In-Situ Growth of CoS Nanoparticles Onto Electrospun Graphitized Carbon Nanofibers as an Efficient Counter Electrode for Dye-Sensitized Solar Cells.

One-dimensional graphitized carbon nanofibers (G-CNFs) were prepared by employing facile electrospinning technique using 10 wt% of polyacrylonitrile (PAN) solution in N,N-dimethyl formamide (DMF) as precursor followed by successive stabilization, carbonization and purification processes. Cobalt sulfide (CoS) nanoparticles were grown onto G-CNFs by hydrothermal method using cobalt chloride and L-cysteine as precursors. The results of X-ray diffraction (XRD) and Raman spectroscopy confirmed the phase formation and degree of graphitization, respectively. Field-emission scanning electron microscope (FE-SEM) and transmission electron microscope (TEM) images confirmed the morphology, growth and distribution of CoS nanoparticles over G-CNFs (CoS/G-CNFs). The electrochemical studies such as cyclic voltammetry (CV), electrochemical impedance and Tafel polarization revealed that CoS/G-CNFs have lower overpotential, low charge transfer resistance and higher exchange current density for triiodide (I− 3 reduction reaction. The superior electrocat- alytic activity of CoS/G-CNFs than std. Pt is due to combined contribution of interconnected pore structure with high surface area of G-CNFs and excellent electrocatalytic activity of CoS. In addition, the dye sensitized solar cell (DSSC) based on platinum-free CoS/G-CNFs has exhibited higher photo-conversion efficiency (PCE) under a simulated solar light irradiation of 100 mW cm−2 when compared to standard platinum (std. Pt) which is attributed to the synergistic effect of CoS with G-CNFs.

Novel therapies for memory cells in autoimmune diseases.

Autoimmune diseases are a major cause of morbidity, and their incidence and prevalence continue to rise. Treatments for these diseases are non-specific and result in significant adverse effects. Targeted therapies may help in improving the risk : benefit ratio associated with treatment. Immunological memory is an important feature of the vertebrate immune system that results in the production of cells that are long-lived and able to respond to antigens in a more robust manner. In the setting of autoimmunity this characteristic becomes detrimental due to the ongoing response to a self-antigen(s). These memory cells have been shown to play key roles in various autoimmune diseases such as type 1 diabetes, multiple sclerosis and psoriasis. Memory T cells and B cells can be identified based on various molecules expressed on their surface. Memory T cells can be divided into three main categories - central memory, effector memory and resident memory cells. These subsets have different proliferative potential and cytokine-producing abilities. Utilizing differentially expressed surface molecules or downstream signalling pathway proteins in these cells it is now possible to target memory cells while sparing naive cells. We will discuss the various available options for such a strategy and several potential strategies that may yield successful therapies in the future.

A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma. PATIENTS AND METHODS: Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Patients were followed for toxicity, treatment response, and survival. RESULTS: Treatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively. CONCLUSION: Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

Diroximel fumarate to treat multiple sclerosis.

On October 29, 2019, the Food and Drug Administration (FDA) of the United States approved diroximel fumarate (DRF) as an oral fumarate for the treatment of relapsing forms of multiple sclerosis. Another oral fumarate, dimethyl fumarate (DMF), was approved for the same indication on March 27, 2013. Prior to its approval, DRF did not undergo rigorous testing to determine its efficacy, as its active metabolite, monomethyl fumarate, is the same as that of DMF (bioequivalency). The efficacy, safety and tolerability of DMF have previously been demonstrated in a number of clinical trials and real-world studies. For DRF, one phase III study has been completed, and another is in progress to determine its safety, tolerability and efficacy. In this paper, we review the pharmacology, pharmacokinetics, metabolism, clinical studies and drug safety of DRF.

Nucleosome mobility and the maintenance of nucleosome positioning.

