Abstract Gefitinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase is an effective agent used in the treatment of patients with advanced non-small cell lung cancer (NSCLC). ...Adverse drug reactions were frequently observed in the skin, gastrointestinal tract, and liver, but they were generally mild in severity and reversible. Therefore, gefitinib has been regarded as a relatively safe agent. As a serious adverse effect, however, acute lung injury has been reported. The present report describes a patient with NSCLC who developed bilateral subdural hemorrhage as a possible adverse drug reaction after gefitinib therapy. We expect that this case may provide a reference for clinicians being involved in the treatment with gefitinib.
This study was conducted to evaluate the efficacy and safety of the combination of mitomycin-C (MMC) and S-1 as third-line chemotherapy for patients with advanced colorectal cancer (CRC) showing ...resistance to irinotecan- and oxaliplatin-containing regimens. Patients were recruited into the study from January 2009 and 10 patients were enrolled for 10 months. However, since no patients had shown a response by 10 months, the study was terminated early according to the protocol. MMC 7 mg/m2 was administered intravenously on day 1 every 6 weeks in the first 4 cycles. S-1 was administered twice daily at 35 mg/m2, within 1 h of meals on days 1-14. Following a rest for 7 days, S-1 was administered again on days 22-35, followed by a 7-day rest. A total of 14 cycles were delivered for 10 patients. All 10 patients were assessable for response. A total of 3 patients (30%) had stable disease and the remaining 7 showed disease progression. With a median follow-up of 7 months, the median overall survival was 10.5 months. Grade 3-4 myelotoxicities included neutropenia in two patients, anemia in two and thrombocytopenia in one. Grade 1-2 nausea and vomiting developed in 5 patients. One patient experienced grade 3 diarrhea. Grade 1-2 hand-foot syndrome occurred in 4 patients. In conclusion, the combination of MMC and S-1 as third-line chemotherapy in patients with advanced CRC appears to be well tolerated but has poor activity.
The aim of the Korean Imatinib Discontinuation Study was to identify predictors for safe and successful imatinib discontinuation. A total of 90 patients with a follow-up of ≥12 months were analyzed. ...After a median follow-up of 26.6 months after imatinib discontinuation, 37 patients lost the major molecular response. The probability of sustained major molecular response at 12 months and 24 months was 62.2% and 58.5%, respectively. All 37 patients who lost major molecular response were retreated with imatinib therapy for a median of 16.9 months, and all achieved major molecular response again at a median of 3.9 months after resuming imatinib therapy. We observed newly developed or worsened musculoskeletal pain and pruritus in 27 (30%) patients after imatinib discontinuation. Imatinib withdrawal syndrome was associated with a higher probability of sustained major molecular response (P=0.003) and showed a trend for a longer time to major molecular response loss (P=0.098). Positivity (defined as ≥ 17 positive chambers) of digital polymerase chain reaction at screening and longer imatinib duration before imatinib discontinuation were associated with a higher probability of sustained major molecular response. Our data demonstrated that the occurrence of imatinib withdrawal syndrome after imatinib discontinuation and longer duration of imatinib were associated with a lower rate of molecular relapse. In addition, minimal residual leukemia measured by digital polymerase chain reaction had a trend for a higher molecular relapse. (Trial registered at ClinicalTrials.gov: NCT01564836).
This study was to evaluate responsiveness to IFN-α and investigate the benefits of sustained response (SR) in patients who were presumed as being vertically transmitted in Korea. A total of 46 ...patients of presumed vertical transmission with biopsy-proven HBeAg-positive chronic HBV infection were treated with IFN-α and followed. We tried to find the factors associated with SR and compared the cumulative rate of HCC and survival between SR group and non-sustained/non-responder (NSR) group. HBeAg loss was acquired in 35% (16/46) within a year but SR was observed in 22% (10/46). Age <35 years and ALT levels >7×ULN were significant favorable factors for SR (OR 0.56, 0.49, 95%CI 0.38–0.82, 0.29–0.81, respectively) (both
P<0.05). There were no significant differences of cumulative HCC-free survival (100 vs. 68% at 12 years,
P=0.36) and survival (100 vs. 73% at 12 years,
P=0.3) between SR group and NSR group. In conclusion, age below 35 years old and serum ALT levels above 7×ULN may predict IFN-α therapy-induced SR among them, although we cannot affirm the effects on HCC prevention or survival.
Abstract
Conventional imaging and recognition systems require an extensive amount of data storage, pre-processing, and chip-to-chip communications as well as aberration-proof light focusing with ...multiple lenses for recognizing an object from massive optical inputs. This is because separate chips (
i
.
e
., flat image sensor array, memory device, and CPU) in conjunction with complicated optics should capture, store, and process massive image information independently. In contrast, human vision employs a highly efficient imaging and recognition process. Here, inspired by the human visual recognition system, we present a novel imaging device for efficient image acquisition and data pre-processing by conferring the neuromorphic data processing function on a curved image sensor array. The curved neuromorphic image sensor array is based on a heterostructure of MoS
2
and poly(1,3,5-trimethyl-1,3,5-trivinyl cyclotrisiloxane). The curved neuromorphic image sensor array features photon-triggered synaptic plasticity owing to its quasi-linear time-dependent photocurrent generation and prolonged photocurrent decay, originated from charge trapping in the MoS
2
-organic vertical stack. The curved neuromorphic image sensor array integrated with a plano-convex lens derives a pre-processed image from a set of noisy optical inputs without redundant data storage, processing, and communications as well as without complex optics. The proposed imaging device can substantially improve efficiency of the image acquisition and recognition process, a step forward to the next generation machine vision.
