Heat shock protein 90 targeting therapy

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a role in stabilizing and activating more than 200 client proteins. It is required for the stability and function of numerous oncogenic signaling proteins that determine the hallmarks of cancer. Since the initial discovery of the first Hsp90 inhibitor in the 1970s, multiple phase II and III clinical trials of several Hsp90 inhibitors have been undertaken. This review provides an overview of the current status on clinical trials of Hsp90 inhibitors and future perspectives on novel anticancer strategies using Hsp90 inhibitors

Traumatic Lumbosacral Dislocation Treated with Posterior Lumbar Interbody Fusion Using Intersomatic Cages

A 35-year-old man was struck by a car on his right side and presented with paraparesis of both lower extremities. Radiographic examination revealed multiple transverse process fractures and anterior displacement of L5 on S1. Computed tomography revealed a bilateral anterior facet dislocation of the fifth lumbar vertebra on the sacrum. MRI showed rupture of the posterior ligamentous complex. A posterior lumbar interbody fusion using two intersomatic cages and pedicle screw instrumentation and posterior fusion were performed. Although no major disc lesion was found at the level of L5-S1 on preoperative MRI, a severely collapsed L5-S1 disc was found intraoperatively. Two years after surgery, the patient was asymptomatic with normal neurological findings, and has resumed normal activity. We believe that lumbosacral dislocation can be considered a three-column injury with an L5-S1 disc lesion, and, therefore, requires a solid circumferential segmental arthrodesis to improve fusion rate

Plasma-assisted CO2 and N2 conversion to plant nutrient

Colossal research on CO2 and N2 conversion using non-thermal plasma (NTP) technology has been ongoing since many years. The primary focus is on CO and NH3 production through CO2 and N2 conversion, respectively, with high conversion efficiency and low energy consumption with or without catalysts. Although in the present study, we propose that the NTP can assist in converting CO2 and N2 to plant nutrients in the form of plasma-treated/activated water. We used a homemade streamer plasma device and produced plasma-activated water (PAW) using CO2 and N2 feed gas, CO2-activated water (CAW) and N2-activated water (NAW). Later, we used CAW and NAW to treat the radish seeds and evaluate the germination rate, germination percentage, and seeding growth. To understand the chemical changes in PAW after the NTP treatment, we performed a chemical analysis to detect NO2¯, NO3¯, NH4+, and H2O2 along with the PAW pH and temperature shift. Additionally, to understand the other species produced in the gas phase, we simulated chemical reactions using COMSOL Multiphysics® software. Our results show that NOx and NHx species are less produced in CAW than in NAW, but CO2-generated PAW offers a significantly more substantial effect on enhancing the germination rate and seeding growth than NAW. Therefore, we suggested that CO and H2O2 formed during CAW production trigger early germination and growth enhancement. Furthermore, the total plasma reactor energy consumption, NO3¯ and NH4+ selective production percentage, and N2 conversion percentage were calculated. To our best knowledge, this is the first study that uses plasma-assisted CO2 conversion as a nutrient for plant growth

PRE-SOWING SEED TREATMENT WITH PHYSICAL STRESSORS INDUCES CHANGES IN AMOUNT OF SECONDARY METABOLITES IN NEEDLES OF PICEA ABIES SEEDLINGS

Tree resistance to pathogens is related to the general viability of trees, their growth energy, and ability to synthesize and to mobilize secondary metabolites (SMs), usually phenolic compounds, in tissues. The total phenolic content (TPC) in Norway spruce needles was determined during two vegetation seasons in order to compare the chemical background and ability of different Norway spruce half-sib families to synthesize TPC in response to seed treatment with physical stressors: cold plasma for 1 and 2 min (CP1, CP2) and electromagnetic field for 2 min (EMF2). TPC in seedling needles significantly differed between affected and control groups, but differences were stronger exerted during the first year of vegetation. In the first vegetation season, the strongest positive effects on TPC synthesis were induced by EMF2 treatment in 463 and 577 half-sib families, by CP1 treatment − in 457 half-sib family and by CP2 treatment − in 541 half-sib family; in the second vegetation season strongest effects were detected in CP1 treated 457 half-sib family and in CP2 treated 548 and 477 half-sib families. The half-sib families of Picea abies with higher TPC induced by seed treatment with different physical stressors could be more resistant to pathogens and diseases. The variance component of family for TPC variated from 14±10 % till 17±11 %, and was significant. The interaction of genotype and environment on TPC was as high as 49 ± 20%

ErbB2 and NFκB Overexpression as Predictors of Chemoradiation Resistance and Putative Targets to Overcome Resistance in Muscle-Invasive Bladder Cancer

Radical cystectomy for muscle-invasive bladder cancer (MIBC) patients frequently impairs their quality of life (QOL) due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR) to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS) were investigated. Of the 35 patients, 11 (31%) achieved pathological CR, while tumors in the remaining 24 patients (69%) were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014), 15.4 (P = 0.024) and 14.3 (P = 0.038). The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001). The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056) along with chemoradiation resistance (P = 0.003) and hydronephrosis (P = 0.018). The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018). Thus, erbB2 and NFκB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC

Detrimental effect of anemia after mechanical thrombectomy on functional outcome in patients with ischemic stroke

BackgroundAnemia can occur due to an aspiration maneuver of blood with thrombi during mechanical thrombectomy (MT) for stroke. However, the association between postoperative anemia and stroke outcomes is unknown.MethodsIn a registry-based hospital cohort, consecutive patients with acute ischemic stroke who underwent MT were retrospectively recruited. Patients were divided into the following three groups according to their hemoglobin (Hb) concentrations within 24 h after MT; no anemia (Hb concentrations ≥13 g/dL for men and ≥ 12 g/dL for women), mild anemia (Hb concentrations of 11–13 g/dL and 10–12 g/dL, respectively), and moderate-to-severe anemia (Hb concentrations &lt;11 g/dL and &lt; 10 g/dL, respectively). A 3-month modified Rankin Scale score of 0–2 indicated a favorable outcome.ResultsOf 470 patients, 166 were classified into the no anemia group, 168 into the mild anemia group, and 136 into the moderate-to-severe anemia group. Patients in the moderate-to-severe anemia group were older and more commonly had congestive heart failure than those in the other groups. Patients in the moderate-to-severe anemia group also had more device passes than those in the other groups (p &lt; 0.001). However, no difference was observed in the rate of final extended thrombolysis in cerebral infarction ≥2b reperfusion or intracranial hemorrhage among the groups. A favorable outcome was less frequently achieved in the moderate-to-severe anemia group than in the no anemia group (adjusted odds ratio, 0.46; 95% confidence interval, 0.26–0.81) independent of the baseline Hb concentration. A restricted cubic spline model with three knots showed that the adjusted odds ratio for a favorable outcome was lower in patients with lower Hb concentrations within 24 h after MT.ConclusionModerate-to-severe anemia within 24 h after MT is independently associated with a reduced likelihood of a favorable outcome.Clinical trial registrationhttps://www.clinicaltrials.gov, NCT02251665

Practical "1-2-3-4-Day" Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study

BACKGROUND: The "1-3-6-12-day rule" for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. METHODS: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0-7), moderate (8-15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. RESULTS: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)-initiating DOACS within 1, 2, 3, and 4 days, respectively-than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27-0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27-0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. CONCLUSIONS: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation