Phase Ib dose-escalation trial of taselisib (GDC-0032) in combination with HER2-directed therapies in patients with advanced HER2+ breast cancer.

BACKGROUND: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control. PATIENTS AND METHODS: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant. RESULTS: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months. CONCLUSIONS: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.

A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Tuned in to communication sounds: Neuronal sensitivity in the túngara frog midbrain to frequency modulated signals.

For complex communication signals, it is often difficult to identify the information-bearing elements and their parameters necessary to elicit functional behavior. Consequently, it may be difficult to design stimuli that test how neurons contribute to communicative processing. For túngara frogs (Physalaemus pustulosus), however, previous behavioral testing with numerous stimuli showed that a particular frequency modulated (FM) transition in the male call is required to elicit phonotaxis and vocal responses. Modeled on such behavioral experiments, we used awake in vivo recordings of single units in the midbrain to determine if their excitation was biased to behaviorally important FM parameters. Comparisons of stimulus driven action potentials revealed greatest excitation to the behaviorally important FM transition: a downward FM sweep or step that crosses ~600 Hz. Previous studies using long-duration acoustic exposure found immediate early gene expression in many midbrain neurons to be most sensitive to similar FM. However, those data could not determine if FM coding was accomplished by the population and/or individual neurons. Our data suggest both coding schemes could operate, as 1) individual neurons are more sensitive to the behaviorally significant FM transition and 2) when single unit recordings are analytically combined across cells, the combined code can produce high stimulus discrimination (FM vs. noise driven excitation), approaching that found in behavioral discrimination of call vs. noise.

Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND: In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. PATIENTS AND METHODS: HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. RESULTS: Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

A scoping review protocol: Mapping the range of policy-related evidence influencing maternal health outcomes in a fragile, low-income country.

AIM: The aim of this scoping review is to map the range of policy-related evidence influencing maternal health outcomes and determine the cultural and contextual factors influencing maternal health in Myanmar, a low-income, fragile setting. DESIGN: Eligible studies identified will include maternal health-related policies, policy documents and research. All types of health-related policies aimed at targeting population health and well-being influencing maternal mortality and morbidity will be considered. METHODS: This scoping review has been developed using the Joanna Briggs Institute recommendations. The database search will include MEDLINE, CINAHL, Web of Science, Cochrane Library and the grey literature. Documents published in English and Burmese in the past 10 years will be included. Numerical data will be extracted and summarized in diagrammatic form, and a descriptive format will be used to present narrative accounts. Funding approval was granted by the Economic and Social Research Council in January 2020. This protocol was registered with OSF registries (Open-ended Registration) on 30 March 2021. DISCUSSION: Little is known about which strategies work best as there is less evidence related to health policy and contextual factors in which maternal health care is delivered in fragile, low-income settings. Understanding the context of maternal health is key to the planning and implementation of effective maternal health services designed to address women's needs. IMPACT: This review will map the range of policy-related evidence influencing maternal health outcomes in Myanmar and will underpin future large-scale research in other low-income and fragile settings. The results of this scoping review will provide recommendations for developing and improving practice and education for nurses and midwives working in resource-restricted contexts.

Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer.

BACKGROUND: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. PATIENTS AND METHODS: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. RESULTS: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. CONCLUSIONS: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.

Estrogenic Modulation of Retinal Sensitivity in Reproductive Female Túngara Frogs.

Although mate searching behavior in female túngara frogs (Physalaemus pustulosus) is nocturnal and largely mediated by acoustic cues, male signaling includes visual cues produced by the vocal sac. To compensate for these low light conditions, visual sensitivity in females is modulated when they are in a reproductive state, as retinal thresholds are decreased. This study tested whether estradiol (E2) plays a role in this modulation. Female túngara frogs were injected with either human chorionic gonadotropin (hCG) or a combination of hCG and fadrozole. hCG induces a reproductive state and increases retinal sensitivity, while fadrozole is an aromatase inhibitor that blocks hCG-induced E2 synthesis. In an analysis of scotopic electroretinograms (ERGs), hCG treatment lowered the threshold for eliciting a b-wave response, whereas the addition of fadrozole abolished this effect, matching thresholds in non-reproductive saline-injected controls. This suggests that blocking E2 synthesis blocked the hCG-mediated reproductive modulation of retinal sensitivity. By implicating E2 in control of retinal sensitivity, our data add to growing evidence that the targets of gonadal steroid feedback loops include sensory receptor organs, where stimulus sensitivity may be modulated, rather than more central brain nuclei, where modulation may affect mechanisms involved in motivation.

