A phase III placebo-controlled study in advanced head and neck cancer using intratumoural cisplatin/epinephrine gel

Patients with recurrent or refractory head and neck squamous cell carcinoma received cisplatin/epinephrine injectable gel or placebo gel injected directly into the clinically dominant tumour. The double-blind phase III trial comprised of up to 6 weekly treatments over 8 weeks, 4 weekly evaluation visits, and then monthly follow-up; open-label dosing began as needed after three blinded treatments. Tumour response was defined as complete (100% regression) or partial (50–99% regression) sustained for ⩾28 day, and patient benefit as attainment of palliative or preventive goals prospectively selected by investigators and patients. With cisplatin/epinephrine gel, 25% (14 out of 57) of tumours responded (16% complete regression, 9% partial regression), vs 3% (one out of 35, complete regression) with placebo (P=0.007). Patient benefit was positively associated with target tumour response in the blinded period among cisplatin/epinephrine gel recipients (P=0.024): 43% (six out of 14) of responders benefited, vs 12% (five out of 43) of non-responders. The most frequent adverse event was pain during injection and the next most frequent was local cytotoxic effects consistent with the gel's mode of action. Systemic adverse events typical of intravenous cisplatin were uncommon. Intratumoural therapy with cisplatin/epinephrine gel provided safe, well-tolerated, effective palliative treatment for patients with locally advanced head and neck squamous cell carcinoma, who lack other satisfactory treatment options

Low Levels of Human HIP14 Are Sufficient to Rescue Neuropathological, Behavioural, and Enzymatic Defects Due to Loss of Murine HIP14 in Hip14−/− Mice

Huntingtin Interacting Protein 14 (HIP14) is a palmitoyl acyl transferase (PAT) that was first identified due to altered interaction with mutant huntingtin, the protein responsible for Huntington Disease (HD). HIP14 palmitoylates a specific set of neuronal substrates critical at the synapse, and downregulation of HIP14 by siRNA in vitro results in increased cell death in neurons. We previously reported that mice lacking murine Hip14 (Hip14−/−) share features of HD. In the current study, we have generated human HIP14 BAC transgenic mice and crossed them to the Hip14−/− model in order to confirm that the defects seen in Hip14−/− mice are in fact due to loss of Hip14. In addition, we sought to determine whether human HIP14 can provide functional compensation for loss of murine Hip14. We demonstrate that despite a relative low level of expression, as assessed via Western blot, BAC-derived human HIP14 compensates for deficits in neuropathology, behavior, and PAT enzyme function seen in the Hip14−/− model. Our findings yield important insights into HIP14 function in vivo

SAF-A Regulates Interphase Chromosome Structure through Oligomerization with Chromatin-Associated RNAs

Higher eukaryotic chromosomes are organized into topologically constrained functional domains; however, the molecular mechanisms required to sustain these complex interphase chromatin structures are unknown. A stable matrix underpinning nuclear organization was hypothesized, but the idea was abandoned as more dynamic models of chromatin behavior became prevalent. Here, we report that scaffold attachment factor A (SAF-A), originally identified as a structural nuclear protein, interacts with chromatin-associated RNAs (caRNAs) via its RGG domain to regulate human interphase chromatin structures in a transcription-dependent manner. Mechanistically, this is dependent on SAF-A’s AAA+ ATPase domain, which mediates cycles of protein oligomerization with caRNAs, in response to ATP binding and hydrolysis. SAF-A oligomerization decompacts large-scale chromatin structure while SAF-A loss or monomerization promotes aberrant chromosome folding and accumulation of genome damage. Our results show that SAF-A and caRNAs form a dynamic, transcriptionally responsive chromatin mesh that organizes large-scale chromosome structures and protects the genome from instability

Portrait of Bishop Milton Wright

Bishop Milton Wright at age about 61. This image is attributed to C.S. Roshon, Lebanon, Pennsylvania.https://corescholar.libraries.wright.edu/special_ms1_photographs/2635/thumbnail.jp

Members of the Twentieth General Conference of the Church of the United Brethren in Christ

Composite portrait photograph of the members of the Twentieth General Conference of the Church of the United Brethren in Christ. Bishop Milton Wright is pictured at the top, center. This image is attributed to C.S. Roshon, Lebanon, Pennsylvania. This photograph was taken between 05/09/1880 and 05/19/1880.https://corescholar.libraries.wright.edu/special_ms1_photographs/2652/thumbnail.jp

Testing the Use of the Water Milfoil ( Myriophyllum spicatum L.) in Laboratory Toxicity Assays

Abstract Tests aiming to determine the toxic properties of compounds discharged into aquatic systems have relied more on fish or invertebrates than on primary producers and among a number of producers; algae are the most popular test organisms. Macrophytes are important ecological elements in freshwaters and are therefore potentially key organisms for use in toxicity testing of compounds suspected of acting in primary producers. The most common macrophyte used in toxicity testing is Lemna sp., but as a floating plant, it has the limitation of being exposed to toxic compounds only through its lower leaf surface, including roots and rhizoids. Therefore, it is questionable whether tests with Lemna may accurately predict potential effects on submersed and exposed plant species, which have different routs of exposure and morphology. Few other submersed macrophytes have been tested, notably Myriophyllum. In the Iberian peninsula M. spicatum is the most common species within its genus and has been presented as a good bioaccumulator of heavy metals (Wang et al. 1996) and as being sensitive to several toxicants (e.g. Hanson et al. 2003). The aim of this study was to assess the potential of M. spicatum as a testing organism in laboratory assays, by obtaining axenic cultures of this plant and exposing them to several reference compounds to determine the sensitive endpoints