Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood.

Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.

A self-sustaining layer of early-life-origin B cells drives steady-state IgA responses in the adult gut.

The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing stratified murine adult B cells based on the timing of output, revealing that a substantial portion originated within a restricted neonatal window. In addition to B-1a cells, early-life time-stamped B cells included clonally interrelated IgA plasma cells in the gut and bone marrow. These were actively maintained by B cell memory within gut chronic germinal centers and contained commensal microbiota reactivity. Neonatal rotavirus infection recruited recurrent IgA clones that were distinct from those arising by infection with the same antigen in adults. Finally, gut IgA plasma cells arose from the same hematopoietic progenitors as B-1a cells during ontogeny. Thus, a complex layer of neonatally imprinted B cells confer unique antibody responses later in life.

Developmental changes in the rules for B cell selection.

The autoimmune checkpoint during B cell maturation eliminates self-antigen reactive specificities from the mature B cell repertoire. However, an exception to this rule is illustrated by B-1 cells, an innate-like self-reactive B cell subset that is positively selected into the mature B cell pool in a self-antigen-driven fashion. The mechanisms by which B-1 cells escape central tolerance have puzzled the field for decades. A key clue comes from their restricted developmental window during fetal and neonatal life. Here we use B-1 cells as a prototypic early life derived B cell subset to explore developmental changes in the constraints of B cell selection. We discuss recent advancements in the understanding of the molecular program, centered around the RNA binding protein Lin28b, that licenses self-reactive B-1 cell output during ontogeny. Finally, we speculate on the possible link between the unique rules of early life B cell tolerance and the establishment of B cell - microbial mutualism to propose an integrated model for how developmental and environmental cues come together to create a protective layer of B cell memory involved in neonatal immune imprinting.

Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer.

PURPOSE: Here, we investigated the potential predictive and elucidating efficacy of cell-free DNA (cfDNA) changes on clinical outcomes and biological effects, respectively, after short-term palbociclib and fulvestrant treatment for patients with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer (ABC). METHODS: In this secondary analysis of the Japan Breast Cancer Research Group-M07 (FUTURE) trial, blood cfDNA was obtained before palbociclib treatment and on day 15 of cycle one (28-day cycle). Target enrichment was performed using next-generation sequencing; progression-free survival (PFS) was compared based on cfDNA changes between baseline and day 15 of cycle one after combination therapy. RESULTS: Fifty-six patients (112 paired blood samples) were examined. The median follow-up time was 8.9 months. PIK3CA (30.4%, 17/56), FOXA1 (30.4%, 17/56), and ESR1 (28.6%, 16/56) were most frequently mutated at baseline. The number of mutated genes was significantly decreased on day 15 compared with that at baseline (paired t test: P value = 0.025). No significant difference was observed in PFS (decrease group, 7.9 m vs the others, 9.3 m; log-rank P value = 0.75; hazard ratio, 1.13; 95% confidence interval, 0.53-2.41). Among patients without previous aromatase inhibitor treatment (n = 15), three (20%) had ESR1 mutations after progression to fulvestrant. CONCLUSION: No significant association was observed between changes in mutated genes after short-term palbociclib and fulvestrant treatment and disease progression; a significant reduction in cfDNA mutation level was observed on day 15 of cycle one. Clinical meanings of cfDNA should be investigated in the future trials.

A perioperative study of Safusidenib in patients with IDH1-mutated glioma.

This is a single arm, open label perioperative trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with safusidenib following biopsy, and prior to surgical resection in patients with IDH1 mutated glioma who have not received radiation therapy or chemotherapy. Fifteen participants will receive treatment in two parts. First, biopsy followed by one cycle (28 days) of safusidenib, an orally available, small molecular inhibitor of mutated IDH1, then maximal safe resection of the tumor (Part A). Second, after recovery from surgery, safusidenib until disease progression or unacceptable toxicity (Part B). This research will enable objective measurement of biological activity of safusidenib in patients with IDH1 mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention.Clinical Trial Registration: NCT05577416 (ClinicalTrials.gov).