To study nucleosome mobility and positioning, the R3 lac repressor was used with an adenosine triphosphate (ATP)-dependent chromatin assembly system to establish the positioning of five nucleosomes, with one nucleosome located between two R3 lac operators. When R3 protein was dissociated from DNA with isopropyl beta-D-thiogalactopyranoside, the R3-induced nucleosome positions remained unchanged for at least 60 minutes in the absence of ATP but rearranged within 15 minutes in the presence of ATP. These results suggest that nucleosomes are dynamic and mobile rather than static and that a DNA binding factor is continuously required for the maintenance of nucleosome positioning.

Management strategy for facial arteriovenous malformations.

Arteriovenous malformations (AVMs) are uncommon errors of vascular morphogenesis; haemodynamically, they are high-flow lesions. Approximately 50% of AVMs are located in the craniofacial region. Subtotal excision or proximal ligation of the feeding vessel frequently results in rapid progression of the AVMs. Hence, the correct treatment consists of highly selective embolisation (super-selective) followed by complete resection 24-48 hours later. We treated 20 patients with facial arteriovenous malformation by using this method. Most of the lesions (80%) were located within the cheek and lip. There were no procedure related complications and cosmetic results were excellent.

Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE.

BACKGROUND AND PURPOSE: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging. MATERIALS AND METHODS: Brain MR imaging using T1-weighted MP2RAGE at 500-µm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry. RESULTS: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage. CONCLUSIONS: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications.

Practice Patterns and Outcomes for Pemetrexed Plus Platinum Doublet as Neoadjuvant Chemotherapy in Adenocarcinomas of Lung: Looking Beyond the Usual Paradigm.

AIMS: Neoadjuvant chemotherapy (NACT) is the standard of care in non-small cell lung cancers (NSCLC) with locally advanced N2 disease. There is a scarcity of data for the pemetrexed-platinum regimen as NACT. Also, apart from N2 disease, the role of NACT in locally advanced NSCLCs for tumour downstaging is unclear. MATERIALS AND METHODS: Non-metastatic adenocarcinomas of lung treated with pemetrexed-platinum-based NACT were analysed. The patients with locoregionally advanced N2 disease and those who were borderline candidates for upfront definitive treatment were planned for NACT after discussion in a multidisciplinary clinic. In total, four cycles of 3-weekly pemetrexed and platinum were delivered in the combined neoadjuvant and adjuvant setting. A response assessment was carried out using RECIST criteria. Progression-free (PFS) and overall survival were calculated using the Kaplan-Meier method. RESULTS: Of 114 patients, 96 evaluable patients received NACT with pemetrexed-platinum. The most common indication for NACT was N2 disease at baseline (46.8%). The objective response rate was 36.4% (95% confidence interval 22-52%), including two complete and 32 partial responses, whereas 12.5% of patients had progressive disease on NACT. The median PFS was 14 months (95% confidence interval 10.7-17.3) and the median overall survival was 22 months (95% confidence interval 15.6-28.4) at a median follow-up of 16 months. There was a significant improvement in the overall survival of patients undergoing definitive therapy versus no definitive therapy (median overall survival 25 months [95% confidence interval 19.6-30.4] versus 12 months [95% confidence interval 3.2-20.7], respectively; P = 0.015, hazard ratio 0.56 [95% confidence interval 0.3-0.9]). Among patients who could not undergo definitive chemoradiation upfront due to dosimetric constraints (n = 34), 24 (70.6%) patients finally underwent definitive therapy after NACT. CONCLUSIONS: Pemetrexed-platinum-based NACT seems to be an effective option and many borderline cases, where upfront definitive therapy is not feasible, may become amenable to the same after incorporation of NACT.

Hair dye poisoning.

Hair dye ingestion is an uncommon form of poisoning in the west, however, in some parts of the world such as East Africa and Indian Sub-continent it is not uncommon. The main component of hair dye causing toxicity is Paraphenylenediamine (PPD). This compound has been found to cause angioneurotic edema, rhabdomyolysis and renal failure. We present a case of hair dye poisoning who presented with respiratory distress due to laryngeal edema and later developed trismus and carpopedal spasm. This case report highlights the combined toxicities of sodium EDTA and PPD.

Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis.

AIM: Patterns of care for metastatic renal cell carcinomas (mRCC) have seen tremendous reform in the last decade. Here, we present our pattern of care in second-line targeted therapy for mRCC. METHODS: Patients with mRCC treated with second-line therapy were included from a prospective database. Demographics, risk stratification, and treatment details were noted. Event-free survival (EFS) and overall survival (OS) was calculated using Kaplan-Meier method. Log-rank test was used to identify factors affecting EFS and OS. Multivariate analysis was performed using cox regression. RESULTS: Nearly 21.7% (46/212) of patients received second-line targeted treatment. Heng score for risk stratification showed 21.7% of patients in low risk, 36.9% in intermediate, and 34.8% in high risk group. Everolimus followed by pazopanib were the most common second-line therapies used in 65.2% and 13% of patients, respectively. The estimated median EFS was 3.5 months (95% confidence interval [CI] 2.7-4.26 months) and estimated median OS from the start of second-line therapy was 6.2 months (95% CI 3.4-9.0 months) with a median follow-up of 4.3 months. On univariate log-rank analysis, EFS of more than 6 months with first-line therapy was associated with improvement in EFS with second-line therapy (9.5 vs. 2.0 months; hazard ratio (HR) 0.364; P = 0.002). There was no factor independently associated with EFS or OS on multivariate analysis. CONCLUSION: Patterns of care for second line targeted therapy tend to vary with setting. A longer EFS with first-line therapy predicts improved outcomes with second-line treatment.

Seminal plasmin, a bovine seminal plasma protein, lyses dividing but not resting mammalian cells.

Seminal plasmin, an antimicrobial and transcription-inhibitory protein of bovine seminal plasma, is shown to lyse dividing mammalian cells in vitro. It lyses cells in culture such as CHO, Vero, HeLa and L929. It also lyses regenerating rat liver parenchymal cells and cells of two ascitic tumours of rat--the Zajdela ascitic hepatoma and the AK-5. However, it does not lyse resting cells such as adult liver parenchymal cells, erythrocytes, or resting lymphocytes, though it binds to their cell surface. It can be used, therefore, to distinguish cells that are in the division cycle from cells that are in the resting phase. The cell-lytic activity of seminal plasmin is inhibited by Ca2+.

A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer.

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On the basis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v. infusion schedule is warranted.

A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers.

PURPOSE: A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias, was conducted in patients with advanced cancers to: (a) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of squalamine lactate when given as a 120-h continuous i.v. infusion every two weeks; and (b) to obtain information on prolonged (>120-h) continuous i.v. infusions in patients who have tolerated 120-h infusions. EXPERIMENTAL DESIGN: A rapid dose escalation scheme was used that permitted intrapatient dose escalation. Three or more patients were treated at each dose, of which at least one patient started treatment de novo at that dose. Once DLT was encountered, the dose was decreased by one dose level, and the duration of infusion was prolonged from 10 up to 30 days in 5-day increments. RESULTS: Nineteen patients were treated at eight squalamine dose levels; the number of patients/dose level who received 120-h infusions were [expressed as dose in mg/m(2)/day (number of patients initiated de novo at that dose/total number of patients treated at that dose)]: 6 (3/3), 12 (3/6), 24 (1/5), 48 (2/6), 96 (4/10), 192 (2/6), 384 (3/8), and 538 (1/5). DLT was encountered at 384 mg/m(2)/day (1/3 de novo patients, 5/8 total patients) and 538 mg/m(2)/day (1/1 de novo patients, 4/5 total patients) and consisted of hepatotoxicity, characterized by grade 3 transaminase elevations that resolved 3-11 days after ceasing squalamine infusion. Three patients did not experience hepatotoxicity when first treated at 384 mg/m(2)/day but developed DLT at the same dose when de-escalated from 538 mg/m(2)/day. Other toxicities included grade 1-3 fatigue, grade 1-2 nausea, anorexia, and neuromuscular symptoms. The maximum duration of continuous i.v. infusion was 20 days at a dose rate of 192 mg/m(2)/day in one patient without adverse effects. Pharmacokinetic calculations revealed a linear relationship between area under the curve or Cmax and squalamine dose rate up to 384 mg/m(2)/day, with a prolonged terminal squalamine persistence in patient plasma (median t(1/2) = 18 h; range, 8-48 h). Transient tumor responses were observed in a patient with synovial cell sarcoma and a patient with breast carcinoma with cutaneous metastases. CONCLUSIONS: The best tolerated dose rate of squalamine when administered as a 120-h continuous i.v. infusion was 192 mg/m(2)/day; however, patients without prior exposure to squalamine appeared to tolerate a dose rate of 384 mg/m(2)/day without DLT. On the basis of preclinical evidence of synergy with cytotoxic agents and demonstration of human safety from this trial, additional clinical trials have been initiated with squalamine in combination with chemotherapy for patients with late stage lung cancer and ovarian cancer.

