CaV channels and cancer: canonical functions indicate benefits of repurposed drugs as cancer therapeutics

The importance of ion channels in the hallmarks of many cancers is increasingly recognised. This article reviews current knowledge of the expression of members of the voltage-gated calcium channel family (Ca(V)) in cancer at the gene and protein level and discusses their potential functional roles. The ten members of the Ca(V) channel family are classified according to expression of their pore-forming α-subunit; moreover, co-expression of accessory α2δ, β and γ confers a spectrum of biophysical characteristics including voltage dependence of activation and inactivation, current amplitude and activation/inactivation kinetics. Ca(V) channels have traditionally been studied in excitable cells including neurones, smooth muscle, skeletal muscle and cardiac cells, and drugs targeting the channels are used in the treatment of hypertension and epilepsy. There is emerging evidence that several Ca(V) channels are differentially expressed in cancer cells compared to their normal counterparts. Interestingly, a number of Ca(V) channels also have non-canonical functions and are involved in transcriptional regulation of the expression of other proteins including potassium channels. Pharmacological studies show that Ca(V) canonical function contributes to the fundamental biology of proliferation, cell-cycle progression and apoptosis. This raises the intriguing possibility that calcium channel blockers, approved for the treatment of other conditions, could be repurposed to treat particular cancers. Further research will reveal the full extent of both the canonical and non-canonical functions of Ca(V) channels in cancer and whether calcium channel blockers are beneficial in cancer treatment

New targets for overactive bladder-ICI-RS 2109

Aim: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. Methods: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. Results: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide–dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1, TRPV4, TRPA1, and TRPM4) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+-activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathway—the canonical fibrosis pathway. Conclusions: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor

An Evidence-Based Approach to Covid-19 Pandemic Effects on Academics

We discuss our evidence-based approach to understanding and addressing the gendered impact of the pandemic on academics at Queen’s University Belfast, a research-intensive Russell Group UK University. The study was a collaboration between the University-wide Queen’s Gender Initiative, researchers, and Human Resources. A staff survey ran from 23 September until 30 October 2020, assessing academic productivity and personal factors including caring responsibilities, wellbeing, and time spent working. Data from 537 academics showed that multiple challenges were experienced with most of the day spent on work and caregiving tasks. The majority of worktime comprised teaching, at a cost to research productivity and personal wellbeing. These patterns were accentuated for female academics. From this holistic approach to understanding academics’ challenges, recommendations were presented to the University’s Executive Board and other high-level institutional committees. An Action Plan of sustainable solutions designed to mitigate the pandemic effect focused on promotion, research, workload support, and wellbeing. Furthermore, the findings directly informed policies to enhance working life, particularly in new models of flexible working. In summary, we report methodology to integrate research and centralized efforts to address the pandemic’s impact on academics, using a gender lens and incorporating complementarity of work, home-life and wellbeing

Examining public knowledge, attitudes and perceptions towards palliative care: a mixed method sequential study

Background: Palliative care is recognised as a public health issue with the need for earlier integration in the wider healthcare system. However, research indicates that it continues to be accessed late in the course of an illness, public understanding of palliative care is limited, and common misconceptions prevail. Strategies to address this are needed in order to reduce barriers to palliative care delivery and improve access. Methods: An explanatory sequential mixed methods study, comprising a cross-sectional survey and interviews was undertaken. Sociodemographic characteristics, public awareness, knowledge and perceptions of palliative care were examined and strategies to raise awareness and overcome barriers within a public health framework were identified. Survey data were analysed using SPSS v25 with factor analysis and non-parametric statistics and qualitative data were analysed using thematic analysis. Results: A total of 1201 participants completed the survey (58.3% female, mean age 61 years) and 25 took part in interviews. A fifth of participants (20.1%) had previously heard about palliative care and had an accurate understanding of the term. Being female, higher educated, married, and older, increased respondents’ levels of awareness. The three most commonly held misconceptions included: Palliative care is exclusively for people who are in the last 6 months of life (55.4% answered incorrectly); A goal of palliative care is to address any psychological issues brought up by serious illness (42.2% answered incorrectly); and a goal of palliative care is to improve a person’s ability to participate in daily activities (39.6% answered incorrectly). Talking about palliative and end of life care was advocated but societal taboos restricted this occurring with exposure limited to personal experience. Conclusions: Current knowledge gaps and misconceptions derived from limited ad hoc personal experiences and fear of engaging in taboo conversations may deter people from accessing integrated palliative care services early in a disease trajectory. The results indicate the need for public education programmes that move beyond merely raising awareness but provide key messages within a public health approach, which may change attitudes to palliative care thus ultimately improving end of life outcomes

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase–DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

Background: Previously we identified a DNA damage response–deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. Methods: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. Results: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher’s exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response–proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response–proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle–specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. Conclusions: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint–based therapies

'Double or quits': perceptions and management of organ transplantation by adults with cystic fibrosis

Medical sociologists have often considered lay perceptions of the risks of medical interventions, yet in many empirical studies respondents are people who are not likely to be exposed to a particular intervention. Furthermore, it has been well documented that risk perceptions may change over time and with diminishing health state. This paper explores perceptions and management of the risks of organ transplantation amongst adults with cystic fibrosis (CF), the most common autosomal recessive genetic disease in the UK. Although the focus of medical research is now on providing gene replacement therapy to this group, transplantation is currently the last treatment that an adult with CF can be offered when all other treatment has failed to maintain their health. Thirty-one respondents with varying degrees of health state from a specialist CF centre were interviewed as part of a larger study concerning perceptions of health and risks of treatment. Interviews were audiotaped, transcribed and analysed using ATLAS-ti. During analysis respondents' transcripts were divided into two groups: firstly those who did not anticipate needing a transplant in the near future (if at all) and secondly those who were currently being considered for transplantation, on the transplant list, or who had already received donor organs. The paper focuses on themes arising from interview transcripts and finds that although the focus of risk differs between the two groups, the influence of luck is perceived as strong for both groups and emotion work features heavily in those undergoing the transplant process. Contrary to previous research, fears of inheriting donor characteristics are not found amongst adults with CF, but rather body components are commodified when talking of both giving and receiving organs. © 2002 Elsevier Science Ltd. All rights reserved