Glioblastoma stem cells (GSCs) are an important subpopulation in glioblastoma, implicated in tumor growth, tumor recurrence, and radiation resistance. Understanding the cellular mechanisms for chemo- ...and radiation resistance could lead to the development of new therapeutic strategies. Here, we demonstrate that CDC20 promotes resistance to chemotherapy and radiation therapy. CDC20 knockdown does not increase TMZ- and radiation-induced DNA damage, or alter DNA damage repair, but rather promotes cell death through accumulation of the pro-apoptotic protein, Bim. Our results identify a CDC20 signaling pathway that regulates chemo- and radiosensitivity in GSCs, with the potential for CDC20-targeted therapeutic strategies in the treatment of glioblastoma.
Parkinson’s Disease (PD) is the second most common neurodegenerative disease, characterized by progressive motor (such as resting tremor, hypokinesia, postural instability) and non-motor symptoms ...(such as neuropsychiatric decline and autonomic dysfunction). Since its introduction in the late 1980s, deep brain stimulation (DBS) has revolutionized the treatment of PD. Initially used in patients’ with advanced PD with either medically refractory motor symptoms or medication intolerance, DBS typically provides excellent improvement in motor symptoms. Indications for DBS have continued to expand, with demonstrated efficacy in early PD and essential tremor, and promising preliminary results in the treatment of epilepsy, psychiatric disease, and depression. Advancements in DBS hardware, programming, neuroimaging, and surgical techniques have led to progressive improvement in efficacy and safety profiles. Thanks to ongoing research into remote programming, adaptive DBS, new targets, and alternative interventions, such as transcranial magnetic stimulation, the opportunities for further improvements in DBS and neuromodulation are bright.
Pancreatectomy with arterial resection (AR) is performed infrequently. As indications evolve, we evaluated indications, outcomes, and predictors of mortality, morbidity, and survival after AR.
We ...performed a single-institution review of elective pancreatectomies with AR (from July1990 to July 2017). Univariate and multivariate analyses were performed for predictors of outcomes and survival.
A total of 111 patients underwent pancreatectomy with AR including any hepatic (54%), any celiac (44%), any superior mesenteric (14%), or multiple ARs (14%), with revascularization in 55%. The majority of cases were planned (77%) and performed post-2010 (78%). Overall 90-day major morbidity (≥grade III) and mortality were 54% and 13%, respectively, due to post-pancreatectomy hemorrhage (PPH), postoperative pancreatic fistula (POPF), or ischemia in the majority of cases. There was a significant decrease in mortality post-2010 (9% vs 29%, p = 0.02), and this was protective on multivariate analysis (odds ratio OR 0.1, p = 0.004); PPH increased mortality (OR 6.1, p < 0.001). Post-pancreatectomy hemorrhage was associated with major morbidity (OR 5.1, p = 0.005), reoperation (OR = 23.0, p = 0.004), ICU (OR 5.5, p < 0.001), and readmission (OR 2.6, p = 0.004). Other morbidity predictors were AR with graft (OR 4.0, p = 0.031) and POPF (OR 3.1, p = 0.003). Median survival was 28.5 months and improved for ductal adenocarcinoma after neoadjuvant chemotherapy (p = 0.038). There were no differences in survival based on AR type.
Regardless of indication or type, pancreatectomy with AR is associated with risks greater than standard resections. Mortality has decreased in the modern era; however, morbidity remains high from hemorrhagic, fistula, or ischemia-related complications. Mitigation measures are needed if advanced resections are considered with increasing frequency given the potential oncologic benefit of AR in selected cases after modern chemotherapy.
