App-based support for breast cancer patients to reduce psychological distress during therapy and survivorship - a multicentric randomized controlled trial.

Introduction: The negative impact of unmanaged psychological distress on quality of life and outcome in breast cancer survivors has been demonstrated. Fortunately, studies indicate that distress can effectively be addressed and even prevented using evidence-based interventions. In Germany prescription-based mobile health apps, known as DiGAs (digital health applications), that are fully reimbursed by health insurances, were introduced in 2020. In this study, the effectiveness of an approved breast cancer DiGA was investigated: The personalized coaching app PINK! Coach supports and accompanies breast cancer patients during therapy and follow-up. Methods: PINK! Coach was specifically designed for breast cancer (BC) patients from the day of diagnosis to the time of Follow-up (aftercare). The app offers individualized, evidence-based therapy and side-effect management, mindfulness-based stress reduction, nutritional and psychological education, physical activity tracking, and motivational exercises to implement lifestyle changes sustainably in daily routine. A prospective, intraindividual RCT (DRKS00028699) was performed with n = 434 patients recruited in 7 German breast cancer centers from September 2022 until January 2023. Patients with BC were included independent of their stage of diseases, type of therapy and molecular characteristics of the tumor. Patients were randomized into one of two groups: The intervention group got access to PINK! over 12 weeks; the control group served as a waiting-list comparison to "standard of care." The primary endpoint was psychological distress objectified by means of Patient Health Questionnaire-9 (PHQ-9). Subgroups were defined to investigate the app's effect on several patient groups such as MBC vs. EBC patients, patients on therapy vs. in aftercare, patients who received a chemotherapy vs. patients who did not. Results: Efficacy analysis of the primary endpoint revealed a significant reduction in psychological distress (least squares estimate -1.62, 95% confidence interval [1.03; 2.21]; p<0.001) among intervention group patients from baseline to T3 vs, control group. Subgroup analysis also suggested improvements across all clinical situations. Conclusion: Patients with breast cancer suffer from psychological problems including anxiety and depression during and after therapy. Personalized, supportive care with the app PINK! Coach turned out as a promising opportunity to significantly improve psychological distress in a convenient, accessible, and low-threshold manner for breast cancer patients independent of their stage of disease (EBC/MBC), therapy phase (aftercare or therapy) or therapy itself (chemotherapy/other therapy options). The app is routinely available in Germany as a DiGA. Clinical Trial Registration: DRKS Trial Registry (DRKS00028699).

Ongoing introgression of a secondary sexual plumage trait in a stable avian hybrid zone.

Hybrid zones are dynamic systems where natural selection, sexual selection, and other evolutionary forces can act on reshuffled combinations of distinct genomes. The movement of hybrid zones, individual traits, or both are of particular interest for understanding the interplay between selective processes. In a hybrid zone involving two lek-breeding birds, secondary sexual plumage traits of Manacus vitellinus, including bright yellow collar and olive belly color, have introgressed asymmetrically ~50 km across the genomic center of the zone into populations more genetically similar to Manacus candei. Males with yellow collars are preferred by females and are more aggressive than parental M. candei, suggesting that sexual selection was responsible for the introgression of male traits. We assessed the spatial and temporal dynamics of this hybrid zone using historical (1989 - 1994) and contemporary (2017 - 2020) transect samples to survey both morphological and genetic variation. Genome-wide SNP data and several male phenotypic traits show that the genomic center of the zone has remained spatially stable, whereas the olive belly color of male M. vitellinus has continued to introgress over this time period. Our data suggest that sexual selection can continue to shape phenotypes dynamically, independent of a stable genomic transition between species.

Inequalities in the recovery of colorectal cancer services during the COVID-19 pandemic: a national population-based study.

AIM: Evidence is lacking on whether there were inequalities in the recovery of colorectal cancer (CRC) services within the English National Health Service (NHS) following the COVID-19 pandemic. The aim of this study was to evaluate recovery according to patient age and socioeconomic status. METHOD: Using routinely collected data, CRC patients diagnosed and treated in the English NHS were identified for two timeframes: the 'initial pandemic period' (April-June 2020) and the 'pandemic period' (April 2020-March 2022). Poisson models evaluated changes in numbers of diagnoses, major resections, adjuvant chemotherapy and neoadjuvant radiotherapy use for each timeframe, relative to the equivalent pre-pandemic timeframe (April-June 2019 and April 2018-March 2020, respectively), stratified by age and socioeconomic status. Tumour stage at presentation was evaluated over time. RESULTS: Substantial deficits in diagnoses, major resections and adjuvant chemotherapy were identified in the initial pandemic period, whilst the use of neoadjuvant radiotherapy increased. Overall, these deficits recovered. Patients outside screening age, and in the most deprived group, had greater deficits in diagnoses and major resections. There was no evidence of stage migration by June 2021. CONCLUSIONS: CRC services showed recovery to baseline during the pandemic. However, evident inequalities must be addressed in ongoing recovery efforts. Long-term outcomes will fully establish the impact of the pandemic on CRC patients.

