A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide,ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced solid tumours

Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.Methods We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.Results Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10–300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1–2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3–18) weeks. Four of 18 evaluable patients (22%) had stable disease.Conclusions Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.Subject terms: Drug development, Drug safety     

Aramid-wrapped CNT hybrid sol–gel sorbent for polycyclic aromatic hydrocarbons

This work describes the preparation of an analytical microextraction sorbent using a simple and versatile sol–gel hybrid composite, i.e., aramid oligomers wrapping multi-walled carbon nanotubes (CNTs) covalently bonded to a porous silica network. To overcome the inherent shortcomings of the CNTs'' solubility and dispersion in both organic phases and in the sol–gel solution, the outer surface of the CNTs was initially functionalized with carboxylic acid groups and then reacted with both aramid oligomers and 3-aminopropyl triethoxysilane (APTES). The obtained sorbent was characterized by FT-IR, scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). Using sol–gel chemistry, the functionalized CNTs were coated onto SPME fibers and used in conjunction with GC-MS for the analysis of polycyclic aromatic hydrocarbons (PAHs) in water and soil samples. Excellent repeatability (run-to-run RSD% ∼ 8) and reproducibility (fiber-to-fiber RSD% ∼ 6) were achieved in addition to low LODs (0.10–0.30 ng mL⁻¹) and noticeable recovery%. The present method of sorbent preparation led to enhanced thermal and chemical stabilities, a long sorbent lifetime and good affinity towards PAHs. Moreover, the present sorbent enhanced the extraction capability by more than 30% compared to that of commercially available PDMS counterparts.

This work describes the preparation of an analytical microextraction sorbent using a simple and versatile sol–gel hybrid composite, i.e., aramid oligomers wrapping multi-walled carbon nanotubes (CNTs) covalently bonded to a porous silica network.     

Prenatal Bisphenol a Exposure and Postnatal Trans Fat Diet Alter Small Intestinal Morphology and Its Global DNA Methylation in Male Sprague-Dawley Rats,Leading to Obesity Development

In this study, we aimed to determine whether a postnatal trans fat diet (TFD) could aggravate prenatal bisphenol A (BPA) exposure effects on offspring’s small intestine and adulthood obesity, due to the relatively sparse findings on how the interaction between these two variables interrupt the small intestinal cells. Twelve pregnant rats were administered with either unspiked drinking water (control; CTL) or BPA-spiked drinking water throughout pregnancy. Twelve weaned pups from each pregnancy group were then given either a normal diet (ND) or TFD from postnatal week (PNW) 3 until PNW14, divided into control offspring on normal diet (CTL-ND), BPA-exposed offspring on normal diet (BPA-ND), control offspring on trans fat diet (CTL-TFD), and BPA offspring on trans fat diet (BPA-TFD) groups. Body weight (BW), waist circumference, and food and water intake were measured weekly in offspring. At PNW14, small intestines were collected for global DNA methylation and histological analyses. Marked differences in BW were observed starting at PNW9 in BPA-TFD (389.5 ± 10.0 g; p < 0.05) relative to CTL-ND (339.0 ± 7.2 g), which persisted until PNW13 (505.0 ± 15.6 g). In contrast, water and food intake between offspring were significantly different (p < 0.01–0.05) at earlier ages only (PNW4–6 and PNW7–9, respectively). Furthermore, substantial differences in the general parameters of the intestinal structures were exclusive to ileum crypt length alone, whereby both BPA-ND (150.5 ± 5.1 μm; p < 0.001), and BPA-TFD (130.3 ± 9.9 μm; p < 0.05) were significantly longer than CTL-ND (96.8 ± 8.9 μm). Moreover, BPA-ND (2.898 ± 0.147%; p < 0.05) demonstrated global small intestinal hypermethylation when compared to CTL-ND and CTL-TFD (1.973 ± 0.232% and 1.913 ± 0.256%, respectively). Prenatal BPA exposure may significantly affect offspring’s physiological parameters and intestinal function. Additionally, our data suggest that there might be compensatory responses to postnatal TFD in the combined BPA prenatal group (BPA-TFD).     

Label-free metabolic imaging of non-alcoholic-fatty-liver-disease (NAFLD) liver by volumetric dynamic optical coherence tomography

Label-free metabolic imaging of non-alcoholic fatty liver disease (NAFLD) mouse liver is demonstrated ex vivo by dynamic optical coherence tomography (OCT). The NAFLD mouse is a methionine choline-deficient (MCD)-diet model, and two mice fed the MCD diet for 1 and 2 weeks are involved in addition to a normal-diet mouse. The dynamic OCT is based on repeating raster scan and logarithmic intensity variance (LIV) analysis that enables volumetric metabolic imaging with a standard-speed (50,000 A-lines/s) OCT system. Metabolic domains associated with lipid droplet accumulation and inflammation are clearly visualized three-dimensionally. Particularly, the normal-diet liver exhibits highly metabolic vessel-like structures of peri-vascular hepatic zones. The 1-week MCD-diet liver shows ring-shaped highly metabolic structures formed with lipid droplets. The 2-week MCD-diet liver exhibits fragmented vessel-like structures associated with inflammation. These results imply that volumetric LIV imaging is useful for visualizing and assessing NAFLD abnormalities.     

