Aromatase inhibitors (AI) are frequently prescribed in gynecologic oncology. We sought to define the frequency and duration of AI use, characterize AI side effects and determine the reasons for ...discontinuation in these patients.
Uterine and ovarian cancer patients with AI use for gynecologic cancer therapy were identified retrospectively. Data were abstracted from the electronic medical record, including cancer type, stage, prior cancer treatments, body mass index, concurrent medications, prevalence of AI side effects before and during AI therapy, length of AI treatment and reason for AI discontinuation.
146 women received AI therapy, with 68 for ovarian cancer (46.6%) and 78 for uterine cancer (53.4%). The majority (71.9%) had advanced stage disease at diagnosis. 54.1% noted AI-associated side effects within the first three visits after starting AI therapy. The most common side effects were arthralgias (29.5%), hot flashes (25.3%), new/worsening fatigue (16.4%), muscle or joint stiffness (8.2%) and myalgias (6.8%). The mean duration of therapy was 14.7 months. Gabapentin or selective serotonin reuptake inhibitor (SSRI) use was associated with decreased musculoskeletal side effects (gabapentin: p < .001, OR 0.88, 95% CI 0.83–0.94; SSRI: p < .001, OR 0.82, 95% CI 0.77–0.89). The most common reason for AI discontinuation was disease progression (87.9%), with 5.0% discontinuing due to side effects and 7.1% for other reasons.
AI therapy for gynecologic cancers is frequently associated with musculoskeletal side effects, but rarely leads to treatment discontinuation. Thus, AI side effects should be assessed in gynecologic cancer patients to allow potential mitigation of symptoms through adjunct therapies.
•Over half of gynecologic cancer patients reported aromatase inhibitor side effects, and almost one-third had arthralgias•Only 5% of patients discontinued aromatase inhibitor therapy due to side effects•Patients with measurable cancer burden less frequently reported aromatase inhibitor musculoskeletal side effects•Gabapentin or SSRI use was associated with decreased musculoskeletal side effects during aromatase inhibitor therapy
Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using ...cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.
We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. ...Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3-5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7-35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.
The molecular logic gates that regulate gene circuits are necessarily intricate and highly regulated, particularly in the critical commitments necessary for pathogenesis. We now report simple AND and ...OR logic gates to be accessible within a single protein receptor. Pathogenesis by the bacterium Rhizobium radiobacter is mediated by a single histidine kinase, VirA, which processes multiple small molecule host signals (phenol and sugar). Mutagenesis analyses converged on a single signal integration node, and finer functional analyses revealed that a single residue could switch VirA from a functional AND logic gate to an OR gate where each of two signals activate independently. Host range preferences among natural strains of R. radiobacter correlate with these gate logic strategies. Although the precise mechanism for the signal integration node requires further analyses, long-range signal transmission through this histidine kinase can now be exploited for synthetic signaling circuits.
Dopamine is crucial for neuroplasticity, which is considered to be the neurophysiological foundation of learning and memory. The specific effect of dopamine on plasticity such as long-term ...potentiation (LTP) and long-term depression (LTD) is determined by receptor subtype specificity, concentration level, and the kind of plasticity induction technique. In healthy human subjects, the dopamine precursor levodopa (L-DOPA) exerts a dosage-dependent non-linear effect on motor cortex plasticity. Low and high dosage L-DOPA impaired or abolished plasticity, while medium-dose preserved and reversed plasticity in previous studies. Similar dosage-dependent effects were also observed for selective D1-like and D2-like receptor activation that favor excitatory and inhibitory plasticity, respectively. However, such a dosage-dependent effect has not been explored for a nonselective dopamine agonist such as apomorphine in humans. To this aim, nonfocal and focal motor cortex plasticity induction using paired associative stimulation (PAS) and transcranial direct current stimulation (tDCS) were performed respectively in healthy participants under 0.1, 0.2, 0.3 mg apomorphine or placebo drug. Transcranial magnetic stimulation-elicited motor-evoked potentials were used to monitor motor cortical excitability alterations. We hypothesized that, similar to L-DOPA, apomorphine will affect motor cortex plasticity. The results showed that apomorphine with the applied dosages has an inhibitory effect for focal and nonfocal LTP-like and LTD-like plasticity, which was either abolished, diminished or reversed. The detrimental effect on plasticity induction under all dosages of apomorphine suggests a predominantly presynaptic mechanism of action of these dosages.
Some chlorine-resistant
isolates harbor the locus of heat resistance (LHR), a genomic island conferring heat resistance. In this study, the protective effect of the LHR for cells challenged by ...chlorine and oxidative stress was quantified. Cloning of the LHR protected against NaClO (32 mM; 5 min), H
O
(120 mM; 5 min), and peroxyacetic acid (105 mg/liter; 5 min) but not against 5.8 mM KIO
, 10 mM acrolein, or 75 mg/liter allyl isothiocyanate. The lethality of oxidizing treatments for LHR-negative strains of
was about 2 log
CFU/ml higher than that for LHR-positive strains of
The oxidation of cytoplasmic proteins and membrane lipids was quantified with the fusion probe roGFP2-Orp1 and the fluorescent probe BODIPY
, respectively. The fragment of the LHR coding for heat shock proteins protected cytoplasmic proteins but not membrane lipids against oxidation. The middle fragment of the LHR protected against the oxidation of membrane lipids but not of cytoplasmic proteins. The addition of H
O
, NaClO, and peroxyacetic acid also induced green fluorescent protein (GFP) expression in the oxidation-sensitive reporter strain
O104:H4 Δ
::
::
Cloning of pLHR reduced phage induction in
O104:H4 Δ
::
::
after treatment with oxidizing chemicals. Screening of 160 strains of Shiga toxin-producing
(STEC) revealed that none of them harbors the LHR, additionally suggesting that the LHR and Stx prophages are mutually exclusive. Taking our findings together, the contribution of the LHR to resistance to chlorine and oxidative stress is based on the protection of multiple cellular targets by different proteins encoded by the genetic island.
