Examining Patient Preferences for Express, Telemedicine, and Standard Visits in a Sexual Health Clinic in New York City.

ABSTRACT: This study, completed at an sexually transmitted infection (STI) clinic in 2019 to 2020, evaluated patient preferences for telemedicine, express, and standard visits. Active PrEP users preferred telemedicine and express visits, patients with prior STIs preferred express visits, and cisgender women preferred standard visits. Configuring STI clinic visit types requires shared decision making and individualization.

Engaging communities as partners in health crisis response: a realist-informed scoping review for research and policy.

BACKGROUND: Health is increasingly affected by multiple types of crises. Community engagement is recognised as being a critical element in successful crisis response, and a number of conceptual frameworks and global guideline documents have been produced. However, little is known about the usefulness of such documents and whether they contain sufficient information to guide effective community engagement in crisis response. We undertake a scoping review to examine the usefulness of conceptual literature and official guidelines on community engagement in crisis response using a realist-informed analysis [exploring contexts, mechanisms, and outcomes(CMOs)]. Specifically, we assess the extent to which sufficient detail is provided on specific health crisis contexts, the range of mechanisms (actions) that are developed and employed to engage communities in crisis response and the outcomes achieved. We also consider the extent of analysis of interactions between the mechanisms and contexts which can explain whether successful outcomes are achieved or not. SCOPE AND FINDINGS: We retained 30 documents from a total of 10,780 initially identified. Our analysis found that available evidence on context, mechanism and outcomes on community engagement in crisis response, or some of their elements, was promising, but few documents provided details on all three and even fewer were able to show evidence of the interactions between these categories, thus leaving gaps in understanding how to successfully engage communities in crisis response to secure impactful outcomes. There is evidence that involving community members in all the steps of response increases community resilience and helps to build trust. Consistent communication with the communities in time of crisis is the key for effective responses and helps to improve health indicators by avoiding preventable deaths. CONCLUSIONS: Our analysis confirms the complexity of successful community engagement and the need for strategies that help to deal with this complexity to achieve good health outcomes. Further primary research is needed to answer questions of how and why specific mechanisms, in particular contexts, can lead to positive outcomes, including what works and what does not work and how to measure these processes.

Comparing social responses to Ebola and Covid-19 in Sierra Leone: an institutional analysis.

This paper compares community responses to Ebola and Covid-19 in two regions of southern and eastern Sierra Leone with reference to the theory of institutional dynamics proposed by the anthropologist Mary Douglas. Institutions, Douglas argued, are conveyed by styles of thought, shaped by the ways human communities, through everyday practices, reinforce systems of classification and denotation. Pandemic advice to 'follow the science' proved problematic, since there is no single institution of science, and institutions never stand alone but are bundled with other institutions, reflecting the manifold and intertwined practices of human social life. The paper explores some of the ways a traumatic epidemic of Ebola Virus Disease in Sierra Leone shaped a distinctive local response to this deadly infectious disease in the absence of an effective vaccine. This local approach emphasised social rules based on ideas about sequestration and testing. Communities then proposed to continue this rules-based approach to the pandemic of Covid-19 and showed little initial enthusiasm for vaccination. With Ebola, the adoption of rules resulted in dramatic drops in infection rates. But Covid-19 spreads in different ways, and good results from the application of social rules were much less apparent. The paper shows how communities began to grapple with this new situation. In some cases, vaccine hesitation was overcome by treating the requirement for vaccination as a new form of social discipline. More generally, it is concluded that epidemiologists need to pay specific attention to institutions and institutional dynamics in order to better understand and anticipate public reactions to new disease threats.

Age-Independent Preoperative Chemosensitivity and 5-Year Outcome Determined by Combined 70- and 80-Gene Signature in a Prospective Trial in Early-Stage Breast Cancer.

BACKGROUND: The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status. METHODS: The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18-90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. > 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors. RESULTS: MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%; p = 0.64) or High-Risk tumors (14.5% vs. 11.5%; p = 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype. CONCLUSION: Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer.