Tunable Syngas Formation at Industrially Relevant Current Densities via CO2 Electroreduction and Hydrogen Evolution over Ni and Fe-derived Catalysts obtained via One-Step Pyrolysis of Polybenzoxazine Based Composites.

Simultaneous electroreduction of CO2 and H2 O to syngas can provide a sustainable feed for established processes used to synthesize carbon-based chemicals. The synthesis of MOx /M-N-Cs (M = Ni, Fe) electrocatalysts reported via one-step pyrolysis that shows increased performance during syngas electrosynthesis at high current densities with adaptable H2 /CO ratios, e.g., for the Fischer-Tropsch process. When embedded in gas diffusion electrodes (GDEs) with optimized hydrophobicity, the NiOx /Ni-N-C catalyst produces syngas (H2 /CO = 0.67) at -200 mA cm-2 while for the FeOx /Fe-N-C syngas production occurs at ≈-150 mA cm-2 . By tuning the electrocatalyst's microenvironment, stable operation for >3 h at -200 mA cm-2 is achieved with the NiOx /Ni-N-C GDE. Post-electrolysis characterization revealed that the restructuring of the catalyst via reduction of NiOx to metallic Ni NPs still enables stable operation of the electrode at -200 mA cm-2 , when embedded in an optimized microenvironment. The ionomer and additives used in the catalyst layer are important for the observed stable operation. Operando Raman measurements confirm the presence of NiOx during CO formation and indicate weak adsorption of CO on the catalyst surface.

Fetal bladder morphology as a predictor of outcome in fetal lower urinary tract obstruction.

OBJECTIVE: We evaluate survival of fetuses with severe Lower Urinary Tract Obstruction (LUTO) based on bladder morphology. We hypothesize that fetuses with a "floppy" appearing bladder on initial prenatal ultrasound will have worse infant outcomes than fetuses with full/rounded bladders. METHOD: We retrospectively reviewed all cases of LUTO evaluated in our fetal center between January 2013 and December 2021. Ultrasonographic assessment, renal biochemistry, and bladder refilling contributed to a "favorable" or "unfavorable" evaluation. Bladder morphology on initial ultrasound was classified as "floppy" or "full/rounded." Vesicoamniotic shunting was offered for favorably evaluated fetuses. Baseline demographics, ultrasound parameters, prenatal evaluations of fetal renal function, and infant outcomes were collected. Fetuses diagnosed with severe LUTO were included in analysis using descriptive statistics. The primary outcome measured was survival at 6 months of life. RESULTS: 104 LUTO patients were evaluated; 24 were included in analysis. Infant survival rate at 6 months was 60% for rounded bladders and 0% for floppy bladders (p = 0.003). Bladder refill adequacy was lower in fetuses with floppy bladders compared with rounded bladders (p value < 0.00001). CONCLUSION: We propose that bladder morphology in fetuses with severe LUTO may be a prognostication factor for predicting infant outcomes and provides a valuable, noninvasive assessment tool.

Utility of kidney ultrasonography during initial evaluation of pediatric nephrotic syndrome.

BACKGROUND: Current guidelines note a gap in high-quality evidence regarding utility of kidney ultrasonography (KUS) during initial evaluation of nephrotic syndrome (NS) due to presumed minimal change disease (pMCD). However, KUS is frequently obtained at our institution. This retrospective chart review assessed incidence and impact of abnormal sonographic findings in these patients. METHODS: Patients 1-18 years, newly diagnosed at our institution with NS from pMCD between 2011 and 2021, were identified. Hypertension, urinalysis, kidney function, and steroid responsiveness data were collected. Imaging findings were abstracted from radiology reports. Clinical impact of KUS was defined by actions taken in response to KUS. RESULTS: A total of 173 patients identified with new NS; 98 met inclusion criteria. Of these, 54% had KUS during the initial encounter. Demographic and laboratory data did not differ between those with and without KUS. KUS were abnormal in 70% of studies: increased kidney echogenicity (39.6%) and nephromegaly (35.8%) were the most common abnormal findings. Other findings included decreased corticomedullary differentiation, lobular kidney contour, solitary simple kidney cyst, and mild unilateral hydronephrosis. Steroid resistance was not associated with either nephromegaly or abnormal echogenicity. CONCLUSIONS: Our data showed no clinically relevant ultrasound findings causing deviations from the standard of care for pMCD. There was no association between KUS findings and steroid resistance. These data suggest there is little to no benefit from routine KUS imaging in patients with pMCD upon initial presentation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Undergraduate College Pathway Programs Designed to Attract and Matriculate Students from Underrepresented Groups into Medicine.