OBJECTIVE Risk of ischemia during aneurysm surgery is significantly related to temporary clipping time and final clipping that might incorporate a perforator. In this study, the authors attempted to ...assess the potential added benefit to patient outcomes of "awake" neurological testing when compared with standard neurophysiological testing performed under general anesthesia. The procedure is performed after the induction of conscious sedation, and for the neurological testing, the patient is fully awake. METHODS The authors conducted an institutional review board-approved prospective study of clipping unruptured intracranial aneurysms (UIAs) in 30 consecutive adult patients who underwent awake clipping. The end points were the incidence of stroke/cerebrovascular accident (CVA), death, discharge to a long-term facility, length of stay, and 30-day modified Rankin Scale score. All clinical and neurophysiological intraoperative monitoring data were recorded. RESULTS The median patient age was 52 years (range 27-63 years); 19 (63%) female and 11 (37%) male patients were included. Twenty-seven (90%) aneurysms were anterior, and 3 (10%) were posterior circulation aneurysms. Five (17%) had been coiled previously, 3 (10%) had been clipped previously, 2 (7%) were partially calcified, and 2 (7%) were fusiform aneurysms. Three patients developed synchronous clinical neurological and neurophysiological changes during temporary clipping with consequent removal of the temporary clip and reversal of those clinical and neurophysiological changes. Three patients developed asynchronous clinical neurological and neurophysiological changes. These 3 patients developed hemiparesis without changes in neurophysiological monitoring results. One patient developed linked clinical neurological and neurophysiological changes during final clipping that were not reversed by reapplication of the clip, and the patient had a CVA. Four patients with internal carotid artery ophthalmic segment aneurysms underwent visual testing with final clipping, and 1 of these patients required repositioning of the clip. Three patients who required permanent occlusion of a vessel as part of their aneurysm treatment underwent a 10-minute intraoperative clinical respective-vessel test occlusion. The median length of stay was 3 days (range 1-5 days). The median modified Rankin Scale score was 1 (range 0-3). All of the patients were discharged to home from the hospital except for 1 who developed a CVA and was discharged to a rehabilitation facility. There were no deaths in this series. CONCLUSIONS The 3 patients who developed neurological deterioration without a concomitant neurophysiological finding during temporary clipping revealed a potential advantage of awake aneurysm surgery (i.e., in decreasing the risk of ischemic injury).
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting ...transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed.
As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates' target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis.
With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo.
Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.
Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na(+)-K(+)-2 Cl(-) cotransporter, NKCC1, and ...consequent paradoxical excitatory actions of GABAA receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in EGABA. Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures.
We determined whether adherence to recommendations for coronary angiography more than 12 h after symptom onset but prior to hospital discharge after acute myocardial infarction (AMI) resulted in ...better survival. Using propensity scores, we created a matched retrospective sample of 19,568 Medicare patients hospitalized with AMI during 1994–1995 in the United States. Twenty-nine percent, 36%, and 34% of patients were judged necessary, appropriate, or uncertain, respectively, for angiography while 60% of those judged necessary received the procedure during the hospitalization. The 3-year survival benefit was largest for patients rated necessary mean survival difference (95% CI): 17.6% (15.1, 20.1) and smallest for those rated uncertain 8.8% (6.8, 10.7). Angiography recommendations appear to select patients who are likely to benefit from the procedure and the consequent interventions. Because of the magnitude of the benefit and of the number of patients involved, steps should be taken to replicate these findings.
Carbapenem-resistant
(CRE) represent a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly being highlighted as important potential ...reservoirs. We investigated a large
carbapenemase (KPC)-producing
outbreak and wider CRE incidence trends in the Central Manchester University Hospital NHS Foundation Trust (CMFT) (United Kingdom) over 8 years, to determine the impact of infection prevention and control measures. Bacteriology and patient administration data (2009 to 2017) were linked, and a subset of CMFT or regional hospital KPC-producing
isolates (
= 268) were sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (
= 184,539 screens), environmental sampling, enhanced cleaning, and ward closure and plumbing replacement. Segmented regression of time trends for CRE detections was used to evaluate the impact of interventions on CRE incidence. Genomic analysis (
= 268 isolates) identified the spread of a KPC-producing
outbreak clone (strain A, sequence type 216 ST216;
= 125) among patients and in the environment, particularly on 2 cardiac wards (wards 3 and 4), despite control measures. ST216 strain A had caused an antecedent outbreak and shared its KPC plasmids with other
lineages and
species. CRE acquisition incidence declined after closure of wards 3 and 4 and plumbing replacement, suggesting an environmental contribution. However, ward 3/ward 4 wastewater sites were rapidly recolonized with CRE and patient CRE acquisitions recurred, albeit at lower rates. Patient relocation and plumbing replacement were associated with control of a clonal KPC-producing
outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and the persistence of
in
, including pathogenic lineages, are of concern.
PDF
