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.

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.

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.

Light represses transcription of asparagine synthetase genes in photosynthetic and nonphotosynthetic organs of plants.

Asparagine synthetase (AS) mRNA in Pisum sativum accumulates preferentially in plants grown in the dark. Nuclear run-on experiments demonstrate that expression of both the AS1 and AS2 genes is negatively regulated by light at the level of transcription. A decrease in the transcriptional rate of the AS1 gene can be detected as early as 20 min after exposure to light. Time course experiments reveal that the levels of AS mRNA fluctuate dramatically during a "normal" light/dark cycle. This is due to a direct effect of light and not to changes associated with circadian rhythm. A novel finding is that the light-repressed expression of the AS1 gene is as dramatic in nonphotosynthetic organs such as roots as it is in leaves. Experiments demonstrate that the small amount of light which passes through the soil is sufficient to repress AS1 expression in roots, indicating that light has a direct effect on AS1 gene expression in roots. The negative regulation of AS gene expression by light was shown to be a general phenomenon in plants which also occurs in nonlegumes such as Nicotiana plumbaginifolia and Nicotiana tabacum. Thus, the AS genes can serve as a model with which to dissect the molecular basis for light-regulated transcriptional repression in plants.

A deletion mutation in the SH2-N domain of Shp-2 severely suppresses hematopoietic cell development.

Shp-1 and Shp-2 are cytoplasmic protein tyrosine phosphatases that contain two Src homology 2 (SH2) domains. A negative regulatory role of Shp-1 in hematopoiesis has been strongly implicated by the phenotype of motheaten mice with a mutation in the Shp-1 locus, which is characterized by leukocyte hypersensitivity, deregulated mast cell function, and excessive erythropoiesis. A targeted deletion of 65 amino acids in the N-terminal SH2 (SH2-N) domain of Shp-2 leads to an embryonic lethality at midgestation in homozygous mutant mice. To further dissect the Shp-2 function in hematopoietic development, we have isolated homozygous Shp-2 mutant embryonic stem (ES) cells. Significantly reduced hematopoietic activity was observed when the mutant ES cells were allowed to differentiate into embryoid bodies (EBs), compared to the wild-type and heterozygous ES cells. Further analysis of ES cell differentiation in vitro showed that mutation in the Shp-2 locus severely suppressed the development of primitive and definitive erythroid progenitors and completely blocked the production of progenitor cells for granulocytes-macrophages and mast cells. Reverse transcriptase PCR analysis of the mutant EBs revealed reduced expression of several specific marker genes that are induced during blood cell differentiation. Stem cell factor induction of mitogen-activated protein kinase activity was also blocked in Shp-2 mutant cells. Taken together, these results indicate that Shp-2 is an essential component and primarily plays a positive role in signaling pathways that mediate hematopoiesis in mammals. Furthermore, stimulation of its catalytic activity is not sufficient, while interaction via the SH2 domains with the targets or regulators is necessary for its biological functions in cells. The in vitro ES cell differentiation assay can be used as a biological tool in dissecting cytoplasmic signaling pathways.

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.

Computed tomography in child abuse and cerebral contusion.

Cerebral contusion is considered to be the lesion leading to neurological sequelae of mental retardation and cerebral palsy in abused children. This has been difficult to document other than at autopsy or craniotomy by previously available techniques. Acute contusion or hemorrhage presumably secondary to contusion is readily documented by computed tomography (CT). We are reporting the cases of four children with alleged or suspected abuse and CT evidence of cerebral contusion. The contusion has been found both with and without external evidence of head injury.

Intrategmental infusion of cocaine decreases dopamine release and enhances norepinephrine release in the medial prefrontal cortex.

