hits that were confirmed in vivo as effective against brain metastasis. METPlatform allows to dissect the molecular mechanisms downstream of target inhibition using omic approaches. METPlatform has a potential value as a patient \"avatar\". Graphical Abstract A novel drug‐screening platform compatible with patient‐derived samples identifies effective therapies to prevent brain metastasis.

Background Spinal lipomas not associated with dysraphism are rare and have an unknown natural history. In this report, we describe two cases; they showed recurrence during long-term follow-up, which makes us doubt a benign malformative etiology. Case reports Two patients, a 19-year-old South American woman and a 14-year-old boy with spinal lipomas, underwent surgical resection. The lipomas were not associated with dysraphism and were located in the cervicothoracic and craniocervical junctions. In both cases, we decided to operate due to clinical progression; the former had a progressive natural course, and the latter experienced clinical worsening after recurrence from previous surgeries. The surgery took place with the assistance of neurophysiological monitoring and intraoperative ultrasound; a partial resection and medullary decompression were done, following the more recent recommendations. Discussion The natural history of these lesions is currently unknown due to their rarity and the heterogeneity in the long-term follow-up of previously reported cases. Although previous reports describe good outcomes after surgical resection, long follow-ups, especially in young subjects, may show differences in these outcomes with progression and recurrence. We contribute to this last piece of evidence by describing two more cases of progression and recurrence. Lessons Long-term close follow-up should be done in young subjects with spinal lipomas, as they are more prone to an aggressive course. Metabolism and hormonal changes may be behind this progression. Reoperation must be considered if neurological decline is detected.

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity. A comprehensive analysis of models of brain metastasis and multiple cohorts of patient samples identifies a targetable molecular mechanism underlying the resistance to whole-brain radiotherapy that can inform patient selection for personalized radiotherapy.

BackgroundCranioplasty carries a high risk of surgical site infections (SSIs) for a scheduled procedure, particularly with antibiotic-resistant bacteria.MethodsThe goal of this retrospective study was to measure the effect of tailored antibiotic prophylaxis on SSIs resulting from cranioplasties. The authors collected a prospective database of cranioplasties from 2009 to 2018. Risk factors for SSI were registered, as well as infection occurring during the first year postoperatively. A new protocol was initiated in 2016 consisting of antibiotic prophylaxis tailored to the colonizing flora of the skin of the scalp and decolonization of patients who were nasal carriers of methicillin-resistant S. aureus (MRSA); infection rates were compared.ResultsOne hundred nine cranioplasties were identified, 64 in the old protocol and 45 in the new protocol. Of the 109 cranioplasties, 16 (14.7%) suffered an infection, 14 (21.9%) in the old protocol group and 2 (4.4%) in the new protocol group (OR for the new protocol 0.166, 95% CI 0.036–0.772). Multiple surgeries (OR 3.44), Barthel ≤ 70 (OR 3.53), and previous infection (OR 3.9) were risk factors for SSI. Of the bacteria identified in the skin of the scalp, 22.2% were resistant to routine prophylaxis (cefazoline). Only one patient was identified as a nasal carrier of MRSA and was decolonized.ConclusionsA high percentage of bacteria resistant to routine prophylaxis (cefazoline) was identified in the skin of these patients’ scalps. The use of tailored antibiotic prophylaxis reduced significantly the infection rate in this particular set of patients.

Exosomes are extracellular vesicles responsible for transporting biological cargo between cells and may be present in all body fluids. As such, exosomes have been indicated in many bodily functions as well as in pathological roles. This makes them a particularly exciting target for research, as learning more about them can permit the formulation of new treatments, diagnostic methods, or drug-delivery systems with exosomes as nanocarriers.These vesicles have been previously associated with various stages of cancer progression, including the establishment of the pre-metastatic niche and tumor homing. Here, the work focused on evaluating the possibility of cancer cells inducing an exosome-mediated preparation of the pre-metastatic niche using a proxy (intermediary courier) healthy cell (Fibroblasts). A secondary aim of the study was to assess the potential of exosomes as nanocarriers for gold nanoconjugates carrying therapeutic moieties.Here, we validated a protocol of exosome extraction method that uses a combination of Size-Based methods and a Precipitating-Based commercial kit. We did so by characterizing the resultant exosomes using various techniques, including Dynamic Light Scattering, Western-Blot, and two commercial exosome quantification kits.In the study of the metastatic role of exosomes, the results are inconsistent with what was to be expected, suggesting a lower C-MYCexpression after incubation with malignant exosomes. However, this is probably the reflection of experimental errors and thus, further repetitions of this experiment are needed.In the assessment of exosomes as nanocarriers, we successfully achieved encapsulation of gold nanoparticles inside exosomes, as visualized by Dark-Field Fluorescence Microscopy, but not with the intended efficiency. Further optimization of the incubation periods and process is required.Due to the CoVID-19 pandemic, which caused severe constraints to the intensity of laboratory work, the full plan could not be implemented to completion. However, several relevant cues were provided to allow future work within this line of reasoning.