Direct Delivery of Antisense Oligonucleotides to the Middle and Inner Ear Improves Hearing and Balance in Usher Mice.

Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.

Investigating the use of microdialysis and SEC-UV-ICP-MS to assess iodine interactions in soil solution.

Element cycling in the terrestrial environment is heavily reliant upon processes that occur in soil solution. Here we present the first application of microdialysis to sample iodine from soil solution. In comparison to conventional soil solution extraction methods such as Rhizon™ samplers, centrifugation, and high-pressure squeezing, microdialysis can passively sample dissolved compounds from soil solution without altering the in-situ speciation of trace elements at realistic soil moisture conditions. In order to assess the suitability of microdialysis for sampling iodine, the permeability factors and effect of perfusion flowrate on I- and IO3- recovery was examined in stirred solutions. Furthermore, microdialysis was used to sample native soluble iodine at a range of water contents and iodine-enriched soils to investigate iodine soil dynamics. Total iodine concentrations were measured using ICP-MS. Inorganic species and the molecular weight distribution of organically bound iodine were determined by anion exchange and size exclusion chromatography (SEC) coupled to an ICP-MS, respectively. The most effective recovery rates in stirred solution were observed with the slowest perfusion flowrate yielding 66.2 ±â€¯7.1 and 70.5 ±â€¯7.1% for I- and IO3-, respectively. Microdialysis was proven to be capable of sampling dissolved iodine from the soil solution, which accounted for <2.5% of the total soil iodine and speciation followed the sequence: organic-I > I- > IO3-. The use of SEC coupled to (i) UV and (ii) ICP-MS analysis provided detail regarding the molecular weight distribution of dissolved org-I compounds. Dissolved org-I was detected with approximate molecular weights between 0.1 and 4.5 kDa. The results in this study show that microdialysis is a suitable technique for sampling dissolved iodine species from soils maintained at realistic moisture contents. In addition, inorganic iodine added to soils was predominately bound with relatively low molecular weight (<4.5 kDa) soluble organic matter.

Iodine uptake, storage and translocation mechanisms in spinach (Spinacia oleracea L.).

Iodine is an essential micronutrient for human health; phytofortification is a means of improving humans' nutritional iodine status. However, knowledge of iodine uptake and translocation in plants remains limited. In this paper, plant uptake mechanisms were assessed in short-term experiments (24 h) using labelled radioisotopes; the speciation of iodine present in apoplastic and symplastic root solutions was determined by (HPLC)-ICP-QQQ-MS. Iodine storage was investigated in spinach (Spinacia oleracea L.) treated with I- and IO3-. Finally, translocation through the phloem to younger leaves was also investigated using a radioiodine (129I-) label. During uptake, spinach roots demonstrated the ability to reduce IO3- to I-. Once absorbed, iodine was present as org-I or I- with significantly greater concentrations in the apoplast than the symplast. Plants were shown to absorb similar concentrations of iodine applied as I- or IO3-, via the roots, grown in an inert growth substrate. We found that whilst leaves were capable of absorbing radioactively labelled iodine applied to a single leaf, less than 2% was transferred through the phloem to younger leaves. In this paper, we show that iodine uptake is predominantly passive (approximately two-thirds of total uptake); however, I- can be absorbed actively through the symplast. Spinach leaves can absorb iodine via foliar fertilisation, but translocation is severely limited. As such, foliar application is unlikely to significantly increase the iodine content, via phloem translocation, of fruits, grains or tubers.

Reproductive State Modulates Retinal Sensitivity to Light in Female Túngara Frogs.

Visual cues are often a vital part of animal communication and courtship. While a plethora of studies have focused on the role that hormones play in acoustic communication of anurans, relatively few have explored hormonal modulation of vision in these animals. Much of what we do know comes from behavioral studies, which show that a frog's hormonal state can significantly affect both its visual behavior and mating decisions. However, to fully understand how frogs use visual cues to make these mating decisions, we must first understand how their visual system processes these cues, and how hormones affect these processes. To do this, we performed electroretinograms (ERGs) to measure retinal sensitivity of túngara frogs (Physalaemus pustulosus), a neotropical species whose mating behavior includes previously described visual cues. To determine the effect of hormonal state on visual sensitivity, ERGs were recorded under scotopic and photopic conditions in frogs that were either non-reproductive or hormone-treated with human chorionic gonadotropin (hCG) prior to testing. Additionally, measurements of optical anatomy determined how túngara frog eye and retina morphology related to physiological sensitivity. As expected, we found that both sexes display higher visual sensitivity under scotopic conditions compared to photopic conditions. However, hormone injections significantly increased retinal sensitivity of females under scotopic conditions. These results support the hypothesis that hormonal modulation of neural mechanisms, such as those mediating visually guided reproductive behavior in this species, include modulation of the receptor organ: the retina. Thus, our data serve as a starting point for elucidating the mechanism of hormonal modulation of visual sensitivity.