Adult low-grade gliomas (aLGG) are primary brain cancers, defined by mutations in IDH1 or IDH2. When the IDH gene becomes abnormal (mutated), production of a metabolite that causes cancer cells to grow is increased. These tumors grow slowly but invade the normal functioning brain, making them nearly impossible to cure. The current standard of care treatment includes surgery, followed by radiation therapy and chemotherapy, the timing of which depends on the risk of cancer regrowth. Some patients may be suitable for monitoring with MRI scans alone, however recurrences will inevitably occur. Recently developed targeted mutant IDH inhibitors for aLGG patients may be beneficial both at diagnosis and recurrence. Notably, early treatment prior to radiation therapy and chemotherapy delays growth of aLGG and the need for subsequent radiation therapy and chemotherapy. Nevertheless, most patients will eventually suffer further tumor growth and the optimal timing and sequencing of these therapies remains an area of active research. This research investigates the mutant IDH1 inhibitor safusidenib. The researchers are conducting an innovative clinical trial where patients with aLGG, who have not received radiation therapy or chemotherapy, are treated with safusidenib following a biopsy and prior to surgical removal of their tumor. In this study they investigate whether this trial design is safe and feasible, and how safusidenib works; with the goal to better understand the optimal use of IDH inhibitors for patients with aLGG.

Searching for a "Window of Opportunity" in the Treatment of Vulvar Lichen Sclerosus: Evidence for Therapeutic Benefits of an Early Corticosteroid Treatment.

INTRODUCTION: Vulvar lichen sclerosus (VLS) is characterized by progressive anatomical changes which become increasingly severe and irreversible. The objective of this study was to investigate if a "window of opportunity" exists in VLS, i.e., to assess if an early treatment may prevent disease progression and facilitate clearance of symptoms and/or signs. METHODS: This retrospective, cohort study included VLS patients treated for the first time with a topical corticosteroid, namely with mometasone furoate 0.1% ointment, for 12 weeks (2016-2021). Scoring of subjective symptoms (global subjective score, GSS, and dyspareunia) and clinical features (global objective score [GOS] and sclerosis-scarring-atrophy) was performed at baseline (T0) and at the control visit (T1). We assessed if the achievement of clearance in GSS, GOS, sclerosis-scarring-atrophy, or dyspareunia depended on the time elapsed between VLS onset and treatment initiation. RESULTS: Among the 168 patients (59.2 ± 13.2 years) included, the median time between VLS onset and first treatment was 14.0 months. At T1, 48.8% of patients achieved clearance of GSS, 28% of GOS and 11.9% of both GSS and GOS, 57.9% of dyspareunia, and 19.2% of sclerosis-scarring-atrophy. The logistic regression model showed that each 10-month increase in treatment initiation adversely affected the clearance of GSS while starting treatment within 6 months of disease onset was significantly associated with clearance of GOS and sclerosis-scarring-atrophy. CONCLUSION: Early treatment is crucial in determining a complete healing of VLS-related symptoms and signs, especially of tissue sclerosis-scarring-atrophy, which appear poorly responsive, or even unresponsive, after the earliest stages of the disease. Thus our findings provide evidence for a "window of opportunity" in VLS treatment.

The Effect of Statins on Markers of Breast Cancer Proliferation and Apoptosis in Women with In Situ or Early-Stage Invasive Breast Cancer.