At-Home Testing for Sexually Transmitted Infections During the COVID-19 Pandemic.

During the COVID-19 pandemic in New York City, NewYork-Presbyterian Hospital provided HIV prevention patients with gonorrhea/chlamydia testing kits at home. This report describes the program implementation to provide other sexual health clinics with a roadmap in adapting to a "new normal" in providing comprehensive sexual health care virtually to patients.

Cost-Effectiveness Modeling of Surgery Plus Adjuvant Endocrine Therapy Versus Primary Endocrine Therapy Alone in UK Women Aged 70 and Over With Early Breast Cancer.

OBJECTIVES: Approximately 20% of UK women aged 70+ with early breast cancer receive primary endocrine therapy (PET) instead of surgery. PET reduces surgical morbidity but with some survival decrement. To complement and utilize a treatment dependent prognostic model, we investigated the cost-effectiveness of surgery plus adjuvant therapies versus PET for women with varying health and fitness, identifying subgroups for which each treatment is cost-effective. METHODS: Survival outcomes from a statistical model, and published data on recurrence, were combined with data from a large, multicenter, prospective cohort study of over 3400 UK women aged 70+ with early breast cancer and median 52-month follow-up, to populate a probabilistic economic model. This model evaluated the cost-effectiveness of surgery plus adjuvant therapies relative to PET for 24 illustrative subgroups: Age {70, 80, 90} × Nodal status {FALSE (F), TRUE (T)} × Comorbidity score {0, 1, 2, 3+}. RESULTS: For a 70-year-old with no lymph node involvement and no comorbidities (70, F, 0), surgery plus adjuvant therapies was cheaper and more effective than PET. For other subgroups, surgery plus adjuvant therapies was more effective but more expensive. Surgery plus adjuvant therapies was not cost-effective for 4 of the 24 subgroups: (90, F, 2), (90, F, 3), (90, T, 2), (90, T, 3). CONCLUSION: From a UK perspective, surgery plus adjuvant therapies is clinically effective and cost-effective for most women aged 70+ with early breast cancer. Cost-effectiveness reduces with age and comorbidities, and for women over 90 with multiple comorbidities, there is little cost benefit and a negative impact on quality of life.

Fathoming sea turtles: monitoring strategy evaluation to improve conservation status assessments.

Population monitoring must be accurate and reliable to correctly classify population status. For sea turtles, nesting beach surveys are often the only population-level surveys that are accessible. However, process and observation errors, compounded by delayed maturity, obscure the relationship between trends on the nesting beach and the population. We present a simulation-based tool, monitoring strategy evaluation (MoSE), to test the relationships between monitoring data and assessment accuracy, using green sea turtles, Chelonia mydas, as a case study. To explore this first application of MoSE, we apply different treatments of population impacts to virtual true populations, and sample the nests or nesters, with observation error, to test if the observation data can be used to diagnose population status accurately. Based on the observed data, we examine population trend and compare it to the known values from the operating model. We ran a series of scenarios including harvest impacts, cyclical breeding probability, and sampling biases, to see how these factors impact accuracy in estimating population trend. We explored the necessary duration of monitoring for accurate trend estimation and the probability of a false trend diagnosis. Our results suggest that disturbance type and severity can have important and persistent effects on the accuracy of population assessments drawn from monitoring nesting beaches. The underlying population phase, age classes disturbed, and impact severity influenced the accuracy of estimating population trend. At least 10 yr of monitoring data is necessary to estimate population trend accurately, and >20 yr if juvenile age classes were disturbed and the population is recovering. In general, there is a greater probability of making a false positive trend diagnosis than a false negative, but this depends on impact type and severity, population phase, and sampling duration. Improving detection rates to 90% does little to lower probability of a false trend diagnosis with shorter monitoring spans. Altogether, monitoring strategies for specific populations may be tailored based on the impact history, population phase, and environmental drivers. The MoSE is an important framework for analysis through simulation that can comprehensively test population assessments for accuracy and inform policy recommendations regarding the best monitoring strategies.

