A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations.

BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor. PATIENTS AND METHODS: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities. RESULTS: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified. CONCLUSIONS: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.

Stenotic transverse sinus predisposes to poststenting hyperperfusion syndrome as evidenced by quantitative analysis of peritherapeutic cerebral circulation time.

BACKGROUND AND PURPOSE: Hyperperfusion syndrome is a devastating complication of carotid stent placement. The shortening of cerebral circulation time after stent placement is seen as a good indicator of the development of hyperperfusion syndrome. The purpose of our study was to evaluate whether patients with ipsilateral transverse sinus stenosis are prone to having shortened cerebral circulation time after stent placement, subsequently leading to the possible development of hyperperfusion syndrome. MATERIALS AND METHODS: Forty-nine patients with >70% unilateral carotid stenosis undergoing stent placement were recruited for analysis. Group A consisted of patients with a stenotic ipsilateral transverse sinus >50% greater than the diameter of the contralateral transverse sinus; the remaining patients were in group B. Quantitative DSA was used to calculate cerebral circulation time. Cerebral circulation time was defined as the time difference between the relative time to maximal intensity of ROIs in the proximal internal carotid artery and the internal jugular vein. ΔCCT was defined as cerebral circulation time before stent placement minus cerebral circulation time after stent placement. ΔCCT, white matter hyperintensity signals, and sulcal effacement in MR imaging were compared between the 2 groups. RESULTS: ΔCCT was significantly shorter in group A (0.65 ± 1.3) than in group B (-0.12 ± 1.4). Three patients had white matter hyperintensity signals in group A, and 1 developed hyperperfusion syndrome. Group B showed no MR imaging signs of hyperperfusion syndrome. CONCLUSIONS: Ipsilateral hypoplastic transverse sinus was associated with prolonged cerebral circulation time before stent placement and greatly shortened cerebral circulation time after stent placement. Inadequate venous drainage might play a role in impaired cerebral autoregulation and might influence the development of poststenting hyperperfusion syndrome.

Venous hypertension may be a factor in aneurysmal rupture. A case report.

This report describes cerebral aneurysmal rupture with asymmetry of ipsilateral dural sinus hypoplasia using quantitative color-coded I-Flow cerebral venography to identify the venous pressure gradient. We suggest the pressure gradient may be a potential factor in cerebral aneurysmal rupture. We used I-Flow quantitative cerebral venography to measure the venous pressure gradient during acute cerebral aneurysmal rupture and post embolization in a 67-year-old woman who presented with clinical symptoms of left third nerve palsy for several days with mild headache initially without subarachnoid hemorrhage. We encountered a high venous pressure gradient of severe ipsilateral dural sinus hypoplasia during acute rupture of a posterior communicating aneurysm. Venous dural sinus asymmetry has been considered a congenital benign and non-pathological condition. However, this case may present severe hypoplasia of the dural sinus with potential pressure gradient in some unusual condition. A high venous pressure gradient may be another factor in cerebral aneurysmal rupture.

The feasibility of QR-code prescription in Taiwan.

WHAT IS KNOWN AND OBJECTIVE: An ideal Health Care Service is a service system that focuses on patients. Patients in Taiwan have the freedom to fill their prescriptions at any pharmacies contracted with National Health Insurance. Each of these pharmacies uses its own computer system. So far, there are at least ten different systems on the market in Taiwan. To transmit the prescription information from the hospital to the pharmacy accurately and efficiently presents a great issue. METHODS: This study consisted of two-dimensional applications using a QR-code to capture Patient's identification and prescription information from the hospitals as well as using a webcam to read the QR-code and transfer all data to the pharmacy computer system. Two hospitals and 85 community pharmacies participated in the study. RESULTS AND DISCUSSION: During the trial, all participant pharmacies appraised highly of the accurate transmission of the prescription information. The contents in QR-code prescriptions from Taipei area were picked up efficiently and accurately in pharmacies at Taichung area (middle Taiwan) without software system limit and area limitation. The QR-code device received a patent (No. M376844, March 2010) from Intellectual Property Office Ministry of Economic Affair, China. WHAT IS NEW AND CONCLUSION: Our trial has proven that QR-code prescription can provide community pharmacists an efficient, accurate and inexpensive device to digitalize the prescription contents. Consequently, pharmacists can offer better quality of pharmacy service to patients.