Statins, inhibitors of HMG-CoA reductase, have been shown to have potential anti-carcinogenic effects through the inhibition of the mevalonate pathway and their impact on Ras and RhoGTAases. Prior studies have demonstrated a reduction in breast tumor proliferation, as well as increased apoptosis, among women with early-stage breast cancer who received statins between the time of diagnosis and the time of surgery. The aim of this study was to evaluate the impact of short-term oral high-potency statin therapy on the expression of markers of breast tumor proliferation, apoptosis, and cell cycle arrest in a window-of-opportunity trial. This single-arm study enrolled 24 women with stage 0-II invasive breast cancer who were administered daily simvastatin (20 mg) for 2-4 weeks between diagnosis and surgical resection. Pre- and post-treatment tumor samples were analyzed for fold changes in Ki-67, cyclin D1, p27, and cleaved caspase-3 (CC3) expression. Out of 24 enrolled participants, 18 received statin treatment and 17 were evaluable for changes in marker expression. There was no significant change in Ki-67 expression (fold change = 1.4, p = 0.597). There were, however, significant increases in the expression of cyclin D1 (fold change = 2.8, p = 0.0003), p27 cytoplasmic (fold change = 3.2, p = 0.025), and CC3 (fold change = 2.1, p = 0.016). Statin treatment was well tolerated, with two reported grade-1 adverse events. These results align with previous window-of-opportunity studies suggesting a pro-apoptotic role of statins in breast cancer. The increased expression of markers of cell cycle arrest and apoptosis seen in this window-of-opportunity study supports further investigation into the anti-cancer properties of statins in larger-scale clinical trials.

Four ways to define the growing season.

What is addressed as growing season in terrestrial ecosystems is one of the main determinants of annual plant biomass production globally. However, there is no well-defined concept behind. Here, we show different facets of what might be termed growing season, each with a distinct meaning: (1) the time period during which a plant or a part of it actually grows and produces new tissue, irrespective of net carbon gain (growing season sensu stricto). (2) The period defined by developmental, that is, phenological markers (phenological season). (3) The period during which vegetation as a whole achieves its annual net primary production (NPP) or a net ecosystem production (NEP), expressed as net carbon gain (productive season) and (4) the period during which plants could potentially grow based on meteorological criteria (meteorological season). We hypothesize that the duration of such a 'window of opportunity' is a strong predictor for NPP at a global scale, especially for forests. These different definitions have implications for the understanding and modelling of plant growth and biomass production. The common view that variation in phenology is a proxy for variation in productivity is misleading, often resulting in unfounded statements on potential consequences of climatic warming such as carbon sequestration.

AMEERA-4: a randomized, preoperative window-of-opportunity study of amcenestrant versus letrozole in early breast cancer.

BACKGROUND: Window-of-opportunity (WOO) studies provide insights into the clinical activity of new drugs in breast cancer. METHODS: AMEERA-4 (NCT04191382) was a WOO study undertaken to compare the pharmacodynamic effects of amcenestrant, a selective estrogen receptor degrader, with those of letrozole in postmenopausal women with newly diagnosed, operable estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. Women were randomized (1:1:1) to receive amcenestrant 400 mg, amcenestrant 200 mg, or letrozole 2.5 mg once daily for 14 days before breast surgery. The primary endpoint was change in Ki67 between baseline and Day 15 (i.e., day of surgery). RESULTS: Enrollment was stopped early because of slow recruitment, in the context of the COVID-19 pandemic. The modified intent-to-treat population consisted of 95 study participants with baseline and post-treatment Ki67 values, whereas the safety population included 104 participants who had received at least one dose of study medication. Relative change from baseline in Ki67 was - 75.9% (95% confidence interval [CI] - 81.9 to - 67.9) for amcenestrant 400 mg, - 68.2% (- 75.7 to - 58.4) for amcenestrant 200 mg, and - 77.7% (- 83.4 to - 70.0) for letrozole (geometric least-squares mean [LSM] estimates). Absolute change in ER H-score from baseline (LSM estimate) was - 176.7 in the amcenestrant 400 mg arm, - 202.9 in the amcenestrant 200 mg arm, and - 32.5 in the letrozole arm. There were no Grade ≥ 3 treatment-related adverse events. CONCLUSIONS: Both amcenestrant and letrozole demonstrated antiproliferative activity in postmenopausal women with previously untreated, operable ER+/HER2- breast cancer and had good overall tolerability. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04191382 https://clinicaltrials.gov/ct2/show/NCT04191382 . Registered 9 December 2019.

The Future Glioblastoma Clinical Trials Landscape: Early Phase 0, Window of Opportunity, and Adaptive Phase I-III Studies.