OBJECTIVES: Undergraduate college pathway (or pipeline) programs support students' interests as they explore advanced degree and career pathways. Many programs aim to diversify the medical workforce by reducing barriers that may have otherwise prevented desired academic and career goals; however, variability in structure, expectations, benefits, and outcome data exist. This systematic review was conducted to identify and evaluate undergraduate college pathway programs designed to increase the diversity of medical school matriculants. METHODS: We searched Ovid Medline, PsycInfo, Scopus, and the Education Resources Information Center for peer-reviewed, original research publications (1996-2019) describing US pathway/pipeline programs designed for undergraduate-level college students from underrepresented groups to apply and enter medical school. Data extraction included application processes, participant demographics, curricular components, social support systems, mentorship, funding, and program/participant outcomes. We reviewed the journal impact factor to inform us about where articles are being published. RESULTS: Our full-text review included 137 articles; 25 articles met the inclusion criteria. All of the papers were descriptive, requiring an application, minimum grade point average, letters of recommendation, and personal statements. All of the programs aimed to diversify medicine, yet some could not request identification of race/ethnicity because of changes in affirmative action or legal restrictions when reporting demographics. Women represented the majority of enrollees. The program length varied; all reported having one or a combination of academic enrichment, research, field observation/experience, and mentorship. All of the programs included career development and various supplemental social supports. Only two programs provided comparison data; four reported no outcomes. CONCLUSIONS: Pathway programs support the acquisition and enhancement of professional skills. Lacking longitudinal or comparison data leads to questions of the long-term impact on diversifying the medical workforce. This article highlights a need for rigorous data collection methods and transparent reporting of participant outcomes to inform programmatic efficacy.

Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders.

The Nrf2 transcription factor is a master regulator of the cellular response to oxidative stress, and Keap1 is its primary negative regulator. Activating Nrf2 by inhibiting the Nrf2-Keap1 protein-protein interaction has shown promise for treating cancer and inflammatory diseases. A loop derived from Nrf2 has been shown to inhibit Keap1 selectively, especially when cyclized, but there are no reliable design methods for predicting an optimal macrocyclization strategy. In this work, we employed all-atom, explicit-solvent molecular dynamics simulations with enhanced sampling methods to predict the relative degree of preorganization for a series of peptides cyclized with a set of bis-thioether "staples". We then correlated these predictions to experimentally measured binding affinities for Keap1 and crystal structures of the cyclic peptides bound to Keap1. This work showcases a computational method for designing cyclic peptides by simulating and comparing their entire solution-phase ensembles, providing key insights into designing cyclic peptides as selective inhibitors of protein-protein interactions.

Combined stent retriever angioplasty and continuous intra-arterial nimodipine infusion as salvage therapy for cerebral vasospasm and delayed cerebral ischemia after subarachnoid hemorrhage: illustrative case.

BACKGROUND: Delayed cerebral ischemia (DCI) and cerebral vasospasm (CV) are severe complications of spontaneous subarachnoid hemorrhage (SAH) contributing to an inferior outcome. Rescue therapies include intra-arterial balloon angioplasty and repetitive and finally continuous intra-arterial nimodipine infusion. OBSERVATIONS: In the presented case, a young female patient with fulminant refractory DCI and CV, despite induced hypertension and nimodipine application, was treated with three-vessel continuous intra-arterial infusion and additional repetitive angioplasty of the basilar and middle cerebral arteries using a stent retriever, leading to a good clinical outcome. Additional stent retriever dilatation to continuous intra-arterial nimodipine application in three vessel territories may represent a further escalation step in the rescue therapy for severe CV and DCI after SAH. Montreal Cognitive Assessment and SF-36 testing showed satisfactory results 3 months after initial treatment with intra-arterial nimodipine catheters in three vessel territory circulations and additional stent retriever vasodilation of severe CV. LESSONS: We report a unique rescue strategy involving implantation of an additional intra-arterial catheter into the vertebral artery and repetitive stent retriever dilatations of the middle cerebral and basilar arteries as an extra therapy for continuous intra-arterial nimodipine vaspospasmolytic therapy in three vessel territories, resulting in a very good clinical outcome.