First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial.

PURPOSE: The phase 3 MONALEESA-2 study demonstrated that addition of ribociclib (RIB) to letrozole (LET) significantly improved progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Here, we evaluated duration of response (DoR), tumor shrinkage, PFS by treatment-free interval (TFI), and health-related quality of life (HRQoL). METHODS: Postmenopausal women (N = 668) with HR+ , HER2- ABC and no prior systemic therapy for ABC were randomized to RIB (600 mg/day; 3 weeks on/1 week off) plus LET (2.5 mg/day; continuous) or placebo (PBO) plus LET. Primary end point was PFS; HRQoL was the secondary end point; DoR was exploratory end point and PFS by TFI was post hoc analysis. RESULTS: Of 501 pts with measurable disease and confirmed complete or partial response, median DoR was 26.7 months (95% CI, 24.0-NR) in the RIB arm versus 18.6 months (95% CI, 14.8-23.1) in the PBO arm. At 8 weeks, more pts in the RIB arm (32%) versus the PBO arm (17%) experienced best percentage change ≥ 60%. The average pain reduction was greater in the RIB arm (26%) versus the PBO arm (15%). PFS benefit was seen with RIB vs PBO, irrespective of TFI. CONCLUSION: RIB plus LET versus PBO plus LET is associated with earlier and more durable tumor response, greater degree of tumor shrinkage and pain reduction, and PFS benefit irrespective of TFI. These data further support RIB plus LET as a first-line treatment option for postmenopausal women with HR+ , HER2- ABC.

A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation.

PURPOSE: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1). METHODS: Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS). RESULTS: Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran-Mantel-Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine. CONCLUSIONS: The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.

Pertuzumab/Trastuzumab/CT Versus Trastuzumab/CT Therapy for HER2+ Breast Cancer: Results from the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST).

BACKGROUND: Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping. METHODS: Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment. RESULTS: In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%). CONCLUSIONS: The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.

Insulin-like peptide 5 is an orexigenic gastrointestinal hormone.

The gut endocrine system is emerging as a central player in the control of appetite and glucose homeostasis, and as a rich source of peptides with therapeutic potential in the field of diabetes and obesity. In this study we have explored the physiology of insulin-like peptide 5 (Insl5), which we identified as a product of colonic enteroendocrine L-cells, better known for their secretion of glucagon-like peptide-1 and peptideYY. i.p. Insl5 increased food intake in wild-type mice but not mice lacking the cognate receptor Rxfp4. Plasma Insl5 levels were elevated by fasting or prolonged calorie restriction, and declined with feeding. We conclude that Insl5 is an orexigenic hormone released from colonic L-cells, which promotes appetite during conditions of energy deprivation.

A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer.

Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

Impact of Tumor Size on Probability of Pathologic Complete Response After Neoadjuvant Chemotherapy.

BACKGROUND: The prospective Neoadjuvant Breast Symphony Trial (NBRST) study found that MammaPrint/BluePrint functional molecular subtype is superior to conventional immunohistochemistry/fluorescence in situ hybridization subtyping for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy. The purpose of this substudy was to determine if the rate of pCR is affected by tumor size. METHODS: The NBRST study includes breast cancer patients who received neoadjuvant chemotherapy. MammaPrint/BluePrint subtyping classified patients into four molecular subgroups: Luminal A, Luminal B, HER2 (human epidermal growth factor receptor 2), and Basal type. Probability of pCR (ypT0/isN0) as a function of tumor size and molecular subgroup was evaluated. RESULTS: A total of 608 patients were evaluable with overall pCR rates of 28.5 %. Luminal A and B patients had significantly lower rates of pCR (6.1 and 8.7 %, respectively) than either basal (37.1 %) or HER2 (55.0 %) patients (p < 0.001). The probability of pCR significantly decreased with tumor size >5 cm [p = 0.022, odds ratio (OR) 0.58, 95 % confidence interval (CI) 0.36, 0.93]. This relationship was statistically significant in the Basal (p = 0.026, OR 0.46, 95 % CI 0.23, 0.91) and HER2 (p = 0.039, OR 0.36, 95 % CI 0.14, 0.95) subgroups. In multivariate logistic regression analyses, the dichotomized tumor size variable was not significant in any of the molecular subgroups. DISCUSSION: Even though tumor size would intuitively be a clinical determinant of pCR, the current analysis showed that the adjusted OR for tumor size was not statistically significant in any of the molecular subgroups. Factors significantly associated with pCR were PR status, grade, lymph node status, and BluePrint molecular subtyping, which had the strongest correlation.

