First reported case of concurrent sonidegib and radiotherapy for recurrent, advanced basal cell carcinoma

Basal cell carcinoma (BCC ) is the most common human malignancy. Systemic therapy with a sonic hedgehog (SHH) pathway inhibitor plays an important role in the treatment of advanced BCC . Literature on concurrent use of radiation therapy (RT) with SHH inhibitors has been minimal and has solely been focused on vismodegib. We present a case report of a patient with recurrent basal cell carcinoma involving the high-risk area of the face, who was denied surgery due to comorbidities and difficulty in obtaining complete tumor removal without cosmetic or functional impairment. The patient received combined treatment of fractionated radiation with concurrent sonidegib and had complete clinical response with no significant toxicities. This is the first reported case on the use of concurrent RT with sonidegib for management of recurrent basal cell carcinoma of the head and neck

Comparative Study of the Stapled Hemorrhoidectomy Against Conventional Hemorrhoidectomy

Introduction: Till recently Milligan – Morgan haemorrhoidectomy i.e. conventional or open haemorrhoidectomy is the most popular surgical treatment for haemorrhoids. With the advent of minimal invasive surgery, the scenario has changed. More recently, stapler haemorrhoidectomy is becoming popular as a day care procedure with minimal post-operative pain and early return to work. The present study is designed to compare make a comparative assessment of the Stapled haemorrhoidectomy against Conventional haemorrhoidectomy in the surgical treatment of haemorrhoids. Material & Methods: A hospital based Non-randomised comparative study was conducted in Dept. of Surgery of at a tertiary care hospital. A total of 50 eligible cases scheduled for haemorrhoidectomy in our hospital were included in the study.  These 50 patients were then divided into two groups i.e. 25 for stapled procedure and other 25 patients for conventional procedureData was analyzed using statistical software SPSS ver. 21. Results: Mean operative time was significantly less in stapler group (39.12 vs 45.75 mins; p<0.01) while mean hospital stay was significantly longer in conventional surgery group (7.02 vs 3.01 days; p<0.01). Post-op complain of pain, immediately after surgery (6 hrs.) and at day 1 and day 3 was significantly less in stapler group (p<0.01).&nbsp

A Critical Review on Hygrothermal and Sound Absorption Behavior of Natural-Fiber-Reinforced Polymer Composites

Increasing global environmental problems and awareness towards the utilization of eco-friendly resources enhanced the progress of research towards the development of next-generation biodegradable and environmentally friendly material. The development of natural-based composite material has led to various advantages such as a reduction in greenhouse gases and carbon footprints. In spite of the various advantages obtained from green materials, there are also a few disadvantages, such as poor interfacial compatibility between the polymer matrix and natural reinforcements and the high hydrophilicity of composites due to the reinforcement of hydrophilic natural fibers. This review focuses on various moisture-absorbing and sound-absorbing natural fiber polymer composites along with the synopsis of preparation methods of natural fiber polymer composites. It was stated in various studies that natural fibers are durable with a long life but their moisture absorption behavior depends on various factors. Such natural fibers possess different moisture absorption behavior rates and different moisture absorption behavior. The conversion of hydrophilic fibers into hydrophobic is deemed very important in improving the mechanical, thermal, and physical properties of the natural-fiber-reinforced polymer composites. One more physical property that requires the involvement of natural fibers in place of synthetic fibers is the sound absorption behavior. Various researchers have made experiments using natural-fiber-reinforced polymer composites as sound-absorbing materials. It was found from various studies that composites with higher thickness, porosity, and density behaved as better sound-absorbing materials

A glycan-based approach to therapeutic angiogenesis.

Angiogenesis, the sprouting of new blood vessels from existing vasculature, involves multiple complex biological processes, and it is an essential step for hemostasis, tissue healing and regeneration. Angiogenesis stimulants can ameliorate human disease conditions including limb ischemia, chronic wounds, heart disease, and stroke. The current strategies to improve the bioavailability of pro-angiogenic growth factors, including VEGF and FGF2, have remained largely unsuccessful. This study demonstrates that small molecules, termed click-xylosides, can promote angiogenesis in the in vitro matrigel tube formation assay and the ex ovo chick chorioallantoic membrane assay, depending on their aglycone moieties. Xyloside treatment enhances network connectivity and cell survivability, thereby, maintaining the network structures on matrigel culture for an extended period of time. These effects were achieved via the secreted xyloside-primed glycosaminoglycans (GAG) chains that in part, act through an ERK1/2 mediated signaling pathway. Through the remodeling of GAGs in the extracellular matrix of endothelial cells, the glycan approach, involving xylosides, offers great potential to effectively promote therapeutic angiogenesis

Model of xyloside effects on angiogenesis: When dosed at the optimal concentration, xylosides exhibit minimal decoy effect and prime GAG chains that can contribute to growth factor stabilization and signaling, thereby, promoting angiogenesis.