What is the impact of hospital and surgeon volumes on outcomes in rectal cancer surgery?

AIM: Evidence for a positive volume-outcome relationship for rectal cancer surgery is unclear. This study aims to evaluate the volume-outcome relationship for rectal cancer surgery at hospital and surgeon level in the English National Health Service (NHS). METHOD: All patients undergoing a rectal cancer resection in the English NHS between 2015 and 2019 were included. Multilevel multivariable logistic regression was used to model relationships between outcomes and mean annual hospital and surgeon volumes (using a linear plus a quadratic term for volume) with adjustment for patient characteristics. RESULTS: A total of 13 858 patients treated in 166 hospitals were included. Six hospitals (3.6%) performed fewer than 10 rectal cancer resections per year, and 381 surgeons (45.0%) performed fewer than five such resections per year. Patients treated by high-volume surgeons had a reduced length of stay (p = 0.016). No statistically significant volume-outcome relationships were demonstrated for 90-day mortality, 30-day unplanned readmission, unplanned return to theatre, stoma at 18 months following anterior resection, positive circumferential resection margin and 2-year all-cause mortality at either hospital or surgeon level (p values > 0.05). CONCLUSION: Almost half of colorectal surgeons in England do not meet national guidelines for rectal cancer surgeons to perform a minimum of five major resections annually. However, our results suggest that centralizing rectal cancer surgery with the main focus of increasing operative volume may have limited impact on NHS surgical outcomes. Therefore, quality improvement initiatives should address a wider range of evidence-based process measures, across the multidisciplinary care pathway, to enhance outcomes for patients with rectal cancer.

Polygenic genetic variation affecting antibody formation underlies hypertensive renal injury in the stroke-prone spontaneously hypertensive rat.

During development of the spontaneously hypertensive rat (SHR), several distinct but closely related lines were generated. Most lines are resistant to hypertensive renal disease. However, the SHR-A3 line (stroke-prone SHR) experiences end-organ injury (EOI) and provides a model of injury susceptibility that can be used to uncover genetic causation. In the present study, we generated a congenic line in which three distinct disease loci in SHR-A3 are concurrently replaced with homologous loci from an injury-resistant SHR line (SHR-B2). Verification that all three loci were homozygously replaced in this triple congenic line [SHR-A3(Trip B2)] while the genetic background of SHR-A3 was fully retained was obtained by whole genome sequencing. Congenic genome substitution was without effect on systolic blood pressure [198.9 ± 3.34 mmHg, mean ± SE, SHR-A3(Trip B2) = 194.7 ± 2.55 mmHg]. Measures of renal injury (albuminuria, histological injury scores, and urinary biomarker levels) were reduced in SHR-A3(Trip B2) animals, even though only 4.5 Mbases of the 2.8 Gbases of the SHR-B2 genome (0.16% of the genome) was transferred into the congenic line. The gene content of the three congenic loci and the functional effects of gene polymorphism within suggest a role of immunoglobulin in EOI pathogenesis. To prove the role of antibodies in EOI in SHR-A3, we generated an SHR-A3 line in which expression from the immunoglobulin heavy chain gene was knocked out (SHR-A3-IGHKO). Animals in the SHR-A3-IGHKO line lack B cells and immunoglobulin, but the hypertensive phenotype is not affected. Renal injury, however, was reduced in this line, confirming a pathogenic role for immunoglobulin in hypertensive EOI in this model of heritable risk.NEW & NOTEWORTHY Here, we used a polygenic animal model of hypertensive renal disease to show that genetic variation affecting antibody formation underlies hypertensive renal disease. We proved the genetic thesis by generating an immunoglobulin knockout in the susceptible animal model.

Adjuvant Therapy for Elderly Breast Cancer Patients after Breast-Conserving Surgery: Outcomes in Real World Practice.

