Shear‐Induced Crystallization and Shear‐Induced Dissolution of Poly(ethylene oxide) in Mixtures with Tetrahydronaphthalene and Oligo(dimethyl siloxane‐b‐ethylene oxide)

Cloud point temperatures (T_cp) and crystallization temperatures (T_l/s) were measured at different constant shear rates for the ternary system tetrahydronaphthalene/poly(ethylene oxide)/oligo(dimethyl siloxane‐b‐ethylene oxide) using a rheo‐optical device and in the case of T_l/s additionally a viscometer. This system enables for the first time a joint investigation of both transitions with a given mixture. Shear favors the homogeneous liquid state and the formation of crystals. T_cp (liquid/liquid demixing, UCST) shifts to lower and T_l/s (liquid/solid, segregation of PEO) to higher temperatures by several degrees as the shear rate, , is increased up to 500 s^?1. The normalized shift in T_cp fits well into previous results for high molecular weight blends, oligomer mixtures, polymer solutions in single solvents and low molecular weight mixtures. A phase separated near critical blend was examined 1 K below its T_cp by means of a shear cell (Linkam) in the quiescent state and under shear with respect to its morphology. Upon an increase in one observes a transition from the co‐continuous structures existing in the quiescent state via deformed and oriented particles to string like morphologies. Finally, at sufficiently high shear rates the mixture becomes homogeneous and structures can no longer be seen under the microscope. The morphologies developing after the secession of shear are pointing to pronounced influences of the flow history of the system on the final structure of two phase blends.

Equilibrium phase diagram of the system THN/COP/PEO at the indicated temperatures as obtained from turbidimetric titration. The curve for 42 °C indicates the compositions under which the mixtures segregate the first solid PEO particles upon cooling. The curves for the higher temperatures denote the demixing of the homogeneous system into two liquid phases.     

Design of Chronomodulated Drug Delivery System of Valsartan: In Vitro Characterization

The aim of the present study was to design and evaluate a chronomodulated time-clock pulsatile tablets of valsartan to release it after a certain lag time, independent of the gastrointestinal pH, in its absorption window to cope with the circadian rhythm of human body for blood pressure elevation. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH101, croscarmellose sodium, magnesium stearate and Aerosil. The core tablets were then sprayed coated with a sealing layer formed of ethyl cellulose that was subsequently coated with a release-controlling layer. Three different aqueous dispersions namely; carnauba wax or beeswax or a mixture in a ratio of 2.5:1, respectively, were used to form five time-clock tablet formulations having the release controlling layer with different thickness {B5, B10, B20, BW5 and CW5}. Quality control testing were carried out to the core tablets. Differential scanning calorimetry was also performed to detect the possible drug excipient interaction in the core tablet formulation. The release was carried out, for the prepared time-clock tablet formulations, in 0.1 N hydrochloric acid for the first 2 h, followed by phosphate buffer (pH 6.8) for 4.5 h. The effect of pH on valsartan release was studied through a release study in 0.1 N hydrochloric acid for 6.5 h. Two phase dissolution study was performed to the selected time-clock tablet formulation to predict the drug permeation through the gastrointestinal tract. Stability study of the selected formula was performed at 25°/60% RH and at 40°/75% RH for 3 months. Results showed that a release-controlling layer composed of a mixture of carnauba wax and beeswax in a ratio of 2.5:1 showed a reasonable release lag time. The release lag time of the tablets increased with the increase of the coat thickness, thus B20>B10>B5 with corresponding lag time values of 4.5, 3 and 2.5 h, respectively. Selected B5 tablet formula exhibited a reasonable lag time after which the highest, complete % drug release at pH 6.8 was obtained. In addition, a good partitioning of valsartan, between the aqueous and organic phases in a ratio of 1:7, was observed. The selected formula was stable for at least 3 months under standard long-term and accelerated storage conditions. In conclusion, in vitro studies revealed that the novel time-clock system could be used successfully to deliver valsartan in a pulsatile pH-independent manner. It provided a desirable lag time followed by a rapid and complete drug release accompanied by an expected effective permeation through the biological membranes upon release in the duodenum; the window of absorption, as indicated by the two phase release study.     