The severe acute respiratory syndrome coronavirus (SARS-CoV) RNA genome is replicated by a virus-encoded RNA replicase, the key component of which is the nonstructural protein 12 (nsp12). In this ...report, we describe the biochemical properties of a full-length recombinant SARS-CoV nsp12 RNA-dependent RNA polymerase (RdRp) capable of copying viral RNA templates. The purified SARS-CoV nsp12 showed both primer-dependent and primer-independent RNA synthesis activities using homopolymeric RNA templates. The RdRp activity was strictly dependent on Mn
2+
. The nsp12 preferentially copied homopolymeric pyrimidine RNA templates in the absence of an added oligonucleotide primer. It was also able to initiate
de novo
RNA synthesis from the 3’-ends of both the plus- and minus-strand genome of SARS-CoV, using the 3’-terminal 36- and 37-nt RNA, respectively. The
in vitro
RdRp assay system established with a full-length nsp12 will be useful for understanding the mechanisms of coronavirus replication and for the development of anti-SARS-CoV agents.
We have previously shown using a spinal cord injury (SCI) model that gap junctions contribute to the early spread of astrocyte activation in the lumbar spinal cord and that this astrocyte ...communication plays critical role in the induction of central neuropathic pain. Sigma-1 receptors (Sig-1Rs) have been implicated in spinal astrocyte activation and the development of peripheral neuropathic pain, yet their contribution to central neuropathic pain remains unknown. Thus, we investigated whether SCI upregulates spinal Sig-1Rs, which in turn increase the expression of the astrocytic gap junction protein, connexin 43 (Cx43) leading to the induction of central neuropathic pain. A thoracic spinal cord hemisection significantly increased both astrocyte activation and Cx43 expression in lumbar dorsal horn. Sig-1Rs were also increased in lumbar dorsal horn astrocytes, but not neurons or microglia. Intrathecal injection of an astrocyte metabolic inhibitor (fluorocitrate); a gap junction/hemichannel blocker (carbenoxolone); or a Cx43 mimetic peptide (43Gap26) significantly reduced SCI-induced bilateral below-level mechanical allodynia. Blockade of Sig-1Rs with BD1047 during the induction phase of pain significantly suppressed the SCI-induced development of mechanical allodynia, astrocyte activation, increased expression of Cx43 in both total and membrane levels, and increased association of Cx43 with Sig-1R. However, SCI did not change the expression of oligodendrocyte (Cx32) or neuronal (Cx36) gap junction proteins. These findings demonstrate that SCI activates astrocyte Sig-1Rs leading to increases in the expression of the gap junction protein, Cx43 and astrocyte activation in the lumbar dorsal horn, and ultimately contribute to the induction of bilateral below-level mechanical allodynia.
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•SCI induces activation of spinal astrocytes and increases in astrocytic Cx43 expression.•Sig-1Rs are upregulated in astrocytes of the lumbar dorsal horn following SCI.•Sig-1R antagonism suppresses the development of mechanical allodynia in SCI mice.•Sig-1R antagonism reduces SCI-induced astrocyte activation and Cx43 overexpression.•Sig-1R antagonism decreases Cx43 association with Sig-1R.
There are a few reports regarding the outcome evaluation of balloon-expandable intracranial stent placement (BEICS). The purpose of our study was to evaluate the outcome and factors related to the ...adverse events (AEs) of BEICS.
We evaluated 100 consecutive patients who underwent BEICS. We assessed the procedural success (residual stenosis < 50%), AEs (minor strokes, major strokes, and death), clinical outcome, and restenosis (> 50%) at 6 months. We also analyzed 18 factors including symptom patterns related to AE rate. Symptom patterns revealed 1) stable patients (n = 73) with improving, stationary, or resolved symptoms; and 2) unstable patients (n = 27) with gradual worsening or fluctuating symptoms (National Institutes of Health Stroke Scale NIHSS > or = 4) within 2 days before stent placement.
The procedural success rate was 99%. Overall, there were 10 (10%) AEs within the 6 months: 4 (4%) minor strokes, 3 (3%) major strokes, and 3 (3%) deaths including a death from myocardial infarction. AE rate was 4.1% in stable and 25.9% in unstable patients. Restenosis at 6 months revealed 0% (0/59). Good outcome (modified Rankin Scale < or = 2) at 6 months was 97% (71/73) in stable and 67% (18/27) in unstable patients. Stepwise logistic regression model revealed that symptom pattern (unstable versus stable) was the only significant risk factor (OR, 8.167; 95% CI, 1.933-34.500; P = .004).
BEICS revealed a low AE and good outcome rate at 6 months, especially in the stable patients. Midterm outcome was also favorable in the unstable patient group.
A new Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral ...absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion <70 nm in size when in contact with aqueous medium. In an in vitro dissolution test in a nonsink condition, the amphiphilic polymer noticeably retarded drug precipitation and maintained >80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different (P>0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients.
Understanding complex biological systems requires the system-wide characterization of both molecular and cellular features. Existing methods for spatial mapping of biomolecules in intact tissues ...suffer from information loss caused by degradation and tissue damage. We report a tissue transformation strategy named stabilization under harsh conditions via intramolecular epoxide linkages to prevent degradation (SHIELD), which uses a flexible polyepoxide to form controlled intra- and intermolecular cross-link with biomolecules. SHIELD preserves protein fluorescence and antigenicity, transcripts and tissue architecture under a wide range of harsh conditions. We applied SHIELD to interrogate system-level wiring, synaptic architecture, and molecular features of virally labeled neurons and their targets in mouse at single-cell resolution. We also demonstrated rapid three-dimensional phenotyping of core needle biopsies and human brain cells. SHIELD enables rapid, multiscale, integrated molecular phenotyping of both animal and clinical tissues.
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