Cerebral thromboembolism: value of susceptibility-weighted imaging in the initial diagnosis of acute infarction.

Susceptibility-weighted imaging (SWI) is commonly used to diagnose cerebral hemorrhage, calcification, and other T2* lesions. Its role in the detection of cerebral thromboemboli has been suggested for emboli of the anterior division of the middle cerebral artery (MCA). The purpose of our study was to determine SWI's accuracy and sensitivity in detection of all sites of cerebral thromboemboli, not just MCA emboli. Two neuroradiologists retrospectively reviewed consecutive MRI brain examinations with SWI for cerebral thromboemboli in 100 patients with clinical suspicion for stroke determined by the NIH Stroke Scale (NIHSS) score. FLAIR, MRA, CT, and catheter angiography were reviewed for thromboemboli in the same patients. Thromboembolic sites included: the internal carotid artery (ICA) terminus, anterior MCA, posterior MCA, any other cerebral artery, or if not present. The exclusion criteria included: no magnetic resonance angiogram (MRA) or catheter angiogram for comparison, lack of restricted diffusion, lacunar infarcts, and the presence of massive hemorrhage. The accuracy, sensitivity, and specificity of each imaging modality were determined. Twenty-four patients were excluded based on the aforementioned criteria. Cerebral thromboemboli were identified in 35 of the remaining 76 patients. Of the 35 patients with thromboemboli, 30 were identified on SWI. FLAIR detected 22/35 emboli, MRA 30/33, CT 18/35, and catheter angiography 12/12. The accuracies for SWI, FLAIR, and CT were 97%, 84%, and 74%, respectively. The sensitivities for SWI, FLAIR, and CT were 85%, 61%, and 52%, respectively. The specificities for SWI, FLAIR, and CT were 100%, 98%, and 93%, respectively. There is an adjunctive role of SWI to identify cerebral thromboemboli in patients with acute infarction. SWI is superior to FLAIR and CT, and complementary to MRA and catheter angiography in emboli detection. This study supports SWI detection of MCA emboli, but also emphasizes its utility in emboli detection of other arteries based on a high accuracy and sensitivity.

Susceptibility-weighted imaging, an additional tool to diagnose brain death: initial experience.

We describe findings suggestive of brain death on susceptibility-weighted imaging. We retrospectively reviewed brain magnetic resonance (MR) images of 15 patients who had cardiac arrest and found four cases with evidence of brain death. We then reviewed susceptibility-weighted imaging (SWI) findings on these cases. SWI images in the four cases with brain death showed deoxygenated blood in intracranial arteries. This preliminary result suggests that SWI may be used to diagnose brain death.

Practical Aspects of Shortening Acquisition Time in Brain MR Susceptibility-Weighted Imaging.

Magnetic resonance susceptibility-weighted imaging (SWI), a novel 3D gradient echo MRI sequence exploiting phase and magnitude data for post-processing, is able to detect blood, iron, calcification and deoxygenated hemoglobin content for brain. SWI has been widely used to evaluate cerebral vascular disorders, trauma, multiple sclerosis, and tumors. We have also used SWI to evaluate acute stroke patients to identify thrombosis and possible penumbra. The acquisition was too long for examining acute stroke patients due to motion from agitation and mental changes. We have altered the parameters of phase resolution, voxel size, matrix size and partial Fourier to shorten the acquisition time to improve the diagnostic quality of SWI for acute stroke patients. The result was to reduce the acquisition time from 3:46 min to 2:14 min thereby providing a helpful tool in screening stroke patients.

Synthesis of some new tricyclic 4(3H)-quinazolinone derivatives.