Broadband Dielectric Relaxation Spectroscopy of Functionalized Biobased Castor Oil Copolymer Thermosets

Novel biorenewable copolymer thermosets are successfully synthesized by the ring‐opening metathesis polymerization (ROMP) of norbornenyl‐functionalized castor oil (NCO) and norbornenyl‐functionalized castor oil alcohol (NCA) with controlled amounts of 0.8 and 1.8 norbornene rings per fatty acid chain, respectively. The NCO and NCA monomers are mixed in different concentrations and simultaneously polymerized via ROMP using Grubbs catalyst. Broadband dielectric relaxation spectroscopy (BDRS) is used to investigate the molecular dynamics of the fully cured copolymer thermosets over a wide range of frequencies (5 × 10^?2 to 0.5 × 10⁷ Hz) at different constant temperatures (?70 to 125 °C). Four phenomena, namely α‐, β‐, and γ‐relaxation processes and ionic conductivity are observed for all the measured samples.

     

Recurrence After Transanal Excision of T1 Rectal Cancer: Should We Be Concerned?

PURPOSE Transanal excision is an appealing treatment for low rectal cancers because of its low morbidity, mortality, and better functional results than transabdominal procedures. However, controversy exists about whether it compromises the potential for cure. Several, recent reports of high recurrence rates after local excision prompted us to review our results of transanal excision alone in patients with T1 rectal cancers.METHODS All patients with T1 low rectal cancer undergoing local excision alone between 1980 through 1998 were reviewed for local recurrence, distant metastasis, disease-free interval, results of salvage surgery, and overall and disease-free survival. Demographics, tumor size, distance from anal verge, and preoperative endoluminal ultrasound results also were recorded. Patients with poorly differentiated tumors, perineural or lymphovascular invasion, or with mucinous component were excluded.RESULTS Fifty-two patients underwent transanal excision during the study period. Five-year recurrence was estimated to be 29.38 percent (95 percent confidence interval, 15.39–43.48). For 52 patients, five-year, cancer-specific and overall survival rates were 89 and 75 percent respectively. Fourteen of 15 patients with recurrence underwent salvage treatment with 56.2 percent (95 percent confidence interval, 35.2–90) five-year survival rate. Gender, preoperative staging by endorectal ultrasound, distance from the anal verge, tumor size, location, and T1 status discovered after transanal excision of a villous adenoma did not influence local recurrence or tumor-specific survival.CONCLUSIONS Transanal excision for T1 rectal tumors with low-grade malignancy has a high rate of recurrence. Although overall cancer survival rates might be regarded as satisfactory, this high recurrence and low salvage rate raises the issue about the role of transanal excision alone for early rectal cancer and the possible need for adjuvant therapy or increased role of resective surgery.Presented at the meeting of The American Society of Colon and Rectal Surgeons, Chicago, Illinois, June 3 to 7, 2002.     

Predictors of long-term survival after pancreaticoduodenectomy for peri-ampullary adenocarcinoma: A retrospective study of 5-year survivors

Background: Pancreaticoduodenectomy(PD) is the standard curative treatment for periampullary tumors. The aim of this study is to report the incidence and predictors of long-term survival( ≥ 5 years) after PD. Methods: This study included patients who underwent PD for pathologically proven periampullary adenocarcinomas. Patients were divided into 2 groups: group(I) patients who survived less than 5 years and group(II) patients who survived ≥ 5 years. Results: There were 47(20.6%) long-term survivors( ≥ 5 years) among 228 patients underwent PD for periampullary adenocarcinoma. Patients with ampullary adenocarcinoma represented 31(66.0%) of the long-term survivors. Primary analysis showed that favourable factors for long-term survival include age 60 years old, serum CEA 5 ng/mL, serum CA 19-9 37 U/mL, non-cirrhotic liver, tumor size 2 cm, site of primary tumor, postoperative pancreatic fistula, R0 resection, postoperative chemotherapy, and no recurrence. Multivariate analysis demonstrated that CA 19-9 37 U/mL [OR(95% CI) = 1.712(1.24 8–2.34 8), P = 0.001], smaller tumor size [OR(95% CI) = 1.335(1.032–1.726), P = 0.028] and R0 resection [OR(95% CI) = 3.098(2.095–4.582), P 0.001] were independent factors for survival ≥ 5 years. The prognosis was best for ampullary adenocarcinoma, for which the median survival was 54 months and 5-year survival rate was 39.0%, and the poorest was pancreatic head adenocarcinoma, for which the median survival was 27 months and 5-year survival rate was 7%. Conclusions: The majority of long-term survivors after PD for periampullary adenocarcinoma are patients with ampullary tumor. CA 19-9 37 U/mL, smaller tumor size, and R0 resection were found to be independent factors for long-term survival ≥ 5 years.     

Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.Malaria is a global health problem with 214 million new cases of malaria and 438,000 deaths reported in 2015, mostly in sub-Saharan Africa (1). The endoperoxide class of antimalarial drugs, such as artemisinin (ART), is the first line of defense against malaria infection against a backdrop of multidrug-resistant parasites (2) and lack of effective vaccines (3, 4). Given the effectiveness of the ART class, the question arises: how do these drugs kill parasites? A suggested mechanism of action involves the cleavage of the endoperoxide bridge by a source of Fe²⁺ or heme. This cleavage results in the formation of oxyradicals that rearrange into primary or secondary carbon-centered radicals. These radicals have been proposed to alkylate parasite proteins that somehow result in the death of the parasite (5). However, this proposal remains a subject of intense debate (6, 7), while these alkylated proteins are yet to be formally identified. So far, the proposed targets of ART action include a PfATP6 enzyme, the Plasmodium falciparum ortholog of mammalian sarcoendoplasmic reticulum Ca²¹-ATPases (SERCAs) (5), translational controlled tumor protein, and heme (5). Additionally, Haynes et al. (8) proposed that ART may act by impairing parasite redox homeostasis as a consequence of an interaction between the drug and flavin adenine dinucleotide (FADH) and/or other parasite flavoenzymes in the parasite, leading to the generation of reactive oxygen species (ROS). New approaches are required for definitive identification of ART molecular targets. This insight into the drug activation-dependent mechanism of action will be invaluable in the target-led development of more potent drugs with the potential to circumvent the emergence of resistance to current first-line ART-based therapies. The goal of this study was to identify ART-targeted proteins and their interacting partners in P. falciparum. We recently adopted a proteomic approach developed by Speers and Cravatt (9) to synthesize a suite of pyrethroid activity-based protein profiling probes (ABPPs) (10). Using alkyne/azide-coupling partners through “click chemistry,” we identified several cytochrome P450 enzymes that metabolized deltamethrin in rat liver microsomes (10). More recently, a chemical proteomic approach was developed to identify parasite proteins targeted by an albitiazolium antimalarial drug candidate in situ using a photoactivation cross-linking approach (11). However, this generic approach can introduce significant promiscuity in the proteins tagged based on the intracompartmental distribution of drug independent of actual mechanisms.Here, we introduced the design and synthesis of click chemistry-compatible activity-based probes incorporating the endoperoxide scaffold of ART as a warhead to alkylate and identified the ART molecular target(s) in asexual stages of the malaria parasite (Fig. 1). A major advantage of this strategy is that the reporter tags are introduced under “click” reaction conditions performed after the drug has achieved its biological effects, enabling purification, identification, and quantification of alkylated parasite’s proteins and their interacting partners as shown in Fig. 1B. To avoid nonspecific probe-dependent tagging, a common limitation of these approaches, we generated the respective “control” nonperoxide partners to improve the specificity and biological relevance of our resultant tagged protein list.Open in a separate windowFig. 1.Rational design of the ART-ABPPs. (A) Conversion of ART to ART-ABPPs involves the addition of a clickable handle (i.e., an alkyne or azide to the ART drug pharmacophore by the peptide-coupling method illustrated in SI Text). The structures of the alkyne (P1) and azide (P2) probes and respective inactive deoxy controls CP1 and CP2 with in vitro IC₅₀ values are presented. (B) General workflow of copper-catalyzed and copper-free click chemistry approaches used in the identification of alkylated proteins after in situ treatment of P. falciparum parasite with alkyne and azide ART-ABPPs. The azide- and alkyne-modified proteins are tagged with biotin azide and biotin dibenzocyclooctyne (Biotin-DIBO), respectively, via click reactions followed by affinity purification tandem with LC-MS/MS for protein identification.     

Role of p53 Arg72Pro SNP in the pathogenesis of gliomas and its effect on serum level of p53

Gliomas account for almost 80 % of primary malignant brain tumors and are a major cause of morbidity and mortality more than any other tumor. The p53 gene is a tumor suppressor gene that plays a role in genomic stability, cell cycle control, and DNA repair after damage and apoptosis. Malfunction of the p53 pathway is a universal hallmark of human tumors with p53 codon 72 polymorphism reported to affect regulatory networks central to glioma development. The aim of work was to investigate the role of p53 Arg72Pro single nucleotide polymorphism (SNP) in the pathogenesis of gliomas and its effect on the serum level of p53. Forty-five glioma patients and 50 control subjects were included for whom genotyping for p53 Arg72Pro SNP by polymerase chain reaction-restriction fragment length polymorphism as well as measurement of serum p53 level were done. No statistically significant difference was observed in genotype distribution or allele frequency between cases and control and nor was there a significant difference in serum p53 level. In conclusion, in our work, no association was detected between p53 Arg72Pro SNP and the pathogenesis of gliomas, and neither was there an observed effect for the different genotypes on serum p53 levels.