Background Non-adherence to medication is a major obstacle in the treatment of depressive disorders. We systematically reviewed the literature to evaluate the effectiveness of interventions aimed at improving adherence to medication among adults with depressive disorders with emphasis on initiation and implementation phase. Methods We searched Medline, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, Social Science Citation Index and Science Citation Index for randomized or non-randomized controlled trials up to January 2022. Risk of bias was assessed using the criteria of the Cochrane Collaboration. Meta-analyses, cumulative and meta-regression analyses for adherence were conducted. Results Forty-six trials ( n  = 24,324) were included. Pooled estimate indicates an increase in the probability of adherence to antidepressants at 6 months with the different types of interventions (OR 1.33; 95% CI: 1.09 to 1.62). The improvement in adherence is obtained from 3 months (OR 1.62, 95% CI: 1.25 to 2.10) but it is attenuated at 12 months (OR 1.25, 95% CI: 1.02 to 1.53). Selected articles show methodological differences, mainly the diversity of both the severity of the depressive disorder and intervention procedures. In the samples of these studies, patients with depression and anxiety seem to benefit most from intervention (OR 2.77, 95% CI: 1.74 to 4.42) and collaborative care is the most effective intervention to improve adherence (OR 1.88, 95% CI: 1.40 to 2.54). Conclusions Our findings indicate that interventions aimed at improving adherence to medication among adults with depressive disorders are effective up to six months. However, the evidence on the effectiveness of long-term adherence is insufficient and supports the need for further research efforts. Trial registration International Prospective Register for Systematic Reviews (PROSPERO) number: CRD42017065723 .

Cellular energetic deregulation is widely known to produce an overproduction of acidic species in cancer cells. This acid overload must be counterbalanced with a high rate of H + extrusion to maintain cell viability. In this sense, many H + transporters have been reported to be crucial for cell survival and proposed as antineoplastic target. By the way, voltage-gated proton channels (Hv1) mediate highly selective H + outward currents, capable to compensate acid burden in brief periods of time. This structure is canonically described acting as NADPH oxidase counterbalance in reactive oxygen species production. In this work, we show, for the first time in a oncohematologic cell line, that inhibition of Hv1 channels by Zn 2+ and the more selective blocker 2-(6-chloro-1H-benzimidazol-2-yl)guanidine (ClGBI) progressively decreases intracellular pH in resting conditions. This acidification is evident minutes after blockade and progresses under prolonged exposure (2, 17, and 48 h), and we firstly demonstrate that this is followed by cell death through apoptosis (annexin V binding). Altogether, these results contribute strong evidence that this channel might be a new therapeutic target in cancer.

IntroductionVirtual Communities of Practice (VCoP) offer information and exchange possibilities for people with chronic diseases. This could be especially valuable for self-management in patients with multimorbidity. The first phase of this project is based on building a Patient Journey Map through a co-creation process with professionals and patients.MethodsWe employed a tailored experiential design approach to co-design the VCoP with patients and professionals. Inclusion criteria for patients was to have ≥2 chronic diseases and aged 30–60. Fourteen patients were recruited. Participation consisted of virtual meetings with semi-directed questions that allowed us to collect the necessary information to know the needs of these types of patients and design a Patient Journey Map. Subsequently, they were able to test the pilot of the platform with specific content designed.Results of co-creation processPatients and professionals participated addressing barriers and needs. They built the trajectory of care and designed a Patient Journey Map so their needs could be addressed by the vCoP. The testimonies of patients and professionals were very different:Professionals identified 3 very well-defined phases (Pre-diagnosis and diagnosis, after diagnosis and follow-up). These phases were sequential and did not vary from one individual to another.Patients identified several areas of care, where the deficiencies of the health system and the need for respect and empathy starred in his journey map. They did not clearly identify phases on the trajectory, but rather described a circular map where feelings and thoughts were common at various stages.Discussion and ConclusionA person-centered co-design process of a vCoP may facilitate the empowerment of multimorbid patients. e-EMPODERAT project aims to improve the patients‘ understanding of their chronic diseases and enhance self-care quality.

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient’s hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log 10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log 10 copies/mL, p  = 0.003) and second tertile (≥ 8.27 log 10 copies/mL, p  = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO 2 , neutrophils > 7.5 × 10 3 /µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome.

Non-adherence to medication is a major obstacle in the treatment of depressive disorders. We systematically reviewed the literature to evaluate the effectiveness of interventions aimed at improving adherence to medication among adults with depressive disorders with emphasis on initiation and implementation phase. We searched Medline, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, Social Science Citation Index and Science Citation Index for randomized or non-randomized controlled trials up to January 2022. Risk of bias was assessed using the criteria of the Cochrane Collaboration. Meta-analyses, cumulative and meta-regression analyses for adherence were conducted. Forty-six trials (n = 24,324) were included. Pooled estimate indicates an increase in the probability of adherence to antidepressants at 6 months with the different types of interventions (OR 1.33; 95% CI: 1.09 to 1.62). The improvement in adherence is obtained from 3 months (OR 1.62, 95% CI: 1.25 to 2.10) but it is attenuated at 12 months (OR 1.25, 95% CI: 1.02 to 1.53). Selected articles show methodological differences, mainly the diversity of both the severity of the depressive disorder and intervention procedures. In the samples of these studies, patients with depression and anxiety seem to benefit most from intervention (OR 2.77, 95% CI: 1.74 to 4.42) and collaborative care is the most effective intervention to improve adherence (OR 1.88, 95% CI: 1.40 to 2.54). Our findings indicate that interventions aimed at improving adherence to medication among adults with depressive disorders are effective up to six months. However, the evidence on the effectiveness of long-term adherence is insufficient and supports the need for further research efforts.