Quinazolinones are interesting molecules with a wide range of biological activities. We prepared a number of quinazolinone derivatives by the condensation of 5-bromo- or 5-nitro-substituted anthranilic acids with chloro-acyl chlorides. Anthranilic acid derivatives were treated with either 3-chloro-propionyl chloride or 4-chloro-butyryl chloride to yield the corresponding N-acyl-anthranilic acids. The resultants were reacted with acetic anhydride to afford the benzoxazinone intermediates, which upon condensation with elected amines in either DMF or ethanol gave the corresponding tricyclic 4(3H)-quinazolinone derivatives. It was found that reactions in DMF produced higher yields.

Unusual acute complications of carotid cavernous fistula: therapeutic options.

We aimed to demonstrate the complications of carotid-cavernous fistula (CCF) and their correlation with venous hypertension. From August 2000 to April 2008 we performed more than 2400 catheter angiographic procedures. Among those, six unusual cases presented acute complications of CCF. The presented complications of CCF from our cases showed a possible correlation with venous hypertension. With the experiences from our cases, venous hypertension may complicate CCF with a poor prognosis. The condition should be carefully evaluated and if present prompt treatment is necessary.

Kinetic and conformational studies of adenosine deaminase upon interaction with oxazepam and lorazepam.

Oxazepam and lorazepam inhibit the adenosine deaminase (ADA) differently. In the case of lorazepam temperature increment causes an increase in the inhibition potency whereas higher temperature reduces the inhibitory effect of oxazepam; which proposes the overall profounder structural changes in the case of lorazepam relative to those caused by oxazepam.

The effects of deferiprone and deferasirox on the structure and function of beta-thalassemia hemoglobin.

Transfusional iron overload is a major cause of morbidity and mortality in thalassemia, sickle-cell disease and other chronic anemias. To overcome these problems, orally bio available iron chelators, deferiprone and deferasirox, were used for the treatment of patients suffering from thalassemia. The interactions between deferiprone and deferasirox with the carrier protein, beta-thalassemia hemoglobin (Hb), were investigated using fluorescence, circular dichroism (CD) and UV-visible measurements at physiological condition. Strong fluorescence quenching on interactions of the above drugs with beta-thalassemia Hb were observed. Fluorescence quenching data of thalassemia Hb in the presence of deferasirox have shown greater affinity of binding. The number of binding sites to Hb for deferasirox was found to be more relative to those of the deferiprone. The effects of these drugs on the oxygen affinity of the thalassemia Hb were studied by spectroscopic methods using sodium dithionite. Results indicated that deferiprone reduces oxygen affinity (increases oxygen releasing ability) of Hb, while in the presence of deferasirox, oxygen affinity of Hb has significantly increased by dose-dependent manner. As such, deferasirox exhibited opposite effect relative to deferiprone on the function of thalassemia Hb. In clinical dose of deferiprone, CD results showed that, the alpha-helical content of thalassemia Hb significantly increased. By use of the clinical dose of deferasirox, however, a decrease in alpha-helical content of protein was observed, which resulted in decreasing stability of thalassemia Hb. Our study showed that reduction in stability of thalassemia Hb in the presence of deferasirox induced higher conformational changes in protein.

Endovascular procedures for cerebrovenous disorders.

Cerebral venous anomalies may have a variety of clinical consequences. MR or CT venogram can assist the imaging diagnosis; yet, cerebral angiogram may be required to confirm or establish the correct diagnosis. Venous anomalies predisposing venous hypertension may be categorized into three major entities such as congenital variations, outflow obstruction, and increased blood flow. The degree of clinical presentations of venous hypertension depends upon the chronicity or acuteness. Venous hypertension may lead to venous congestion with edema, hemorrhage and encephalopathy. Endovascular therapeutic procedures may be employed to relieve venous congestion either from reducing blood flow or relieving obstruction. Those endovascular treatment options include embolization, thrombolysis and angioplastic stentings.

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil.

