RGS3 is a GTPase-activating protein for g(ialpha) and g(qalpha) and a potent inhibitor of signaling by GTPase-deficient forms of g(qalpha) and g(11alpha)

Many Regulators of G protein Signaling (RGS) proteins accelerate the intrinsic GTPase activity of G(ialpha) and G(qalpha)-subunits [i.e., behave as GTPase-activating proteins (GAPs)] and several act as G(qalpha)-effector antagonists. RGS3, a structurally distinct RGS member with a unique N-terminal domain and a C-terminal RGS domain, and an N-terminally truncated version of RGS3 (RGS3CT) both stimulated the GTPase activity of G(ialpha) (except G(zalpha)) and G(qalpha) but not that of G(salpha) or G(12alpha). RGS3 and RGS3CT had G(qalpha) GAP activity similar to that of RGS4. RGS3 impaired signaling through G(q)-linked receptors, although RGS3CT invariably inhibited better than did full-length RGS3. RGS3 potently inhibited G(qalpha)Q209L- and G(11alpha)Q209L-mediated activation of a cAMP-response element-binding protein reporter gene and G(qalpha)Q209L induced inositol phosphate production, suggesting that RGS3 efficiently blocks G(qalpha) from activating its downstream effector phospholipase C-beta. Whereas RGS2 and to a lesser extent RGS10 also inhibited signaling by these GTPase-deficient G proteins, other RGS proteins including RGS4 did not. Mutation of residues in RGS3 similar to those required for RGS4 G(ialpha) GAP activity, as well as several residues N terminal to its RGS domain impaired RGS3 function. A greater percentage of RGS3CT localized at the cell membrane than the full-length version, potentially explaining why RGS3CT blocked signaling better than did full-length RGS3. Thus, RGS3 can impair Gi- (but not Gz-) and Gq-mediated signaling in hematopoietic and other cell types by acting as a GAP for G(ialpha) and G(qalpha) subfamily members and as a potent G(qalpha) subfamily effector antagonist.     

Reflecting on Palliative Care Integration in Canada: A Qualitative Report

Studies have identified integrated interdisciplinary care as a hallmark of effective palliative care. Although models attempt to show how integration may function, there is little literature available that practically explores how integration is fostered and maintained. In this study we asked palliative care clinicians across Canada to comment on how services are integrated across the healthcare system. This is an analysis of qualitative data from a larger study, wherein clinicians provided written responses regarding their experiences. Content analysis was used to identify response categories. Clinicians (n = 14) included physicians, a nurse and a social worker from six provinces. They identified the benefits of formalized relationships and collaboration pathways with other services to streamline referral and consultation. Clinicians perceived a need for better training of residents and primary care physicians in the community and more acceptance, shared understanding, and referrals. Clinicians also described integrating well with oncology departments. Lastly, clinicians considered integration a complex process with departmental, provincial, and national involvement. The needs and strengths identified by the clinicians mirror the qualities of successfully integrated palliative care programs globally and highlight specific areas in policy, education, practice, and research that could benefit those in Canada.     

Perspectives of hematology oncology clinicians about integrating palliative care in oncology

Patients with hematologic malignancies receive palliative care (pc) less frequently and later than patients with solid tumours. We compared survey responses of hematology oncology clinicians with other oncology clinicians to better understand their challenges with providing primary pc or using secondary pc. Patients’ negative perceptions of pc and limited time or competing priorities were challenges for all clinicians. Compared with other oncology clinicians, more hematology oncology clinicians perceived pc referral criteria as too restrictive (40% vs. 22%, p = 0.021) and anticipated that integrating pc supports into their practice would require substantial change (53% vs. 28%, p = 0.014). This study highlights barriers that may need targeted interventions to better integrate pc into the care of patients with hematologic malignancies.     

Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors

Ampakines are small benzamide compounds that allosterically produce the positive modulation of AMPA receptors and improve performance on a variety of behavioral tasks. To test if the native synaptic membrane is necessary for the effects of such positive modulators, the mechanism of action of the Ampakine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (CX509) was investigated in isolated rat brain AMPA receptors reconstituted in lipid bilayers. The drug increased the open time of AMPA-induced single channel current fluctuations with an EC(50) of 4 microM. The action of CX509 was highly selective since it had no effect on the amplitude or close time of channel events. The open time effect had a maximum enhancement of 70-fold and the modulated currents were blocked by CNQX. It is concluded that the synaptic membrane environment is not necessary for Ampakine effects. In fact, CX509 was about 100 times more potent on the reconstituted AMPA receptors than on receptors in their native membrane. These findings indicate that centrally active Ampakines modulate specific kinetic properties of AMPA currents. They also raise the possibility that AMPA receptors are regulated by factors present in situ, thus explaining the more efficient modulatory effects of CX509 when acting on receptors removed from their synaptic location.     

The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling

Sonic hedgehog (Shh) is a secreted morphogen crucial for cell fate decision, cellular proliferation, and patterning during vertebrate development. The intracellular Shh signalling is transduced by Smoothened (Smo), a seven-transmembrane spanning protein that belongs to the G-protein coupled receptor family. Among four families of Galpha subunits, Galphai has been thought to be responsible for transducing Shh signalling, while several lines of evidence indicated that other signalling pathways may be involved. We found that the G12 family of heterotrimeric G proteins and the small GTPase RhoA are involved in Shh/Smo-mediated cellular responses, including stimulation of target gene promoter and inhibition of neurite outgrowth of neuroblastoma cells. We also found that the G12/RhoA pathway is responsible for Smo-induced nuclear import of GLI3 which is thought to transduce Shh signals to nucleus. Furthermore, misexpression of a G12-specific GTPase-activating protein in rat neural tubes leads to pertubation of motor neurone and interneurone development, mimicking the effects of decreased Shh signalling. These results show that Shh signalling is mediated in part by activating G12 family coupled signalling pathways. The participation of RhoA, a pivotal molecular switch in many signal transduction pathways, may help explain how Shh can trigger a variety of cellular responses.     

Characteristics of a pediatric patient with a capillary hemangioma of the palatal mucosa: a case report

The purpose of this study was to report the case of a capillary hemangioma in a 12-month-old female. The lesion appeared: (1) erythematous to deep purple in appearance; (2) dome-shaped; (3) partially blanched with pressure; and (4) rapidly enlarged in the oropharyngeal region. Magnetic resonance imaging studies demonstrated the affected area and adjacent soft tissues. The lesion was diagnosed as a capillary hemangioma through histopathology. Early detection and biopsy is necessary to determine the clinical behavior of the tumor and potential dentoalveolar complications.     

Oncology Clinicians’ Challenges to Providing Palliative Cancer Care—A Theoretical Domains Framework,Pan-Cancer System Survey

Despite the known benefits, healthcare systems struggle to provide early, integrated palliative care (PC) for advanced cancer patients. Understanding the barriers to providing PC from the perspective of oncology clinicians is an important first step in improving care. A 33-item online survey was emailed to all oncology clinicians working with all cancer types in Alberta, Canada, from November 2017 to January 2018. Questions were informed by Michie’s Theoretical Domains Framework and Behaviour Change Wheel (BCW) and queried (a) PC provision in oncology clinics, (b) specialist PC consultation referrals, and (c) working with PC consultants and home care. Respondents (n = 263) were nurses (41%), physicians (25%), and allied healthcare professionals (18%). Barriers most frequently identified were “clinicians’ limited time/competing priorities” (64%), “patients’ negative perceptions of PC” (63%), and clinicians’ capability to manage patients’ social issues (63%). These factors mapped to all three BCW domains: motivation, opportunity, and capability. In contrast, the least frequently identified barriers were clinician motivation and perceived PC benefits. Oncology clinicians’ perceptions of barriers to early PC were comparable across tumour types and specialties but varied by professional role. The main challenges to early integrated PC include all three BCW domains. Notably, motivation is not a barrier for oncology clinicians; however, opportunity and capability barriers were identified. Multifaceted interventions using these findings have been developed, such as tip sheets to enhance capability, reframing PC with patients, and earlier specialist PC nursing access, to enhance clinicians’ use of and patients’ benefits from an early PC approach.