The protective role of postoperative radiation therapy in low and intermediate grade major salivary gland malignancies: A study of the Canadian Head and Neck Collaborative Research Initiative.

BACKGROUND: The objective of this study was to examine the utility of postoperative radiation for low and intermediate grade cancers of the parotid and submandibular glands. METHODS: The authors conducted a retrospective, Canadian-led, international, multi-institutional analysis of a patient cohort with low or intermediate grade salivary gland cancer of the parotid or submandibular gland who were treated from 2010 until 2020 with or without postoperative radiation therapy. A multivariable, marginal Cox proportional hazards regression analysis was performed to quantify the association between locoregional recurrence (LRR) and receipt of postoperative radiation therapy while accounting for patient-level factors and the clustering of patients by institution. RESULTS: In total, 621 patients across 14 tertiary care centers were included in the study; of these, 309 patients (49.8%) received postoperative radiation therapy. Tumor histologies included 182 (29.3%) acinic cell carcinomas, 312 (50.2%) mucoepidermoid carcinomas, and 137 (20.5%) other low or intermediate grade primary salivary gland carcinomas. Kaplan-Meier LRR-free survival at 10 years was 89.0% (95% confidence interval [CI], 84.9%-93.3%). In multivariable Cox regression analysis, postoperative radiation therapy was independently associated with a lower hazard of LRR (adjusted hazard ratio, 0.53; 95% CI, 0.29-0.97). The multivariable model estimated that the marginal probability of LRR within 10 years was 15.4% without radiation and 8.8% with radiation. The number needed to treat was 16 patients (95% CI, 14-18 patients). Radiation therapy had no benefit in patients who had early stage, low-grade salivary gland cancer without evidence of nodal disease and negative margins. CONCLUSIONS: Postoperative radiation therapy may reduce LLR in some low and intermediate grade salivary gland cancers with adverse features, but it had no benefit in patients who had early stage, low-grade salivary gland cancer with negative margins.

The involvement of Canadian physicians in promoting and providing unproven and unapproved stem cell interventions.

BACKGROUND: Direct to consumer offerings of unproven stem cell interventions (SCIs) is a pressing scientific and policy issue. According to media reports, providers of SCIs have emerged in Canada. This study provides the first systematic scan of Canadian providers and associated trends and claims. METHODS: The study sample consisted of 15 websites retrieved from a Google™ keyword search. The websites were assessed by a rater using a peer-reviewed coding frame that queried treatment location, stem cell offerings, treatment claims, supporting evidence, and legal and regulatory compliance. A second rater reviewed a subset of the websites for purposes of inter-rater reliability. Disagreements between raters were resolved by consensus. Data collected by the raters was analyzed in SPSS. RESULTS: Physicians are the dominant treatment providers in Canada. Providers operate in urban and semi-urban areas in the most populous provinces. SCIs provided are mainly autologous adult stem cells for multiple conditions including musculoskeletal disorders, spinal cord injury (SCI) and diabetes. Efficacy and benefits of treatment are prominently and positively portrayed, while risks are not mentioned or portrayed as trivial. Regulatory concerns are not discussed. CONCLUSIONS: The involvement of physicians in promoting and providing unproven and unapproved SCIs raises significant ethical, legal and regulatory concerns. Treatment claims and trends appear to contravene applicable professional standards, statutory obligations, and consumer protection laws. While the number of providers observed is still marginal, urgent and proactive regulatory response is needed to prevent proliferation of a potentially exploitative and harmful market for unproven SCIs in Canada.

Research on Human Embryos and Reproductive Materials: Revisiting Canadian Law and Policy.

Research involving human embryos and reproductive materials, including certain forms of stem cell and genetic research, is a fast-moving area of science with demonstrated clinical relevance. Canada's current governance framework for this field of research urgently requires review and reconsideration in view of emerging applications. Based on a workshop involving ethics, legal, policy, scientific and clinical experts, we present a series of recommendations with the goal of informing and supporting health policy and decision-making regarding the governance of the field. With a pragmatic and principled governance approach, Canada can continue its global leadership in this field, as well as advance the long-term health and well-being of Canadians.