To identify mechanisms underlying oxaliplatin resistance, a subline of the human gastric adenocarcinoma TSGH cell line, S3, was made resistant to oxaliplatin by continuous selection against increasing drug concentrations. Compared with the parental TSGH cells, the S3 subline showed 58-fold resistance to oxaliplatin; it also displayed 11-, 2-, and 4.7-fold resistance to cis-diammine-dichloroplatinum (II) (CDDP), copper sulphate, and arsenic trioxide, respectively. Interestingly, S3 cells were fourfold more susceptible to 5-fluorouracil-induced cytotoxicity due to downregulation of thymidylate synthase. Despite elevated glutathione levels in S3 cells, there was no alteration of resistant phenotype to oxaliplatin or CDDP when cells were co-treated with glutathione-depleting agent, l-buthionine-(S,R)-sulphoximine. Cellular CDDP and oxaliplatin accumulation was decreased in S3 cells. In addition, amounts of oxaliplatin- and CDDP-DNA adducts in S3 cells were about 15 and 40% of those seen with TSGH cells, respectively. Western blot analysis showed increased the expression level of copper transporter ATP7A in S3 cells compared with TSGH cells. Partial reversal of the resistance of S3 cells to oxaliplatin and CDDP was observed by treating cell with ATP7A-targeted siRNA oligonucleotides or P-type ATPase-inhibitor sodium orthovanadate. Besides, host reactivation assay revealed enhanced repair of oxaliplatin- or CDDP-damaged DNA in S3 cells compared with TSGH cells. Together, our results show that the mechanism responsible for oxaliplatin and CDDP resistance in S3 cells is the combination of increased DNA repair and overexpression of ATP7A. Downregulation of thymidylate synthase in S3 cells renders them more susceptible to 5-fluorouracil-induced cytotoxicity. These findings could pave ways for future efforts to overcome oxaliplatin resistance.

Overexpression of the feedback-insensitive anthranilate synthase gene in tobacco causes tryptophan accumulation.

A total of 35 independent transgenic tobacco plants were produced using the Agrobacterium tumefaciens-leaf segment co-cultivation method followed by selection with kanamycin for the nptII gene. The vector also carried the tobacco feedback-insensitive anthranilate synthase gene (ASA2). Many of the lines showed increased ASA2 mRNA levels but only three contained increased free tryptophan (Trp) and many lines contained lower Trp than the untransformed control. The line with the highest Trp level (threefold that of the untransformed control) contained increased anthranilate synthase activity (AS) both in leaves and a cell suspension culture derived from the plant while the feedback insensitivity was most evident in the suspension culture. Other kinetic data also indicated that the ASA2 encoded AS alpha-subunit was more abundant in the tissue culture than in leaves. Progeny seedlings from this line were resistant to certain toxic Trp analogs, especially alpha-methyltryptophan (alphaMT) and less so to the most commonly used analog, 5-methyltryptophan. Shoots formed more readily from leaves of two of the transgenic lines than from leaves of the untransformed control on alphaMT, indicating that it might be possible to use ASA2 as a selectable marker gene and alphaMT as the selection agent.

Interaction between 3-(p-tolylamino)-1,5-azulenequinone and the deoxyguanosine residue in various oligonucleotides upon photolysis.

Eight single-stranded oligodeoxyribonucleotides 32P-labeled at the 5'-end were synthesized; they were annealed with the complementary oligodeoxyribonucleotides to form the corresponding double-stranded helices. These duplexes possessed standard Watson-Crick base pairs, locally perturbed sites of a base mismatch, or a bulge. Further, 5'-32P-labeled oligodeoxyribonucleotides with a hairpin loop were also synthesized. Cleavage of these single- and double-stranded oligodexyribonucleotides selectively at the deoxyguanosine residue was accomplished by use of 3-(p-tolylamino)-1,5-azulenequinone 1 upon irradiation with 350 nm UV light. The single strands were cleaved more efficiently than the double-helices. For the helices containing a deoxyguanosine residue at a bulge, at a hairpin loop or toward the end, the cleaving efficiency was increased. Computation results indicate that two possibilities exist for agent 1 to form two "Watson-Crick type" hydrogen bonds with guanine in single-stranded oligodeoxyribonucleotides; yet, only one possibility exists in duplexes.