Nose to brain delivery of melatonin lipidic nanocapsules as a promising post-ischemic neuroprotective therapeutic modality

Ischemic stroke accounts for about 87% of all strokes, causing long-term disability in adults, and is the second leading cause of death worldwide. In search of new therapeutic modalities, the use of neuroprotective agents loaded in nanocarriers to be delivered by noninvasive means (i.e. via intranasal route) became a popular approach. In the current study, melatonin (MEL) was loaded in lipidic nanocapsules (LNCs) prepared using the phase inversion method, and characterized in terms of size, polydispersity, zeta potential, in vitro drug release, viscosity, storage stability, and ex vivo permeation across sheep nasal mucosa. Moreover, MEL-LNCs were tested for efficacy in cerebral ischemia/reperfusion (I/R/) injury model through histopathological assessment, and analysis of oxidative stress markers, pro-inflammatory cytokines, and apoptotic markers. Results showed that LNCs exhibited particle size ranging from 18.26 to 109.8 nm, negative zeta potential, good storage stability, spherical morphology, and a burst release followed by a sustained release pattern. LNCs exhibited 10.35 folds higher permeation of MEL than the drug solution across sheep nasal mucosa. Post-ischemic intranasal administration of MEL-LNCs revealed lowering of oxidative stress manifested by a decrease in malondialdehyde levels, and elevation of glutathione and superoxide dismutase levels, lowering of the inflammatory markers tumor necrosis factor-α, NO, myeloperoxidase, and significant inhibition of Caspase-3 activity as an apoptotic marker. Western blot analysis delineated a recovery of protein expression Nrf-2 and HO-1 with downregulation in the parent inflammatory markers nuclear factor kappa B p65, inducible nitric oxide synthase, Bax, and Cytochrome C expressions, and upregulation of B-cell lymphoma-2 Bcl-2, hence promoting neuronal survival. This was supported by histological evidence, revealing significant restoration of hippocampal neurons. In light of the above, it can be concluded that MEL-LNCs could be a promising delivery system for nose to brain delivery for treatment of cerebral ischemia.     

Influence of Gypsum Waste Utilization on Properties and Leachability of Fired Clay Brick

Wastewater treatment activities in the chemical industry have generated abundant gypsum waste, classified as scheduled waste (SW205) under the Environmental Quality Regulations 2005. The waste needs to be disposed into a secure landfill due to the high heavy metals content which is becoming a threat to the environment. Hence, an alternative disposal method was evaluated by recycling the waste into fired clay brick. The brick samples were incorporated with different percentages of gypsum waste (0% as control, 10, 20, 30, 40 and 50%) and were fired at 1050 °C using 1 °C per minute heating rate. Shrinkage, dry density, initial rate of suction (IRS) and compressive strength tests were conducted to determine the physical and mechanical properties of the brick, while the synthetic precipitation leaching procedure (SPLP) was performed to scrutinize the leachability of heavy metals from the crushed brick samples. The results showed that the properties would decrease through the incorporation of gypsum waste and indicated the best result at 10% of waste utilization with 47.5% of shrinkage, 1.37% of dry density, 22.87% of IRS and 28.3% of compressive strength. In addition, the leachability test highlighted that the concentrations of Fe and Al was significantly reduced up to 100% from 4884 to 3.13 ppm (Fe) and from 16,134 to 0.81 ppm (Al), respectively. The heavy metals content in the bricks were oxidized during the firing process, which signified the successful remediation of heavy metals in the samples. Based on the permissible incorporation of gypsum waste into fired clay brick, this study promised a more green disposing method for gypsum waste, and insight as a potential towards achieving a sustainable end product.     

Isolated Ruptured Inter‐Atrial Septal Cystic Echinococcosis during Pregnancy

Herein, we present a case of asymptomatic isolated cardiac cystic echinococcosis localized entirely to the inter‐atrial septum in a pregnant woman. The patient underwent successful surgery. Cardiac cystic echinococcosis is rarely seen in pregnancy. A high index of suspicion is necessary for the diagnosis of a cardiac cyst hydatid. The treatment of cardiac cyst hydatid is surgical and should not be delayed during pregnancy. Early surgery might prevent septic embolization and cardiac life‐threatening complications and save the lives of both mother and baby as in the present case.