Quantifying the relationship between optical anatomy and retinal physiological sensitivity: A comparative approach.

Light intensity varies 1 million-fold between night and day, driving the evolution of eye morphology and retinal physiology. Despite extensive research across taxa showing anatomical adaptations to light niches, surprisingly few empirical studies have quantified the relationship between such traits and the physiological sensitivity to light. In this study, we employ a comparative approach in frogs to determine the physiological sensitivity of eyes in two nocturnal (Rana pipiens, Hyla cinerea) and two diurnal species (Oophaga pumilio, Mantella viridis), examining whether differences in retinal thresholds can be explained by ocular and cellular anatomy. Scotopic electroretinogram (ERG) analysis of relative b-wave amplitude reveals 10- to 100-fold greater light sensitivity in nocturnal compared to diurnal frogs. Ocular and cellular optics (aperture, focal length, and rod outer segment dimensions) were assessed via the Land equation to quantify differences in optical sensitivity. Variance in retinal thresholds was overwhelmingly explained by Land equation solutions, which describe the optical sensitivity of single rods. Thus, at the b-wave, stimulus-response thresholds may be unaffected by photoreceptor convergence (which create larger, combined collecting areas). Follow-up experiments were conducted using photopic ERGs, which reflect cone vision. Under these conditions, the relative difference in thresholds was reversed, such that diurnal species were more sensitive than nocturnal species. Thus, photopic data suggest that rod-specific adaptations, not ocular anatomy (e.g., aperture and focal distance), drive scotopic thresholds differences. To the best of our knowledge, these data provide the first quantified relationship between optical and physiological sensitivity in vertebrates active in different light regimes.

Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors.

BACKGROUND: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. PATIENTS AND METHODS: In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. RESULTS: Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. CONCLUSION: GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. CLINICAL TRIAL NUMBER: NCT01564251.

Conduct and reporting of acceptability, attitudes, beliefs and experiences of pregnant women in randomised trials on diet and lifestyle interventions: A systematic review.

OBJECTIVE: To evaluate the conduct and reporting of views of pregnant women on the acceptability, attitudes, beliefs and their experiences in randomised trials on diet and lifestyle interventions. STUDY DESIGN: We undertook a systematic review of literature of randomised trials identified from our previous search in major electronic databases (until February 2017) without language restrictions. We included trials on diet and lifestyle interventions that reported acceptability, attitudes, beliefs and experiences of pregnant women. The quality of papers was evaluated using the Critical Skills Appraisal Programme (CASP) framework. Data were extracted for the following domains: acceptability, intention, behaviour, attitudes and factors influencing participation. The proportion of studies that reported the various components in each domain was reported in percentages. RESULTS: Of the 110 trials on diet and lifestyle in pregnancy, 24 reported on views of pregnant women. Acceptability of the provided information to the woman was reported in 84% (20/24), compared to 12% (3/24) on acceptability to partner or to family. Mother's intention to adhere to intervention in pregnancy was reported in 68% (17/24) of studies vs.only 16% (4/24) on family's intentions to support adherence. Changes in mother's behaviour were reported for consuming specific components of diet such as nuts (8%, 2/24), olive oil (12%, 3/24) and fruit (40%, 10/24) vs. 16% (4/24) of trials reporting changes in family's behaviour. While knowledge of food ingredients (72%, 18/24), and attitude to gestational weight gain were commonly reported (66%, 16/24) in over two-thirds of studies, only half assessed attitude to participation in research (45%, 11/24). All studies reported facilitators for uptake of intervention such as personalised support (100%, 24/24), with half (52%, 13/24) on beliefs about weight, and less than 10% (2/24) about baby's health. CONCLUSION: The focus on studies is mainly on the mother, and less on family. Further studies are needed with a holistic approach to ensure that such interventions when implemented are accepted by women and their families.