We evaluated the effects of local cocaine infusion into the A10 (ventral tegmental area), the cell body of the mesocorticolimbic dopaminergic pathway, on the extracellular concentrations of dopamine and norepinephrine in the medial prefrontal cortex, one of its terminal fields. A 1-ml Hamilton syringe was used to infuse a cocaine solution, either 20 or 200 microM, into the ventral tegmental area of anesthetized rats for 120 min through a microdialysis probe. The pure artificial cerebrospinal fluid (0 microM cocaine) infusion served as a control and a lidocaine (100 microM) infusion was administered to prevent the local anesthetic effect of cocaine. After intrategmental cocaine infusion (either 20 or 200 microM), extracellular dopamine and norepinephrine in the ventral tegmental area both increased significantly to a steady state level (208 +/- 42 and 148 +/- 23% for low dose and 220 +/- 24 and 150 +/- 15% for high dose). Simultaneously, the 200-microM cocaine infusion caused a significant decrease in extracellular dopamine (77 +/- 5%) but an increase in norepinephrine (140 +/- 6%) in the medial prefrontal cortex. The local anesthetic, lidocaine, produced no effects on the dopamine or norepinephrine output (neither in the ventral tegmental area nor in the medial prefrontal cortex). This study not only supports recent findings of an increase in extracellular dopamine and norepinephrine in the ventral tegmental area on intrategmental cocaine infusion, but also demonstrates that cocaine infused locally in the ventral tegmental area can decrease dopamine and increase norepinephrine at a remote terminal area (medial prefrontal cortex). Finally, the introduction rate of cocaine into the ventral tegmental area by retrograde microdialysis was found to be 0.83 ng/min for the low dose and 8.14 ng/min for the high dose.

Immunochemical demonstration of alpha 3 isozyme of Na,K-ATPase in human brain.

The catalytic alpha (alpha) subunit of the human Na,K-ATPase is encoded by multiple genes, as revealed from molecular cloning studies, yet the presence of the alpha 3 isoform has still not been resolved. We investigated the human alpha 3 isoform by Western blotting employing polyclonal anti-rat brain alpha 3 fusion protein, and purified human and rat axolemma Na,K-ATPase preparations. The antibody to rat brain alpha 3 fusion protein cross-reacted with both human and rat antigens, and the stained band superimposed on the alpha 2 band. This result suggests that alpha 3 isoform also exists in human brain.

Percutaneous transluminal angioplasty adjunct to thrombolysis for acute middle cerebral artery rethrombosis.

PURPOSE: To report three patients, each of whom had acute rethrombosis of a reopened middle cerebral artery after urokinase treatment for proximal stenosis (percutaneous transluminal angioplasty of the stenosis was performed adjunctive to the thrombolytic treatment to preserve the success of the thrombolysis), and a fourth patient who had percutaneous transluminal angioplasty right after the completion of thrombolysis and had no rethrombosis despite a partial dilatation of the severe stenosis. METHODS: Thrombolytic treatment was carried out by a coaxial technique with a Tracker 18 catheter through a 5-F angiographic catheter; 80,000 U in 5 mL of urokinase were intermittently injected every 15 minutes after an initial dose of 250,000 U. All patients were given 3000 U of heparin with a booster dose of 1000 U every hour. Angioplasty was performed with a Stealth catheter balloon, 2 to 3 mm x 1.5 cm. RESULTS: Three patients recovered without hemorrhage after percutaneous transluminal angioplasty and thrombolytic treatment. Percutaneous transluminal angioplasty was unsuccessful in one patient because of the inability to pass a 2-mm Stealth balloon catheter, and the result was a second rethrombosis. This patient had a poor recovery. CONCLUSION: Acute thrombosis of the middle cerebral artery may be associated with severe proximal stenosis. Rethrombosis may occur even after complete thrombolysis. Percutaneous transluminal angioplasty may be safely performed to prevent rethrombosis.

Acute thrombosis of the intracranial dural sinus: direct thrombolytic treatment.