Investigation of alternating and continuous experimental task designs during single finger opposition fMRI: a comparative study.

The purpose of this study was to empirically investigate and compare the effects of alternating and continuous experimental task designs on blood oxygenation level dependent (BOLD) signal contrast. Six healthy volunteers underwent single-finger opposition functional magnetic resonance imaging (fMRI) using T2*-weighted echo planar imaging technique on a 1.5 T MR scanner. Two different acquisition patterns were tested: alternating (ABABAB) and continuous (AAABBB), rest: A, activation: B. The BOLD signal contrast within a primary motor cortex region of interest (ROI) was evaluated using normalized t-values (z-scores) and mean region of interest (ROI) intensity for the two patterns. Analysis of variance (ANOVA) on ROI mean z-score and signal intensities demonstrate that the alternating pattern of administering rest and activation epochs produced a more robust statistical difference than a continuous pattern. The results showed that different patterns of acquisition yield differences in the BOLD signal at field strength of 1.5 T, and that an alternating task design can be considered more optimal than a continuous task design.

Design, synthesis, and SAR of novel carbapenem antibiotics with high stability to Xanthomonas maltophilia oxyiminocephalosporinase type II.

Racemic cis-6-(phenylacetamido)carbapenem (21), 2-hydroxycarbonyl-cis-6-(phenylacetamido)carbapenem (22), 2-methoxycarbonyl-cis-6-(phenylacetamido)carbapenem (30), 2-methoxycarbomethyl-cis-6-(phenylacetamido)carbapenem (33), 2-hydroxyethyl-cis-6-(phenylacetamido)carbapenem (34), and 2-acetoxyethyl-cis-6-(phenylacetamido)carbapenem (35) were synthesized. Formation of the carbapenem nuclei in 21, 22, and 30 involved dehydrophosphonation of the corresponding 2-diphenylphosphono-6-(phenylacetamido)carbapenam precursors 14, 15, and 28 using trimethylsilyl triflate and 1,8-diazabicyclo[5.4.0]undec-7-ene in THF. Syntheses of carbapenems 33-35 involved a Wittig reaction of carbapenam 14 with methyl glyoxylate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. For the antibacterial activities against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiellapneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, and P. aeruginosa 18S-H, carbapenems (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 were found comparable with imipenem ((+)-3), yet they were notably more potent than (+)-3 against Xanthomonas maltophilia GN 12873. On the other hand, unlike (+)-3, carbapenems (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 were stable to X. maltophilia oxyiminocephalosporinase type II. Their beta-lactamase inhibitory properties, however, were found to be more comparable with those of penicillin G ((+)-4) than to those of imipenem ((+)-3). A combination of imipenem ((+)-3) with (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 resulted in synergistic antibacterial activity against X. maltophilia GN 12873. Results from the biological tests were correlated with the distribution of the electron density at C(2)=C(3) of carbapenems upon reaction with transpeptidases or beta-lactamases.

Complicated stent supported cerebrovascular angioplasty: case analyses and review of literature.

BACKGROUND: Hemodynamic lesions of the cervicocerebral vasculature are currently being treated with stent supported percutaneous transluminal angioplasty. These procedures have met with increasing success when compared to the risks and morbidity of more invasive surgical approaches. The versatility of stent-supported angioplasty as a primary therapeutic modality is examined in the following complex cases. CASE DESCRIPTION: We present four cases involving cervical angioplasty with emergent or adjunctive stent placement. Two cases involved the subclavian arteries, whereas the others involved the vertebral and internal carotid arteries. In our experience, complications of cervicocerebral artery angioplasty have been successfully managed by stent placement. CONCLUSION: Our cases demonstrate the emerging role of cervical angioplasty and stent implantation as a successful therapeutic modality, highlighted in these complex cases.