Synthesis, characterization, and biological affinity of a near-infrared-emitting conjugated oligoelectrolyte.

A near-IR-emitting conjugated oligoelectrolyte (COE), ZCOE, was synthesized, and its photophysical features were characterized. The biological affinity of ZCOE is compared to that of an established lipid-membrane-intercalating COE, DSSN+, which has blue-shifted optical properties making it compatible for tracking preferential sites of accumulation. ZCOE exhibits diffuse staining of E. coli cells, whereas it displays internal staining of select yeast cells which also show propidium iodide staining, indicating ZCOE is a "dead" stain for this organism. Staining of mammalian cells reveals complete internalization of ZCOE through endocytosis, as supported by colocalization with LysoTracker and late endosome markers. In all cases DSSN+ persists in the outer membranes, most likely due to its chemical structure more closely resembling a lipid bilayer.

Increased ion conductance across mammalian membranes modified with conjugated oligoelectrolytes.

Variation in conjugated oligoelectrolyte (COE) repeat units is shown to affect the rate of COE insertion into mammalian membrane patches and membrane patch stabilities. These findings suggest that it is possible to find COE structures that do not destroy membranes while at the same time allow for more facile transmembrane movement of ions/substrates.

Improving charge collection in Escherichia coli-carbon electrode devices with conjugated oligoelectrolytes.

It is important to tailor biotic-abiotic interfaces in order to maximize the utility of bioelectronic devices such as microbial fuel cells (MFCs), electrochemical sensors and bioelectrosynthetic systems. The efficiency of electron-equivalent extraction (or injection) across such biotic-abiotic interfaces is dependent on the choice of the microbe and the conductive electrode material. In this contribution, we show that spontaneous intercalation of a conjugated oligoelectrolyte, namely 4,4'-bis(4'-(N,N-bis(6''-(N,N,N-trimethylammonium)hexyl)amino)-styryl)stilbene tetraiodide (DSSN+), into the membranes of Escherichia coli leads to an increase in current generation in MFCs containing carbon-based electrodes. A combination of scanning electron microscopy (SEM) and confocal microscopy was employed to confirm the incorporation of DSSN+ into the cell membrane and biofilm formation atop carbon felt electrodes. Current collection was enhanced by more than 300% with addition of this conjugated oligoelectrolyte. The effect of DSSN+ concentration on electrical output was also investigated. Higher concentrations, up to 25 µM, lead to an overall increase in the number of charge equivalents transferred to the charge-collecting electrode, providing evidence in support of the central role of the synthetic system in improving device performance.

Decreasing intestinal parasites in recent Northern California refugees.

Beginning in 2005, the Centers for Disease Control and Prevention (CDC) expanded the overseas presumptive treatment of intestinal parasites with albendazole to include refugees from the Middle East. We surveyed the prevalence of helminths and protozoa in recent Middle Eastern refugees (2008-2010) in comparison with refugees from other geographical regions and from a previous survey (2001-2004) in Santa Clara County, California. Based on stool microscopy, helminth infections decreased, particularly in Middle Eastern refugees (0.1% versus 2.3% 2001-2004, P = 0.01). Among all refugees, Giardia intestinalis was the most common protozoan found. Protozoa infections also decreased somewhat in Middle Eastern refugees (7.2%, 2008-2010 versus 12.9%, 2001-2004, P = 0.08). Serology for Strongyloides stercoralis and Schistosoma spp. identified more infected individuals than stool exams. Helminth infections are increasingly rare in refugees to Northern California. Routine screening stool microscopy may be unnecessary in all refugees.

Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat.