Acute intracranial dural sinus thrombosis may have severe morbidity or fatal complications without appropriate treatment. Direct dural sinus venography can be performed safely with a soft Tracker catheter to document the fresh thrombus as an adjunct to CT or MR. We are reporting our experience with successful direct urokinase thrombolytic therapy in three cases of superior sagittal sinus and two cases of transverse and sigmoid sinus thrombosis. All five patients have recovered completely without any residual clinical deficit.

Risk of clot formation in femoral arterial sheaths maintained overnight for neuroangiographic procedures.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the presence of blood clots in femoral arterial sheaths maintained after cerebral angiography and the effect of heparinized saline on clot formation. METHODS: Twenty-three sheaths were evaluated in 18 patients. Sheaths were maintained for 14 to 80 hours (average, 33 hours; median, 24 hours). After the sheaths were removed, they were vigorously flushed with 60 mL of normal saline and the number and size of clots found in each sheath were recorded. Additionally, patients' age, catheter size, presence of heparin, amount of time the sheath was kept in the artery, and patients' coagulation status were recorded. RESULTS: Clots were found in 17 (74%) of the 23 sheaths. Ten catheters had continuous heparin drip, of which seven (70%) sustained clots. Of the 13 sheaths without heparin, 10 sustained clots (77%). The difference was not statistically significant. The average number of clots was 2.2, and the maximal length of clots ranged from 0.5 to 105 mm. No thromboembolic complications associated with sheath placement were encountered in our patient population. CONCLUSION: Blood clots are present in the vast majority of intraarterial sheaths maintained after cerebral angiography. These clots constitute a risk of thromboembolic complications in the event of repeat angiography. Sheath exchange should be considered before obtaining repeat cerebral angiograms.

Delayed effects in the treatment of carotid-cavernous fistulas.

Carotid-cavernous fistulas may be classified into: (1) internal carotid, (2) external carotid, or (3) a combination of both. They may result from traumatic or spontaneous rupture of the carotid artery into the cavernous sinus. Intravascular embolization has become the treatment of choice for the management of carotid cavernous fistulas. The authors report the delayed effects after the treatment of carotid-cavernous fistulas with experience of 74 cases over the past 6 years. The delayed effects may be summarized as follows: (1) progressive spontaneous occlusion of the fistula after partial balloon embolization, (2) false aneurysms may decrease in size and be spontaneously sealed off, (3) transient and persistent third or sixth cranial nerve palsy may be seen in about 16% of 74 cases, (4) posttraumatic fibrosis with narrowing of the carotid artery may be apparent after total occlusion of the fistula, (5) a prematurely deflated balloon may be dislodged into the carotid artery or its branch, and (6) spontaneous obliteration of common channels from internal carotid artery may occur after total occlusion of external carotid channels in those cases with a combination of internal carotid- and external carotid-cavernous fistulas. Certainly the delayed effect will alter our future planning in the treatment of carotid cavernous fistulas.

Percutaneous transluminal angioplasty of the carotid artery.

Percutaneous transluminal angioplasty (PTA) is being extensively applied to treat arteriosclerotic lesions. However, this application has not been widely accepted for the treatment of carotid artery stenosis. Successful attempts to relieve cerebral ischemia from extracranial carotid arterial stenosis by PTA are reported. Twenty-seven patients with arteriosclerotic stenosis, fibromuscular disease, and Takayasu carotid arterial stenosis were treated by PTA. All anatomic carotid stenotic lesions were corrected without any neurologic complication. Follow-ups ranged from 3 months to 4 years without recurrent symptoms in any patient. These results may suggest that some patients with cerebral ischemia secondary to extracranial carotid artery stenosis may be treated safely and effectively by PTA.

Transluminal angioplasty of the vertebral and basilar artery.