Dynamics of interaction of RNA polymerase II with nucleosomes. I. Effect of salts.

Mononucleosomes were labeled with the sulfhydryl-specific fluorescence probe 1,5-IAEDANS (5-(2-((iodoacetyl)amino)ethyl)amino-naphthalene-1-sulfonic acid) by attaching the dye to the single cysteine of H3 through a covalent linkage. The enzyme RNA polymerase II (pol II) utilized the native and the reconstituted fluorescent nucleosomes as templates with greatest efficiency when 0.2 M potassium acetate (AcOK) was used as the supporting salt; 0.2 M NaCl was found to be very much inhibitory. Measurement of polarity of the microenvironment of the dye at its binding site in the nucleosome showed the conformation to be more open in the presence of AcOK, compared to that in 0.1 or 0.2 M NaCl. The binding of pol II to the nucleosome resulted in a relatively more compact structure when measured in terms of the polarity of the microenvironment of the dye in various salt-dependent conformations of the nucleosomes. Time-resolved fluorescence spectroscopy showed that the probe molecule at its binding site undergoes certain excited-state processes, and the presence/absence or rate of these excited-state processes depends on the conformation of nucleosomes, which in turn depends on the type and concentration of the ion present in the medium. Time-resolved emission spectra showed that binding of nucleosomes by pol II established some new contacts that resulted in inaccessibility of the dye to the bulk solvent, reflecting a more hydrophobic environment for the dye in the steady-state spectra. Thus, binding or transcription of nucleosomes by pol II did not break open their structure. Rather, some transient internal adjustments within the histone octamer may take place to accommodate the bulky pol II molecule.

Dynamics of interaction of RNA polymerase II with nucleosomes. II. During read-through and elongation.

The sulfhydryl-specific fluorescence probe 1,5-IAEDANS (5-(2-((iodoacetyl)amino)ethyl)amino-naphthalene-1-sulfonic acid) was attached to the single cysteine of H3, and reconstituted fluorescent mononucleosomes were used as the template for in vitro transcription by the yeast RNA polymerase II (pol II). DNase I digestion analysis revealed that transcription of nucleosomes by pol II resulted in an overall loosening of the structure. Monitoring the transcription event by steady-state fluorescence analysis showed that nucleosomes only partially open during transcription. This opening is transient in nature, and nucleosomes close back as soon as the pol II falls off the template. Thus, using the technique of fluorescence spectroscopy, partial opening of nucleosome structure could be differentiated from complete dissociation into free DNA and histone octamer, a distinction that may not be possible by techniques like gel electrophoresis. Time-resolved fluorescence emission spectroscopy suggested that during read-through of the template by the pol II, histone octamers do not fall off the DNA. Only minor conformational changes within the histone octamer take place to accommodate the transcribing polymerase.