<p>(A) Fluoro-xylosides and xylosides dosed at high concentrations can compete with endogenous proteins for the GAG biosynthetic machinery. This reduces cell surface proteoglycan associated GAGs which are necessary for VEGF and FGF2 signaling. (B) When dosed at the optimal concentration which exploits the GAG priming activities and minimizes the decoy effect, xylosides can promote angiogenesis through the stabilization of VEGF and FGF2 signaling. (C) While the overall increase in the amount of GAG chains is a great contributory factor to promoting angiogenesis, the type and structure of GAGs primed are also important to potentiate growth factor (GF) signaling.</p

Structural analysis of xyloside primed GAG chains.

<p>HUVEC cultures were treated with xylosides <b>3</b> or <b>4</b> at 1, 10 or 100 μM with [S³⁵]-SO₄ and incubated for 2 days. GAGs from the media and cell extracts were then purified over a DEAE column. BLUE: Endogenous GAGs, GREEN: Xyloside <b>3</b> primed GAGs, and RED: Xyloside <b>4</b> primed GAGs. (A) 100,000 CPM of purified radiolabeled GAGs when primed at 1 or 10 μM, and 200,000 CPM of GAGs when primed at 100 μM were analyzed separately over a DEAE-3SW column for anion-exchange chromatography. When primed at 10 and 100 μM, xyloside <b>3</b> primed GAGs have similar HS/CS ratios to the endogenous GAGs while xyloside <b>4</b> primed GAGs have approximately 3–4 times the amount of CS than HS. When primed at 1 μM, both <b>3</b> and <b>4</b> primed more CS than HS, although <b>4</b> still primes relatively more CS than <b>3</b> (B). Radiolabeled GAGs were digested with heparitinase I/II/III and analyzed over the CarboPac analytical PA1 column. Generally, xyloside primed GAGs have similar HS compositions to endogenous GAGs with the exception of xyloside <b>4</b> primed at 100 μM that has an extra disulfated peak. (C) Radiolabeled GAGs were digested with chondroitinase ABC and analyzed over YMC PA-G column. The CS disaccharides primed by the xylosides have additional disulfated peaks compared to endogenous CS; All peaks were identified by matching with HS and CS disaccharide standards.</p

Click-xylosides promoted endothelial tube formation in the matrigel tube formation assay.

<p>(A) Nine click-xylosides were preliminary screened for their ability to facilitate HUVEC network formation in matrigel cultures. The respective images were taken at 8 hours after cell seeding. (B) The network properties of the preliminary screening experiment was quantified at 8 hours using the Angiogenesis Analyser ImageJ plugin. The network properties compared are the number of junctions which are branching points, segments which are the tube like elements delimited by two junctions, meshes which are enclosed by segments and the total branching length of the formed network. The data for this preliminary study was averaged over three experiments. No statistical significance were observed between the treatments as determined by one-way ANOVA (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182301#pone.0182301.s001" target="_blank">S1A Table</a>). Two-sample T-tests (unpaired data with unequal variances) were performed for each xyloside treatment against the untreated control. Statistical significance, as determined by the student T-test against the no treatment control, is indicated by * when p<0.05, ** when p<0.005 and *** when p<0.0005 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182301#pone.0182301.s001" target="_blank">S1B Table</a>). (C) TOP: The values were expressed as fold change relative to the no treatment control. Overall, xyloside <b>2</b> treatment produced the greatest effect, while xyloside <b>4</b> has the lowest fold change. BOTTOM: The other seven xylosides, 1, 3 and 5–7, showed similar effects: the fold changes were averaged over the seven compounds. For the fold change values, a one sample T-test against the control mean value of one was carried out and statistical significance as determined by the T-test is indicated by * when p<0.05, ** when p<0.005 and *** when p<0.0005 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182301#pone.0182301.s001" target="_blank">S1C Table</a>). All error bars reflects the standard error.</p

Click-xylosides stabilizes HUVEC networks on matrigel 48 hours after culture.