Transluminal angioplasty of brachiocephalic vessels for atherosclerotic lesions is now being performed in selected cases. We have thus far treated 17 cases of vertebral artery stenosis and one case of basilar artery stenosis by intravascular balloon dilatation techniques. Clinical presenting symptoms included vertebral basilar insufficiency, repeated transient ischemic attacks (TIAs), and multiple strokes. We performed successful transluminal angioplasty in 16 patients with marked narrowing (greater than 70%) of the dominant vertebral artery from atherosclerosis. One patient with basilar artery stenosis with tandem atherosclerotic lesions was also treated by angioplasty techniques. Repeat angiography at 3- to 12-month intervals has revealed continued patency at the angioplasty site. Complications occurred in our one patient with basilar artery angioplasty, who suffered a brainstem infarction after treatment, and in one patient who had a TIA after bilateral vertebral artery angioplasty. Two other patients had residual vertebral stenosis but remained asymptomatic after the procedure. All other patients who had successful dilatation were asymptomatic at 6 months to 2 years (mean, 15 months) of follow-up. These initial studies indicate that vertebral artery angioplasty may be effective for treating high-grade atherosclerotic lesions and for improving blood flow to the posterior circulation. Angioplasty of the basilar artery is technically more difficult and has a higher degree of risk because of the many perforating branches supplying the brainstem.

MR staging of acute dural sinus thrombosis: correlation with venous pressure measurements and implications for treatment and prognosis.

PURPOSE: To correlate parenchymal brain changes, venous sinus pressure measurements, and outcome in 29 patients with acute dural sinus thrombosis. METHODS: A retrospective review of 29 patients with angiographically proved acute dural sinus thrombosis was made from January 1989 to December 1993. MR examinations were performed on either a 0.5- or 1.5-T superconductive scanner in multiple planes. Direct dural sinus venography, cerebral angiography, and MR venography were performed. Venous sinus pressure measurements were obtained in 11 of 29 patients. RESULTS: We identified five distinct stages of brain parenchymal changes; each stage correlated with increasing intradural sinus pressure. The pressures measured in this study ranged from 20 to 50 mm Hg. Brain parenchymal changes were reversible up to stage III if thrombolytic treatment was performed. Beyond stage III, there were some residual changes, even after thrombolysis. All stage V patients died. CONCLUSION: Acute dural sinus thrombosis leads to distinct stages of parenchymal changes, the severity of which depends on the degree of venous congestion, which, in turn, is closely related to intradural sinus pressure. As intradural sinus pressure increases, progression from mild parenchymal change to severe cerebral edema and/or hematoma may occur if thrombolysis is delayed.

Computed tomography in acute posterior fossa infarcts.

Thirty-one cases of acute posterior fossa infarcts are reported. CT evidence of obliterated posterior fossa cisterns and hydrocephalus indicates a grave prognosis due to brainstem compression. Progressive obliteration of posterior fossa cisterns may be used as an indicator for surgical decompression. Patients with intact posterior fossa cisterns had good recoveries without surgical treatment. CT can be used to diagnose the very early phase of an acute posterior fossa infarct and has prognostic value in predicting the outcome.

Therapeutic embolization for vascular trauma of the head and neck.

Therapeutic embolization is an effective and relatively safe method for managing many cases of head and neck trauma. In the last 5 years, 78 traumatic vascular lesions--10 arterial transections and 68 arteriovenous fistula--were treated by intravascular embolization at four medical centers. Selection of embolic materials is discussed and different types of lesions are illustrated. Treatment was successful in every instance. Complications were limited to one case of cerebral infarction and two cases of temporary oculomotor weakness. The indications for embolization have widened beyond life-threatening hemorrhage alone, and continued improvement in techniques and embolic agents should see an increased use of this form of treatment.

Spinal arterial aneurysm: case report.

Isolated aneurysms of the spinal artery (not associated with arteriovenous malformations) are exceptionally rare. Fewer than 17 cases have been reported in the literature. We report a case of an isolated spinal artery aneurysm causing acute subarachnoid hemorrhage. Spinal artery aneurysms are contrasted with the more common intracranial aneurysms in terms of presentation and pathogenesis. The various clinical presentations of spinal artery aneurysms are discussed as well. A summary of all reported cases of spinal aneurysms, with and without associated arteriovenous malformations, is listed.

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.