Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, ...particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes.
Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach.
There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio adjHR, 1.41; 95% CI, 0.98 to 2.04;
= .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18;
= .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92;
< .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40;
< .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67;
< .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70;
= .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes.
Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.
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The aim of the study was to elicit the views and opinions of transgender people in relation to mental health concerns.
Four people who identified as transgender participated in ...semi‐structured interviews.
The main results showed that challenges existed for people around mental health issues.
Mental health nurses can play a key role in the provision of psychosocial supports to transgender people and their families.
Government policy makers are becoming increasingly interested in the views and experiences of people who utilize mental health services to inform rights‐based and socially inclusive health and social care initiatives. However, very little information exists in the available literature about transgender people in this regard. The current research was part of a larger mixed methods study that used surveys and in‐depth semi‐structured interviews. This paper reports on the findings from the interview data that relate to the unique mental health experiences of the people whom identified as transgender (n = 4). The data were subject to thematic analysis, and the main themes that emerged included service experiences, treatment issues, other supports, and hopes and aspirations. Participants identified challenges and opportunities for enhancing mental health service provision for transgender people and their families. Some of the highlighted concerns related to practitioner attributes and relevant psychosocial supports. Mental health nurses are well placed to use their knowledge and therapeutic skills to support people who identify as transgender and significant people in their lives.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
While the outcomes for patients diagnosed with hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast cancers have continued to improve with the ...development of targeted therapies, the same cannot be said yet for those affected with triple-negative breast cancer (TNBC). Currently, the mainstay of treatment for the 10–15% of patients diagnosed with TNBC remains cytotoxic chemotherapy, but it is hoped that through an enhanced characterization of TNBC biology, this disease will be molecularly delineated into subgroups with targetable oncogenic drivers. This review will focus on recent therapeutic innovations for TNBC, including poly-ADP-ribosyl polymerase (PARP) inhibitors, phosphoinositide 3-kinase (PI3K) pathway inhibitors, immune checkpoint inhibitors, and cyclin-dependent kinase (CDK) inhibitors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Poly-ADP-ribose polymerase 1 (PARP-1) and PARP-2 are DNA damage sensors that are most active during S-phase of the cell cycle and that have wider-reaching roles in DNA repair than originally ...described. BRCA1 and BRCA2 (Breast Cancer) proteins are involved in homologous recombination repair (HRR), which requires a homologous chromosome or sister chromatid as a template to faithfully repair DNA double-strand breaks. The small-molecule NAD+ mimetics, olaparib, niraparib, rucaparib, veliparib, and talazoparib, inhibit the catalytic activity of PARP-1 and PARP-2 and are currently being studied in later-stage clinical trials. PARP inhibitor clinical trials have predominantly focused on patients with breast and ovarian cancer with deleterious germline
and
mutations (g
) but are now expanding to include cancers with known, suspected, or more-likely-than-not defects in homologous recombination repair. In ovarian cancer, this group also includes women whose cancers are responsive to platinum therapy. Olaparib was FDA-approved in January 2018 for the treatment of g
metastatic breast cancers. g
+ predisposes women to develop triple-negative breast cancers, while women with g
+ tend to develop hormone-receptor-positive, human epidermal growth factor receptor 2 negative breast cancers. Although PARP inhibitor monotherapy strategies seem most effective in cancers with homologous recombination repair defects, combination strategies may allow expansion into a wider range of cancers. By interfering with DNA repair, PARP inhibitors essentially sensitize cells to DNA-damaging chemotherapies and radiation therapy. Certainly, one could also consider expanding the utility of PARP inhibitors beyond g
cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. Unfortunately, in numerous phase I clinical trials utilizing a combination of cytotoxic chemotherapy at standard doses with dose-escalation of PARP inhibitors, there has generally been failure to reach monotherapy dosages of PARP inhibitors due to myelosuppressive toxicities. Strategies utilizing angiogenesis inhibitors and immune checkpoint inhibitors are generally not hindered by additive toxicities, though the utility of combining PARP inhibitors with treatments that have not been particularly effective in breast cancers somewhat tempers enthusiasm. Finally, there are combination strategies that may serve to mitigate resistance to PARP inhibitors, namely, upregulation of the intracellular PhosphoInositide-3-kinase, AK thymoma (protein kinase B), mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway, or perhaps are more simply meant to interfere with a cell growth pathway heavily implicated in breast cancers while administering relatively well-tolerated PARP inhibitor therapy.
We propose a nonmagnetic, pseudospin-based version of a spin valve, in which the pseudospin polarization in neighboring regions of a graphene bilayer is controlled by external gates. Numerical ...calculations demonstrate a large on-off ratio of such a device. This finding holds promise for the realization of pseudospintronics: a form of electronics based upon the manipulation of pseudospin analogous to the control of physical spin in spintronics applications.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Because of the chiral nature of electrons in a monolayer of graphite (graphene) one can expect weak antilocalization and a positive weak-field magnetoresistance in it. However, trigonal warping ...(which breaks p-->-p symmetry of the Fermi line in each valley) suppresses antilocalization, while intervalley scattering due to atomically sharp scatterers in a realistic graphene sheet or by edges in a narrow wire tends to restore conventional negative magnetoresistance. We show this by evaluating the dependence of the magnetoresistance of graphene on relaxation rates associated with various possible ways of breaking a "hidden" valley symmetry of the system.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection
. Drug targets with genetic support are more likely to be ...therapeutically valid
, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging
. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Down's syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS ...patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug.
Telomerase is a ribonucleoprotein (RNP) complex that synthesizes telomere repeats in tissue progenitor cells and cancer cells. Active human telomerase consists of at least three principal subunits, ...including the telomerase reverse transcriptase, the telomerase RNA (TERC), and dyskerin. Here, we identify a holoenzyme subunit, TCAB1 (telomerase Cajal body protein 1), that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. TCAB1 associates with active telomerase enzyme, established telomerase components, and small Cajal body RNAs that are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevents TERC from associating with Cajal bodies, disrupts telomerase-telomere association, and abrogates telomere synthesis by telomerase. Thus, TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Anaesthetic-induced developmental neurotoxicity (AIDN) has been clearly established in laboratory animal models. The possibility of neurotoxicity during uneventful anaesthetic procedures in human ...neonates or infants has led to serious questions about the safety of paediatric anaesthesia. However, the applicability of animal data to clinical anaesthesia practice remains uncertain. The spectre of cerebral injury due to cerebral hypoperfusion, metabolic derangements, coexisting disease, and surgery itself further muddles the picture. Given the potential magnitude of the public health importance of this issue, the clinician should be cognisant of the literature and ongoing investigations on AIDN, and raise awareness of the risks of both surgery and anaesthesia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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