DNA intervention in transcriptional activation.

Accurate initiation of eukaryotic mRNA synthesis takes place as a result of the interplay between general transcription factors and RNA polymerase II. Activation of transcription from the basal level involves a number of promoter-specific trans-acting factors which interact with cis elements in the promoter DNA. In this paper we have emphasized the importance of even those portions of the promoter stretch which do not have any identifiable binding sites for regulatory proteins. The length and structure of the DNA between cognate binding sites of trans-acting factors may interfere with the level of transcriptional activation. Depending upon the length of the intervening DNA we describe three cases of transcriptional activation. In addition, based on this classification we propose a new third domain, the other two being DNA binding and transcriptional activation domains, which is involved in bending the intervening DNA so that activation from a distance can take place successfully.

Spectroscopic studies on the mode of binding of ATP, UTP and alpha-amanitin with yeast RNA polymerase II.

The binding affinity between the substrates ATP and UTP with the purified yeast RNA polymerase II have been studied here in the presence and absence of Mn2+. In the absence of template DNA, both ATP and UTP showed tight binding with the enzyme without preference for any specific nucleotide, unlike Escherichia coli RNA polymerase. Fluorescence titration of the tryptophan emission of the enzyme by nucleoside triphosphate substrates gave an estimated Kd value around 65 microM in the absence of Mn2+ whereas in the presence of Mn2+, the Kd was 20 microM. The effect of substrates on the longitudinal relaxation of the HDO proton in enzyme-substrate complex also yielded a similar Kd value.

Seminalplasmin and caltrin are the same protein.

The sequence of seminalplasmin, a basic antimicrobial and transcription-inhibitory protein from bovine seminal plasma, has been determined using an automated sequenator. This sequence is slightly different from that reported earlier by Theil and Scheit [(1983) EMBO J. 2, 1159-1163] and identical with that of caltrin, a Ca2+-transport-inhibitory protein of bovine seminal plasma. Caltrin and seminalplasmin are, therefore, the same protein.

Seminalplasmin inhibits transcription and translation of phi80 DNA in vitro.

Seminalplasmin, an antimicrobial protein from bovine seminal plasma that has been earlier shown to inhibit transcription in whole cells and by purified RNA polymerase in vitro, but not translation in whole cells, is now shown to inhibit both transcription and translation independently of each other, in a coupled transcription-translation system from E. coli using phi80dphoAlacZ DNA as the template.

Docetaxel and gemcitabine combinations in non-small cell lung cancer.

Docetaxel and gemcitabine have been shown to be active as single agents in a variety of solid tumors. These two agents have been studied in combination with several different treatment schedules. Two phase I studies used a novel 2-week administration schedule that involved a 1-hour infusion of 35 mg/m2 to 65 mg/m2 docetaxel and gemcitabine administered as either a 30-minute infusion (2,000 to 4,000 mg/m2) or a 10 mg/m2/min infusion (1,000 to 1,200 mg/m2 total dose). Another novel phase I study evaluated the effect of drug sequence on toxicities. Patients received 30 to 40 mg/m2 docetaxel and 800 to 1,250 mg/m2 gemcitabine on days 1 and 8 every 21 days. Two phase I studies of a monthly docetaxel regimen have been conducted. Patients received 800 mg/m2 gemcitabine on days 1, 8, and 15 and 100 mg/m2 docetaxel on day 1 of a 28-day cycle. Finally, in a phase II study, patients received 900 mg/m2 gemcitabine on days 1 and 8 and 100 mg/m2 docetaxel on day 8, with granulocyte colony-stimulating factor administered on days 9 through 15. In these studies, antitumor responses were observed in lung cancer as well as a number of other histologies. Neutropenia was the most frequent dose-limiting toxicity and no difference in clinical toxicity was observed with either sequence of administration. The emerging evidence suggests, therefore, that the combination of gemcitabine and docetaxel is active in a variety of solid tumors and is well tolerated.