We aimed to evaluate the standard of care of adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) in elderly female patients (≥65 years) treated outside of clinical trials and to identify potential factors related to the omission of RT and the interaction with endocrine therapy (ET). All women treated with BCS at two major breast centers between 1998 and 2014 were evaluated. Data were provided by the Tumor Registry Munich. Survival analyses were conducted using the Kaplan-Meier method. Prognostic factors were identified using multivariate Cox regression analysis. The median follow-up was 88.4 months. Adjuvant RT was performed in 82% (2599/3171) of patients. Irradiated patients were younger (70.9 vs. 76.5 years, p < 0.001) and were more likely to receive additional chemotherapy (p < 0.001) and ET (p = 0.014). Non-irradiated patients more often had non-invasive DCIS tumors (pTis: 20.3% vs. 6.8%, p < 0.001) and did not undergo axillary surgery (no axillary surgery: 50.5% vs. 9.5%, p < 0.001). Adjuvant RT was associated with improved locoregional tumor control after BCS in invasive tumors (10-year local recurrence-free survival (LRFS): 94.0% vs. 75.1%, p < 0.001, 10-year lymph node recurrence-free survival (LNRFS): 98.1% vs. 93.1%, p < 0.001). Multivariate analysis confirmed significant benefits for local control with postoperative RT. Furthermore, RT led to increased locoregional control even in patients who received ET (10-year LRFS 94.8% with ET + RT vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.2% vs. 95.0%, p = 0.003). Similarly, RT alone had significantly better locoregional control rates compared to ET alone (10-year LRFS 92.6% with RT alone vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.0% vs. 95.0%, p = 0.014). The present work confirms the efficacy of postoperative RT for breast carcinoma in elderly patients (≥65 years) treated in a modern clinical setting outside of clinical trials, even in patients who receive ET.

Spray-Flame Synthesis of LaFexCo1-xO3 (x = 0.2, 0.3) Perovskite Nanoparticles for Oxygen Evolution Reaction in Water Splitting: Effect of Precursor Chemistry (Acetates and Nitrates).

The product properties of mixed oxide nanoparticles generated via spray-flame synthesis depend on an intricate interplay of solvent and precursor chemistries in the processed solution. The effect of two different sets of metal precursors, acetates and nitrates, dissolved in a mixture of ethanol (35 Vol.%) and 2-ethylhexanoic acid (2-EHA, 65 Vol.%) was investigated for the synthesis of LaFexCo1-xO3 (x = 0.2, 0.3) perovskites. Regardless of the set of precursors, similar particle-size distributions (dp = 8-11 nm) were obtained and a few particles with sizes above 20 nm were identified with transmission electron microscopy (TEM) measurements. Using acetates as precursors, inhomogeneous La, Fe, and Co elemental distributions were obtained for all particle sizes according to energy dispersive X-ray (EDX) mappings, connected to the formation of multiple secondary phases such as oxygen-deficient La3(FexCo1-x)3O8 brownmillerite or La4(FexCo1-x)3O10 Ruddlesden-Popper (RP) structures besides the main trigonal perovskite phase. For samples synthesized from nitrates, inhomogeneous elemental distributions were observed for large particles only where La and Fe enrichment occurred in combination with the formation of a secondary La2(FexCo1-x)O4 RP phase. Such variations can be attributed to reactions in the solution prior to injection in the flame as well as precursor-dependent variations in in-flame reactions. Therefore, the precursor solutions were analyzed by temperature-dependent attenuated total reflection Fourier-transform infrared (ATR-FTIR) measurements. The acetate-based precursor solutions indicated the partial conversion of, mainly La and Fe, acetates to metal 2-ethylhexanoates. In the nitrate-based solutions, esterification of ethanol and 2-EHA played the most important role. The synthesized nanoparticle samples were characterized by BET (Brunauer, Emmett, Teller), FTIR, Mössbauer, and X-ray photoelectron spectroscopy (XPS). All samples were tested as oxygen evolution reaction (OER) catalysts, and similar electrocatalytic activities were recorded when evaluating the potential required to reach 10 mA/cm2 current density (∼1.61 V vs reversible hydrogen electrode (RHE)).

Protocol for the CoNoR Study: A prospective multi-step study of the potential added benefit of two novel assessment tools in colorectal liver metastases technical resectability decision-making.