Evidence of climate-driven ecosystem reorganization in the Gulf of Mexico.

The Gulf of Mexico is one of the most ecologically and economically valuable marine ecosystems in the world and is affected by a variety of natural and anthropogenic phenomena including climate, hurricanes, coastal development, agricultural runoff, oil spills, and fishing. These complex and interacting stressors, together with the highly dynamic nature of this ecosystem, present challenges for the effective management of its resources. We analyze a compilation of over 100 indicators representing physical, biological, and economic aspects of the Gulf of Mexico and find that an ecosystem-wide reorganization occurred in the mid-1990s. Further analysis of fishery landings composition data indicates a major shift in the late 1970s coincident with the advent of US national fisheries management policy, as well as significant shifts in the mid-1960s and the mid-1990s. These latter shifts are aligned temporally with changes in a major climate mode in the Atlantic Ocean: the Atlantic Multidecadal Oscillation (AMO). We provide an explanation for how the AMO may drive physical changes in the Gulf of Mexico, thus altering higher-level ecosystem dynamics. The hypotheses presented here should provide focus for further targeted studies, particularly in regard to whether and how management should adjust to different climate regimes or states of nature. Our study highlights the challenges in understanding the effects of climatic drivers against a background of multiple anthropogenic pressures, particularly in a system where these forces interact in complex and nonlinear ways.

Deepwater Horizon oil spill impacts on sea turtles could span the Atlantic.

We investigated the extent that the 2010 Deepwater Horizon oil spill potentially affected oceanic-stage sea turtles from populations across the Atlantic. Within an ocean-circulation model, particles were backtracked from the Gulf of Mexico spill site to determine the probability of young turtles arriving in this area from major nesting beaches. The abundance of turtles in the vicinity of the oil spill was derived by forward-tracking particles from focal beaches and integrating population size, oceanic-stage duration and stage-specific survival rates. Simulations indicated that 321 401 (66 199-397 864) green (Chelonia mydas), loggerhead (Caretta caretta) and Kemp's ridley (Lepidochelys kempii) turtles were likely within the spill site. These predictions compared favourably with estimates from in-water observations recently made available to the public (though our initial predictions for Kemp's ridley were substantially lower than in-water estimates, better agreement was obtained with modifications to mimic behaviour of young Kemp's ridley turtles in the northern Gulf). Simulations predicted 75.2% (71.9-76.3%) of turtles came from Mexico, 14.8% (11-18%) from Costa Rica, 5.9% (4.8-7.9%) from countries in northern South America, 3.4% (2.4-3.5%) from the United States and 1.6% (0.6-2.0%) from West African countries. Thus, the spill's impacts may extend far beyond the current focus on the northern Gulf of Mexico.

Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease.