Chlorine treatments are used in water and wastewater sanitation; the resistance of
to chlorine is thus of concern to public health. We show that a genetic island termed the locus of heat resistance (LHR) protects
not only against heat but also against chlorine and other oxidizing chemicals, adding to our knowledge of the tools used by
to resist stress. Specific detection of the oxidation of different cellular targets in combination with the cloning of fragments of the LHR provided insight into mechanisms of protection and demonstrated that different fragments of the LHR protect different cellular targets. In
, the presence of the LHR virtually always excluded other virulence factors. It is tempting to speculate that the LHR is maintained by strains of
with an environmental lifestyle but is excluded by pathogenic strains that adapted to interact with vertebrate hosts.
Escherichia coli O104:H4 strain 11-3088 encoding Stx2a is epidemiologically related to the foodborne outbreak associated with sprouts in Germany, 2011. Sprouting provides suitable conditions for ...bacterial growth and may lead to transduction of non-pathogenic strains of E. coli with Stx phages. Although transduction of E. coli by Stx phages in food has been documented, data on the phages from E. coli O104:H4 is limited. This study determined the host range of the bacteriophage Φ11-3088 from E. coli O104:H4 using E. coli O104:H4 ∆stx2::gfp::ampr and demonstrated phage transduction during sprouting. The Φ11-3088∆stx transduced 5/45 strains, including generic E. coli, pap-positive E. coli O103:H2, ETEC, and S. sonnei. The expression level of Φ11-3088∆stx differed among lysogens upon induction. Of the 3 highly induced lysogens, the lytic cycle was induced in E. coli O104:H4∆stx2::gfp::ampr and O103:H2 but not in S. sonnei. E. coli DH5α was the only strain susceptible to lytic infection by Φ11-3088∆stx. To explore the effect of drying and rehydration during seed storage and sprouting on phage induction and transduction, mung beans inoculated with the phage donor E. coli O104:H4∆stx2::gfp::ampr (8 log CFU/g) were dried, rehydrated, and incubated with the phage recipient E. coli DH5α (7 log CFU/g) for 96 h. Sprouted seeds harbored about 3 log CFU/g of putative lysogens that acquired ampicillin resistance. At the end of sprouting, 71 % of putative lysogens encoded gfp, confirming phage transduction. Overall, stx transfer by phages may increase the cell counts of STEC during sprouting by converting generic E. coli to STEC.
•The stx2-encoding Φ11-3088 has a narrow host range (5/45) for lysogenic infection.•The phage Φ11-3088 transmitted stx2 to ETEC and Shigella by transduction.•The induction of the Stx2 prophage differed in different lysogens.•STEC on dry seeds mediated the spread of stx2 during sprouting.
Purpose
Approximately 25% of patients receiving weekly paclitaxel for breast cancer require treatment disruptions to avoid severe, irreversible peripheral neuropathy (PN). Vitamin insufficiencies are ...PN risk factors in many diseases, but their relevance to chemotherapy-induced PN is unknown.
Methods
We investigated whether baseline insufficiency of vitamin D, vitamin B12, folate, or homocysteine increased PN in patients with breast cancer receiving weekly paclitaxel in a retrospective analysis of a prospective observational study. Patient-reported PN was collected at baseline and during treatment on the Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (CIPN20). The primary analysis tested associations between vitamin deficiency and the maximum increase from baseline in the CIPN20 sensory subscale (ΔCIPN8). Secondary analyses tested for association with PN-induced treatment disruptions and adjusted associations for treatment and clinical variables.
Results
25-hydroxy-vitamin D was the only nutrient with sufficient deficiency (< 20 ng/mL) for analysis (15/37 = 41%). Vitamin D-deficient patients had a greater mean PN increase than non-deficient patients (ΔCIPN8 ± SD, 36 ± 23 vs. 16 ± 16,
p
= 0.003) and a non-significant, approximately threefold increase in risk of treatment disruption (OR 2.98, 95% CI 0.72, 12.34,
p
= 0.16). In multivariable models adjusted for clinical and treatment variables, baseline vitamin D level was inversely associated with PN (
β
= − 0.04,
p
= 0.02).
Conclusion
Pre-treatment vitamin D deficiency was associated with PN in women receiving weekly paclitaxel for breast cancer. Vitamin D deficiency may be an easily detected PN risk factor that could be resolved prior to treatment to prevent PN, avoid treatment disruptions, and improve treatment outcomes.
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