PURPOSE OF REVIEW: Innovative clinical trial designs for glioblastoma (GBM) are needed to expedite drug discovery. Phase 0, window of opportunity, and adaptive designs have been proposed, but their advanced methodologies and underlying biostatistics are not widely known. This review summarizes phase 0, window of opportunity, and adaptive phase I-III clinical trial designs in GBM tailored to physicians. RECENT FINDINGS: Phase 0, window of opportunity, and adaptive trials are now being implemented for GBM. These trials can remove ineffective therapies earlier during drug development and improve trial efficiency. There are two ongoing adaptive platform trials: GBM Adaptive Global Innovative Learning Environment (GBM AGILE) and the INdividualized Screening trial of Innovative GBM Therapy (INSIGhT). The future clinical trials landscape in GBM will increasingly involve phase 0, window of opportunity, and adaptive phase I-III studies. Continued collaboration between physicians and biostatisticians will be critical for implementing these trial designs.

Improving oncology first-in-human and Window of opportunity informed consent forms through participant feedback.

BACKGROUND: Although patient advocates have developed templates for standard consent forms, evaluating patient preferences for first in human (FIH) and window of opportunity (Window) trial consent forms is critical due to their unique risks. FIH trials are the initial use of a novel compound in study participants. In contrast, Window trials give an investigational agent over a fixed duration to treatment naïve patients in the time between diagnosis and standard of care (SOC) surgery. Our goal was to determine the patient-preferred presentation of important information in consent forms for these trials. METHODS: The study consisted of two phases: (1) analyses of oncology FIH and Window consents; (2) interviews of trial participants. FIH consent forms were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH information); Window consents were analyzed for the location(s) of information stating the trial may delay SOC surgery (delay information). Participants were asked about their preferred placement of the information in their own trial's consent form. The location of information in the consent forms was compared to the participants' suggestions for placement. RESULTS: 34 [17 FIH; 17 Window] of 42(81%) cancer patients approached participated. 25 consents [20 FIH; 5 Window] were analyzed. 19/20 FIH consent forms included FIH information, and 4/5 Window consent forms included delay information. 19/20(95%) FIH consent forms contained FIH information in the risks section 12/17(71%) patients preferred the same. Fourteen (82%) patients wanted FIH information in the purpose, but only 5(25%) consents mentioned it there. 9/17(53%) Window patients preferred delay information to be located early in the consent, before the "Risks" section.  3/5(60%) consents did this. CONCLUSIONS: Designing consents that reflect patient preferences more accurately is essential for ethical informed consent; however, a one-size fits all approach will not accurately capture patient preferences. We found that preferences differed for FIH and Window trial consents, though for both, patients preferred key risk information early in the consent. Next steps include determining if FIH and Window consent templates improve understanding.

Patient perspectives on window of opportunity clinical trials in early-stage breast cancer.

PURPOSE: Window of opportunity trials (WOT) are increasingly common in oncology research. In WOT participants receive a drug between diagnosis and anti-cancer treatment, usually for the purpose of investigating that drugs effect on cancer biology. This qualitative study aimed to understand patient perspectives on WOT. METHODS: We recruited adults diagnosed with early-stage breast cancer awaiting definitive therapy at a single-academic medical center to participate in semi-structured interviews. Thematic and content analyses were performed to identify attitudes and factors that would influence decisions about WOT participation. RESULTS: We interviewed 25 women diagnosed with early-stage breast cancer. The most common positive attitudes toward trial participation were a desire to contribute to research and a hope for personal benefit, while the most common concerns were the potential for side effects and how they might impact fitness for planned treatment. Participants indicated family would be an important normative factor in decision-making and, during the COVID-19 pandemic, deemed the absence of family members during clinic visits a barrier to enrollment. Factors that could hinder participation included delay in standard treatment and the requirement for additional visits or procedures. Ultimately, most interviewees stated they would participate in a WOT if offered (N = 17/25). CONCLUSION: In this qualitative study, interviewees weighed altruism and hypothetical personal benefit against the possibility of side effect from a WOT. In-person family presence during trial discussion, challenging during COVID-19, was important for many. Our results may inform trial design and communication approaches in future window of opportunity efforts.