Synapse abnormalities in Huntington's disease (HD) patients can precede clinical diagnosis and neuron loss by decades. The polyglutamine expansion in the huntingtin (htt) protein that underlies this disorder leads to perturbations in many cellular pathways, including the disruption of Rab11-dependent endosomal recycling. Impairment of the small GTPase Rab11 leads to the defective formation of vesicles in HD models and may thus contribute to the early stages of the synaptic dysfunction in this disorder. Here, we employ transgenic Drosophila melanogaster models of HD to investigate anomalies at the synapse and the role of Rab11 in this pathology. We find that the expression of mutant htt in the larval neuromuscular junction decreases the presynaptic vesicle size, reduces quantal amplitudes and evoked synaptic transmission and alters larval crawling behaviour. Furthermore, these indicators of early synaptic dysfunction are reversed by the overexpression of Rab11. This work highlights a potential novel HD therapeutic strategy for early intervention, prior to neuronal loss and clinical manifestation of disease.

Chemosensitivity predicted by BluePrint 80-gene functional subtype and MammaPrint in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST).

PURPOSE: The purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response. METHODS: The study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal. RESULTS: A total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2- patients were reclassified by Blueprint as Basal (n = 35) or HER2 (n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal (n = 36) or Basal (n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal (n = 2) or HER2 (n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2- patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior (p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients. CONCLUSIONS: BluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT.

The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15.

The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug's beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.

Phase II study evaluating lapatinib in combination with nab-paclitaxel in HER2-overexpressing metastatic breast cancer patients who have received no more than one prior chemotherapeutic regimen.

Lapatinib, an oral, reversible inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, has proven antitumor activity in HER2-positive metastatic breast cancer (MBC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. This was an open-label, single-arm, multicenter, Phase II study to evaluate the efficacy and safety of nab-paclitaxel plus lapatinib in women with HER2 over-expressing MBC who had received no more than one prior chemotherapeutic regimen. The primary efficacy endpoint was the overall response rate (ORR). This was defined as the percentage of patients having either a complete response (CR) or partial response (PR). Secondary efficacy endpoints included progression-free survival (PFS), overall survival, duration of response (DoR), time to response (TTR), and time to progression (TTP). Investigator-assessed ORR was 53 % (n = 32, 95 % confidence interval (CI): 40.7-66.0) with the majority of patient responses demonstrating a PR (47 %). Four (7 %) patient responses demonstrated a CR, and ten (17 %) a stable disease. The median Kaplan-Meier estimate of investigator-assessed PFS, DoR, TTR, and TTP was 39.7 weeks (95 % CI 34.1-63.9), 48.7 weeks (95 % CI 31.7-57.1), 7.8 weeks (95 % CI 7.4-8.1), and 41 weeks (95 % CI 39.1-64.6), respectively. Lapatinib 1,000 mg with nab-paclitaxel 100 mg/m(2) IV is feasible with manageable and predictable toxicity and an ORR of 53 % comparing favorably with other HER2-based combinations in this setting.

RAD-Seq derived markers flank the shell colour and banding loci of the Cepaea nemoralis supergene.

Studies on the classic shell colour and banding polymorphism of the land snail Cepaea played a crucial role in establishing the importance of natural selection in maintaining morphological variation. Cepaea is also a pre-eminent model for ecological genetics because the outward colour and banding phenotype is entirely genetically determined, primarily by a 'supergene' of at least five loci. Unfortunately, progress in understanding the evolution and maintenance of the Cepaea polymorphism stalled, partly because of a lack of genetic markers. With a view to re-establish Cepaea as a prominent model of molecular ecology, we made six laboratory crosses of Cepaea nemoralis, five of which segregated for shell ground colour (C) and the presence or absence of bands (B). First, scoring of colour and banding in 323 individuals found no recombination between the C and B loci of the supergene. Second, using restriction site-associated DNA sequencing (RAD-Seq) of two parents and 22 offspring, we identified 44 anonymous markers putatively linked to the colour (C) and banding (B) loci. The genotype of eleven of the most promising RAD-Seq markers was independently validated in the same 22 offspring, then up to a further 146 offspring were genotyped. The closest RAD-Seq markers scored are within ~0.6 centimorgan (cM) of the C-B supergene linkage group, with the combined loci together forming a 35.8 cM linkage map of markers that flank both sides of the Cepaea C-B supergene.