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Cardiovascular Drugs and Therapy - The clinical course of COVID-19 may be complicated by acute respiratory distress syndrome (ARDS) and thromboembolic events, which are associated with high risk of...  相似文献   
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Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.  相似文献   
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MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.  相似文献   
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Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability.Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy;however,many infants still experience lifelong disabilities to movement,sensation and cognition.Clinical guidelines,based on strong clinical and preclinical evidence,recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours,with a target brain temperature of 33.5 ±0.5℃ for infants with moderate to severe hypoxic-ischemic encephalopathy.The clinical guidelines also recommend that infants be re warmed at a rate of 0.5℃ per hour,but this is not based on strong evidence.There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy.Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia.In this review,we evaluate the evidence for the optimal start time,duration and depth of hypothermia,and whether the rate of rewarming after treatment affects brain injury and neurological outcomes.  相似文献   
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Implantable motor cortex stimulation (iMCS) has been performed for >25 years to treat various intractable pain syndromes. Its effectiveness is highly variable and, although various studies revealed predictive variables, none of these were found repeatedly. This study uses neural network analysis (NNA) to identify predictive factors of iMCS treatment for intractable pain. A systematic review provided a database of patient data on an individual level of patients who underwent iMCS to treat refractory pain between 1991 and 2017. Responders were defined as patients with a pain relief of >40% as measured by a numerical rating scale (NRS) score. NNA was carried out to predict the outcome of iMCS and to identify predictive factors that impacted the outcome of iMCS. The outcome prediction value of the NNA was expressed as the mean accuracy, sensitivity, and specificity. The NNA furthermore provided the mean weight of predictive variables, which shows the impact of the predictive variable on the prediction. The mean weight was converted into the mean relative influence (M), a value that varies between 0 and 100%. A total of 358 patients were included (202 males [56.4%]; mean age, 54.2 ±13.3 years), 201 of whom were responders to iMCS. NNA had a mean accuracy of 66.3% and a sensitivity and specificity of 69.8% and 69.4%, respectively. NNA further identified 6 predictive variables that had a relatively high M: 1) the sex of the patient (M = 19.7%); 2) the origin of the lesion (M = 15.1%); 3) the preoperative numerical rating scale score (M = 9.2%); 4) preoperative use of repetitive transcranial magnetic stimulation (M = 7.3%); 5) preoperative intake of opioids (M = 7.1%); and 6) the follow-up period (M = 13.1%). The results from the present study show that these 6 predictive variables influence the outcome of iMCS and that, based on these variables, a fair prediction model can be built to predict outcome after iMCS surgery.PerspectiveThe presented NNA analyzed the functioning of computational models and modeled nonlinear statistical data. Based on this NNA, 6 predictive variables were identified that are suggested to be of importance in the improvement of future iMCS to treat chronic pain.  相似文献   
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