How to set the agenda for hepatitis C: a theory-driven policy analysis.

BACKGROUND: Hepatitis C virus (HCV) represents a significant public health burden. When new HCV drugs arrived in 2014, the disease became curable, but the administration remained reluctant to address this public health issue. However, the Swiss parliament recently decided to integrate HCV into the next national HIV programme. This study investigates how HCV came onto the political agenda in Switzerland and which actors and factors were influential in this process. METHODS: The data collection is based on document analysis and semi-structured interviews. The transcripts were coded by deriving the codes from the data in terms of content followed by the application of the multiple streams framework. RESULTS: Health authorities, unlike experts, did not see the HCV epidemic as a relevant public health threat. Due to cost-related restriction of access to treatment, the potential of the new HCV drugs could not be fully exploited. The administration's position proved difficult to change, despite evidence to the contrary. For 30 years, authorities set the agenda in health policy regarding HCV, unheeded by politicians. But recently, a policy entrepreneur has for the first time successfully managed to put HCV on the political agenda. After years of education and lobbying, it used the window of opportunity in the form of the new edition of the national HIV programme. The parliamentary decision to include HCV in this programme broke the long-standing primacy of the administration in the field of HCV, which had long prevented a more active handling of the HCV field. CONCLUSIONS: The case of HCV in Switzerland shows that evidence alone is not enough to bring about health policy changes. A policy entrepreneur is needed who overcomes resistance, brings together the three streams-problem, policy and political-and exploits the window of opportunity at the right time. To be successful, the policy entrepreneur must identify the indicators that map the problem, network and convince decision-makers, recognize policy windows and use them-as has been the case with HCV in Switzerland.

Covid-19 as a chance for more food democracy in European cities? The responses of actors within Vienna's urban food system to the pandemic.

Actors within European cities had to respond to the Covid-19 crisis to maintain their urban food systems' basic functions. In this article, we ask whether these responses merely remedied the immediate challenges and maintained the status quo or the window of opportunity created by Covid-19 was used to transform urban food systems towards food democracy. We combine the food democracy framework and multi-level perspective to examine how actors of an urban food system - from niche and regime levels - reacted to the Covid-19 crisis and to explore the meaning of those responses for food democracy. Using Vienna as a case study, we conducted a media analysis (198 articles) and 11 interviews with niche actors to identify the impacts of the first Covid-19 wave and connected actors' responses. Results show that regime and niche actors responded differently to Covid-19 and that not all responses proved conducive to a transition to more food democracy. Although some responses can contribute to a more just and sustainable urban food system, many actors focused on short-term crisis management and maintaining the status quo. If Covid-19 is to become an opportunity for a transformation towards food democracy, coordinated actions by regime and niche actors are needed.

Accelerated innovation in crises: The role of collaboration in the development of alternative ventilators during the COVID-19 pandemic.

This article discusses the need for accelerated innovation in crisis situations and argues that collaboration plays an important role in enabling such acceleration. The central research question is: How can innovation efforts during crises be accelerated, and what role does collaboration play? We draw on a phenomenon-driven, in-depth qualitative case study of seven initiatives that have developed alternative ventilators in the Netherlands during the COVID-19 crisis. Our results highlight how the COVID-19 pandemic has created a relatively short crisis window of opportunity for accelerated innovation processes that is driven by the urgency to develop solutions to the challenge at hand. Importantly, we show that when collaborative initiatives join other collaborative initiatives- what we define as nested collaboration-a forum for coordinated knowledge and resource exchange between the initiatives is created, increasing the potential for learning and accelerating the innovation process. Finally, we find that purpose is an important intermediating mechanism to accelerate innovation as it enables non-competitive collaboration between the initiatives in favor of the public good. Our results have important implications for accelerated innovation processes to achieve societal missions, goals, or challenges.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

'Layered immunity' and the 'neonatal window of opportunity' - timed succession of non-redundant phases to establish mucosal host-microbial homeostasis after birth.