<p>Representative images of calcein stained HUVECs treated with xylosides <b>2</b>, <b>3</b> or <b>4</b> at 100 μM, and a no treatment control on matrigel matrix (A) after 8 hours, and (B) after 48 hours of culture; Images in the same row are from the same experiment.</p

Click-xyloside 3 loaded collagen gels trigger localized increase in endothelial cell density in chick chorioallantoric membrane.

<p>(A) Placement of collagen gels on the yolk sac membrane Collagen gels loaded with 1 mM, 5 mM and 10 mM xyloside <b>3</b> or DMSO (solvent) control was placed on the yolk sac of the chick embryo at Day 13 of development (Black arrows). Care was taken to ensure that the gels were placed at least 1 cm apart from each other. (B) Ingrowth of blood vessels were observed in the control and the xyloside <b>3</b> loaded collagen gels (white arrows). (C) At the end of the experiment, the collagen gels with the chorioallantoric membrane were sectioned in a plane orthorgonal to the topview shown in A and B. 12 μm thick sections were made across the entire gel and at least 20 cross sections distributed evenly across each gel was chosen for analysis of the endothelial cell density around the collagen gel. An area encompassing the gel and a 50 pixels radius border of each image were selected for analysis. The density of endothelial cells was calculated by dividing the total number of red pixels in the selected area (summed over all images of a single gel) by the total number of selected pixels (summed over all images of a single gel). (D) Cross sections of the collagen gels immunofluorescently stained with antibodies against VEGF Receptor 1 (VEGFR1, green) and VEGF Receptor 2 (VEGFR2, red) for endothelial cells, and DAPI (blue) for nuclei, and brightfield images of the same cross sections overlaid with VEGFR1/VEGFR2 staining. White arrows point to pre-existing large blood vessels. Black arrows point to the interface between the collagen gel and the membrane, arrow head points in the direction of the membrane. The enlarged view of the area enclosed by the black box in the brightfield images are also displayed. (E) The density of the VEGFR1 fluorescence around the gel was calculated and normalized to the control gel of each embryo. The normalized values were averaged between 3 samples for the 1 mM and 10 mM. Data shown for 5 mM is over 2 samples. (F) The 1 mM and 5 mM xyloside <b>3</b> samples were grouped together and averaged. A one sample T-test were performed with the grouped data against control with a mean of 1 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182301#pone.0182301.s005" target="_blank">S5 Table</a>). The treated group has significantly higher endothelial cell density compared to the control group. Significant difference is indicated by * where p < 0.05. Error bars reflect the standard error.</p

Xylosides and xylosides primed GAGs increases network connectivity of the HUVEC networks on matrigel.

<p>(A) Priming activity of the xylosides in HUVECs determined by radiolabeling with [S³⁵]-SO₄ (n = 3) depicted as fold change relative to control (= 1); The network properties of matrigel tube formation assay when cultured in (B) fresh media with xylosides at 100 μM concentration (n = 9), (C) 1 and 10 μM concentration (n = 4 for both concentrations) and (D) conditioned media with unprimed xylosides and xyloside-primed GAGs (n = 3), were quantified after 8 hours with the Angiogenesis Analyzer plugin. Conditioned media was collected from HUVECs treated with 100 μM of xylosides (or no treatment for control samples) for 2 days before use in the matrigel tube formation assay. The network properties compared are the number of junctions that are the branching points, segments that are the tube like elements delimited by 2 junctions, meshes thatare enclosed by segments and the total branching length of the formed network. One-way ANOVA with post-hoc Tukey’s test was used to determine statistical significance (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182301#pone.0182301.s003" target="_blank">S3B, S3C, S3D and S3F Table</a>). The network characteristics are depicted as fold change relative to the untreated control in (E). One sample T-test against the mean value of 1 (control) was used to determine statistical significance (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182301#pone.0182301.s003" target="_blank">S3E and S3G Table</a>). Generally, the greatest fold change was seen when the conditioned media was used, indicating that the differences between the treated samples and the untreated control was more pronounced with the conditioned media. The number of experiments conducted is indicated by the stated n value with 3 technical replicates per experiment. Statistically significant difference is indicated by * when p<0.05, ** when p<0.005 and *** when p<0.0005. All error bars reflect the standard error.</p