BACKGROUND: We have recently reported that serotonin(4) (5-HT(4)) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants. METHODOLOGY/PRINCIPAL FINDINGS: We found that, in acute conditions, the 5-HT(4) agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4) agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT(1A) receptors, that was two to three times stronger when the 5-HT(4) agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound. CONCLUSIONS/SIGNIFICANCE: These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4) agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

Alignment control of self-assembled organosiloxane films derived from alkyloligosiloxane amphiphiles.

Transparent and continuous organosiloxane films with macroscopically oriented mesostructures were prepared by dip-coating a substrate, on which a rubbing-treated polyimide film is formed, with hydrolyzed solutions of oligosiloxane precursors (C(n)H(2n+1)Si(OSi(OMe)(3))(3)). The structure of the films depends on the alkyl chain length of the precursors such that films with two-dimensional (2D) hexagonal and lamellar structures are obtained when n = 10 and 16, respectively. In the 2D hexagonal film, the cylindrical organic moieties are aligned perpendicular to the rubbing direction in the plane of the film over the whole film thickness. On the other hand, the lamellar film changes its orientation with increased distance from the substrate surface. While the orientation of the lamellae at the surface of the film is parallel to the film-air interface, they are perpendicularly aligned in the vicinity of the substrate with the layer normal parallel to the rubbing direction. The observed unique orientation of the mesostructures is attributed to the anisotropic hydrophobic interactions between the alkyl chains of the hydrolyzed oligosiloxane molecules and the polymer chains of the polyimide layer oriented by the rubbing treatment.

Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action.

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

Experimental demonstration of base-catalyzed interconversion of isomeric betaine intermediates in the Corey-Chaykovsky epoxidation.

The collapse of hydroxysulfonium salts has been examined as a model for the epoxidation of aldehydes. The anti diastereomer reacted with retention of stereochemistry and no crossover, while the syn diastereomer gave crossover products along with cis and trans epoxides. Deprotonation and reprotonation on the carbon of the alpha-hydroxy sulfonium ylide is presumed responsible for production of the trans epoxide. This reaction pathway has been proposed to explain losses of enantioselectivity but never directly observed.

An evidence-based estimate of the appropriate rate of utilization of radiotherapy for cancer of the cervix.

PURPOSE: Current estimates of the proportion of cancer patients who will require radiotherapy (RT) are based almost entirely on expert opinion. The objective of this study was to calculate the proportion of incident cases of cervical cancer that should receive RT by application of an evidence-based approach. METHODS AND MATERIALS: A systematic review of the literature was done to identify indications for RT for cervical cancer and to ascertain the level of evidence that supported each indication. A survey of Canadian gynecologic oncologists and radiation oncologists who treat cervical cancer was done to determine the level of acceptance of each indication among doctors who practice in the field. An epidemiologic approach was then used to estimate the incidence of each indication for RT in a typical North American population of patients with cervical cancer. RESULTS: The systematic review of the literature identified 29 different indications for RT for cervical cancer. The majority of the 75 experts who responded to the mail survey stated that they "usually" or "always" recommended RT in all but one of the clinical situations that were identified as indications for RT on the basis of the systematic review. The analysis of epidemiologic data revealed that, in a typical North American population, 65.4% +/- 2.5% of cervical cancer cases will develop one or more indications for RT at some point in the course of the illness, 63.4% +/- 2.3% will develop indications for RT as part of their initial management, and 2.0% +/- 0.9% will develop indications for RT for progressive or recurrent disease. The effects of variations in case mix on the need for RT was examined by sensitivity analysis, which suggested that the maximum plausible range for the appropriate rate of utilization of RT was 54.3% to 67.9%. The proportion of cases that required RT was stage dependent: 10.6% +/- 1.2% in Stage IA, 74.9% +/- 1.3% in Stage IB, 100% in Stages II and III, and 97.2% +/- 1.1% in Stage IV. CONCLUSIONS: This evidence-based estimate of the appropriate rate of use of RT for cervical cancer adds to the growing pool of knowledge about the need for RT that will ultimately provide a rational basis for long-term planning for RT programs and for auditing access to RT in the general population.