INTRODUCTION: Liver resection is the only curative treatment for colorectal liver metastases (CLM). Resectability decision-making is therefore a key determinant of outcomes. Wide variation has been demonstrated in resectability decision-making, despite the existence of criteria. This paper summarises a study protocol to evaluate the potential added value of two novel assessment tools in assessing CLM technical resectability: the Hepatica preoperative MR scan (MR-based volumetry, Couinaud segmentation, liver tissue characteristics and operative planning tool) and the LiMAx test (hepatic functional capacity). METHODS AND ANALYSIS: This study uses a systematic multistep approach, whereby three preparatory workstreams aid the design of the final international case-based scenario survey:Workstream 1: systematic literature review of published resectability criteria.Workstream 2: international hepatopancreatobiliary (HPB) interviews.Workstream 3: international HPB questionnaire.Workstream 4: international HPB case-based scenario survey.The primary outcome measures are change in resectability decision-making and change in planned operative strategy, resulting from the novel test results. Secondary outcome measures are variability in CLM resectability decision-making and opinions on the role for novel tools. ETHICS AND DISSEMINATION: The study protocol has been approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences. Manuscripts will be published. REGISTRATION DETAILS: The CoNoR Study is registered with ClinicalTrials.gov (registration number NCT04270851). The systematic review is registered on the PROSPERO database (registration number CRD42019136748).

Compound heterozygosity of a de novo submicroscopic deletion and an inherited frameshift pathogenic variant in the PKHD1 gene in a fetus with bilaterally enlarged and echogenic kidneys, enlarged abdomen and oligohydramnios.

We present a fetus with bilaterally enlarged and echogenic kidneys. Prenatal testing detected compound heterozygosity for a 0.676 Mb de novo deletion and an inherited pathogenic variant in PKHD1. This is the first case of autosomal recessive polycystic kidney disease (ARPKD) with a prenatally detected disease-causing PKHD1 deletion.

The Mental Health Burden of Patients with Colorectal Cancer Receiving Care during the COVID-19 Pandemic: Results of the PICO-SM Study.

The COVID-19 pandemic has resulted in unprecedented changes to the lives of patients with cancer. To evaluate the impact of the COVID-19 pandemic on the mental health and well-being of patients with colorectal cancer, we conducted a prospective longitudinal questionnaire study at a UK tertiary cancer centre. In total, 216 participants were included: mean age 65 years, 57% (n = 122) male, 92% (n = 198) of white ethnicity. Amongst participants who completed the screening psychometric questionnaire, 24% (n = 48/203) reported anxiety (GAD-7 ≥ 5), 15% (n = 31/204) depressive symptoms (PHQ-9 ≥ 10), 3% (n = 5/190) probable post-traumatic stress disorder (PC-PTSD-5 ≥ 4), and 31% (n = 66/213) poor well-being (WHO-5 < 50). In the subgroup (n = 95/216, 44%) who consented to and completed a follow-up survey 6 months later, there was a significant increase in the number of participants at risk of depression (4% vs. 13%, p = 0.021). Self-reported concern about the COVID-19 pandemic impacting one's mental health is associated with increased likelihood of anxiety, depression, and poor well-being, in respective multivariate analyses. In conclusion, screening for the mental health impact of the COVID-19 pandemic is essential to ensure timely action from all key stakeholders and to avoid potentially longer-term detrimental consequences.

Evolution of the Growth Hormone Gene Duplication in Passerine Birds.

Birds of the order Passeriformes represent the most speciose order of land vertebrates. Despite strong scientific interest in this super-radiation, genetic traits unique to passerines are not well characterized. A duplicate copy of growth hormone (GH) is the only gene known to be present in all major lineages of passerines, but not in other birds. GH genes plausibly influence extreme life history traits that passerines exhibit, including the shortest embryo-to-fledging developmental period of any avian order. To unravel the implications of this GH duplication, we investigated the molecular evolution of the ancestral avian GH gene (GH or GH1) and the novel passerine GH paralog (GH2), using 497 gene sequences extracted from 342 genomes. Passerine GH1 and GH2 are reciprocally monophyletic, consistent with a single duplication event from a microchromosome onto a macrochromosome in a common ancestor of extant passerines. Additional chromosomal rearrangements have changed the syntenic and potential regulatory context of these genes. Both passerine GH1 and GH2 display substantially higher rates of nonsynonymous codon change than non-passerine avian GH, suggesting positive selection following duplication. A site involved in signal peptide cleavage is under selection in both paralogs. Other sites under positive selection differ between the two paralogs, but many are clustered in one region of a 3D model of the protein. Both paralogs retain key functional features and are actively but differentially expressed in two major passerine suborders. These phenomena suggest that GH genes may be evolving novel adaptive roles in passerine birds.

De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial.

PURPOSE: Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS: In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION: The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.