The intricate host-microbial interaction and the overwhelming complexity of the mucosal immune system in the adult host raise the question of how this system is initially established. Here, we propose the implementation of the concept of the 'postnatal window of opportunity' into the model of a 'layered immunity' to explain how the newborn's mucosal immune system matures and how host-microbial immune homeostasis is established after birth. We outline the concept of a timed succession of non-redundant phases during postnatal immune development and discuss the possible influence of external factors and conditions.

The midlife transition and the risk of cardiovascular disease and cancer Part I: magnitude and mechanisms.

Heart disease and cancer are the leading causes of death in the United States. In women, the clinical appearance of both entities-coronary heart disease and cancer (breast, endometrium, and ovary)-escalate during the decades of the midlife transition encompassing the menopause. In addition to the impact of aging, during the interval between the age of 40 and 65 years, the pathophysiologic components of metabolic syndrome also emerge and accelerate. These include visceral adiposity (measured as waist circumference), hypertension, diabetes, and dyslipidemia. Osteoporosis, osteoarthritis, sarcopenia, depression, and even cognitive decline and dementia appear, and most, if not all, are considered functionally related. Two clinical reports confirm the interaction linking the emergence of disease: endometrial cancer and metabolic syndrome. One describes the discovery of unsuspected endometrial cancer in a large series of elective hysterectomies performed in aged and metabolically susceptible populations. The other is from the Women's Health Initiative Observational Study, which found a positive interaction between endometrial cancer and metabolic syndrome regardless of the presence or absence of visceral adiposity. Both provide additional statistical support for the long-suspected causal interaction among the parallel but variable occurrence of these common entities-visceral obesity, heart disease, diabetes, cancer, and the prevalence of metabolic syndrome. Therefore, 2 critical clinical questions require analysis and answers: 1: Why do chronic diseases of adulthood-metabolic, cardiovascular, endocrine-and, in women, cancers of the breast and endometrium (tissues and tumors replete with estrogen receptors) emerge and their incidence trajectories accelerate during the postmenopausal period when little or no endogenous estradiol is available, and yet the therapeutic application of estrogen stimulates their appearance? 2: To what extent should identification of these etiologic driving forces require modification of the gynecologist's responsibilities in the care of our patients in the postreproductive decades of the female life cycle? Part l of this 2-part set of "expert reviews" defines the dimensions, gravity, and interactive synergy of each clinical challenge gynecologists face while caring for their midlife (primarily postmenopausal) patients. It describes the clinically identifiable, potentially treatable, pathogenic mechanisms driving these threats to quality of life and longevity. Part 2 (accepted, American Journal of Obstetrics & Gynecology) identifies 7 objectives of successful clinical care, offers "triage" prioritization targets, and provides feasible opportunities for insertion of primary preventive care initiatives. To implement these goals, a reprogrammed, repurposed office visit is described.

On the application of the window of opportunity and complex network to risk analysis of process plants operations during a pandemic.

To quantify the pandemic specific impact with respect to the risk related to the chemical industry, a novel risk analysis method is proposed. The method includes three parts. Firstly, the two types of "window of opportunity" (WO) theory is proposed to divide an accident life cycle into two parts. Then, a qualitative risk analysis is conducted based on WO theory to determine possible risk factors, evolution paths and consequences. The third part is a quantitative risk analysis based on a complex network model, integrating two types of WO. The Fuzzy set theory is introduced to calculate the failure probabilities of risk factors and the concept of risk entropy is used to represent the uncertainty. Then the Dijkstra algorithm is used to calculate the shortest path and the corresponding probability of the accident. The proposed method is applied to the SCR denitrition liquid ammonia storage and transportation system. The results show that it is a comprehensive method of quantitative risk analysis and it is applicable to risk analysis during the pandemic.

Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial.

BACKGROUND: The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. METHODS: Postmenopausal women with untreated stage I-III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. RESULTS: Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1-2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (- 73.2%) was superior to both monotherapy arms combined (- 49.9%; p = 0.001) and mVNB (- 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (- 73.2%) was numerically higher compared to LTZ (- 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases. CONCLUSIONS: Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. TRIAL REGISTRATION: NCT02802748 , registered 16 June 2016.