bluuebunny/crossref_metadata_2025_split huggingface dataset:
AGO-OVAR 2.29 (ENGOT-ov34): Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer (ROC).
Authors: Harter Philipp , Marmé Frederik , Pautier Patricia , Reuss Alexander , Lindemann Kristina , Kurzeder Christian , Van Nieuwenhuysen Els , Schmitt Clemens , Cron Nadin , Redondo Andres 
Published: June 2022

TPS5611 Background: Paclitaxel or pegylated liposomal doxorubicin in combination with bevacizumab constitutes a standard treatment option in patients with relapsed ovarian cancer who are not considered candidate for platinum, but responses are short-lived. Immune checkpoint inhibitors like atezolizumab as single agents have limited activity in ovarian cancer. There is a biologic rationale to combine checkpoint inhibitors with chemotherapy and bevacizumab, however, the role of such combination for the management of ovarian cancer is so far undefined. Because of the intimate relationship between angiogenesis and immunosuppression, it is expected that the inhibition of both pathways could lead to synergism and more durable clinical benefit. The addition of a chemotherapeutic agent is expected to lead to the release of tumor antigens and enhance the efficacy of immunotherapy in turn. Therefore, we aim to test the efficacy of atezolizumab in combination with non-platinum-based chemotherapy and bevacizumab vs the combination of a non-platinum-based chemotherapy and bevacizumab alone. Methods: AGO-OVAR 2.29 is a randomized (1:1), double blinded, phase III trial evaluating the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy (weekly paclitaxel or pegylated liposomal doxorubicin) compared with placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after completing platinum-based chemotherapy or 3rd relapse. A de novo tumor biopsy to determine the PD-L1 expression status prior to randomization for stratification is mandatory. Patients are treated with chemotherapy plus bevacizumab + atezolizumab/placebo until progression or unacceptable toxicity. Co-primary endpoints are overall survival and progression-free survival. It is planned to randomize approximately 664 patients. Safety interim analyses were performed after inclusion of 24 and an additional 60 and 120 patients who had completed at least one treatment cycle. As of 09th February 2022, 461 patients have been randomized. Clinical trial information: NCT03353831.
Anlotinib plus tislelizumab combined with chemotherapy as neoadjuvant treatment in triple-negative breast cancer: A prospective, single-arm, open-label phase II study.
Authors: Luo Jing 
Published: June 2022

TPS618 Background: Neoadjuvant anti-PD-(L)1 therapy confers an improvement in pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Combination of antiangiogenic agent plus immune checkpoint inhibitor and chemotherapy therapy for advanced TNBC is reported as a promising anti-tumor strategy presented in the FUTURE-C-PLUS study. Tislelizumab is a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody engineered to minimize binding to FcγR on macrophages. Anlotinib is a novel multi-target tyrosine kinase inhibitor that effectively inhibit VEGFR, FGFR, c-KIT, c-MET and RET. Previous studies have proven the efficacy of both anlotinib monotherapy and combination with immune checkpoint inhibitor in advanced breast cancer. This phase II study aims to evaluate the efficacy and safety of anlotinib plus tislelizumab combined with chemotherapy as neoadjuvant treatment in TNBC. Methods: This is a prospective, single-arm, open-label, phase II trial. Eligible patients (pts) were women, aged 18-75 years, ECOG status 0-1, previously untreated invasive TNBC with histologically confirmed (cT1N1-2M0 or cT2-4N0-2M0). 32 pts will be enrolled and received 5 cycles of anlotinib (8 mg qd, d1-14; 21 days per cycle) with 6 cycles of tislelizumab (200 mg, once every 3 weeks) plus nab-paclitaxel (260 mg/m2, once every 3 weeks) and anthracycline (epirubicin 75 mg/m2 or doxorubicin 60 mg/m2), followed by surgery. The primary endpoint is pathological complete response rate (pCR, ypT0/Tis ypN0) and the secondary endpoints include invasive disease-free survival (iDFS), event-free survival (EFS), overall survival (OS), and safety. A sample size of 32 patients was estimated to provide a 80% power to detect a difference of 25% in pCR at a significance level of α = 0.05. The study was initiated in August 2021. Clinical trial information: NCT04914390.
A phase II study of CPX-351 in younger patients < 60 years old with secondary acute myeloid leukemia: Trial in progress.
Authors: Swaminathan Mahesh , Fazal Salman , Griffiths Elizabeth A. , Thompson James E. , Sung Pamela Jeannette , Green Steven Daniel , Li Emily , Said Meriem , Belko Krista , Mattice Emmalyn , Attwood Kristopher , Wang Eunice S. , Przespolewski Amanda 
Published: June 2022

TPS7073 Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) and therapy-related AML (t-AML) have poor long-term outcomes following standard induction 7+3 chemotherapy. CPX-351, a liposomal formulation of cytarabine and daunorubicin fixed at the synergistic ratio of 5:1, is indicated for the treatment of pts with newly diagnosed s-AML and t-AML based on the results of a phase III trial favorably comparing CPX-351 to 7+3. Although the trial only enrolled pts aged 60-75 years (Y), CPX-351 is approved by the United States Food and Drug Administration for all adult pts with t-AML and AML with myelodysplasia-related changes (AML-MRC). In a prior retrospective analysis of CPX-351 in pts <60 Y with s-AML, we noted that the outcomes of these younger pts appeared inferior to those reported in older pts (60-75 Y) in the phase III trial (Przespolewski et al. Blood 2018 p.2677). Therefore, we designed this prospective study to evaluate the efficacy of CPX-351 in pts <60 Y with untreated s-AML and t-AML. Methods: In this phase II single-arm multi-institutional study, pts aged 18-59 Y with untreated t-AML or AML-MRC, adequate organ function, and ECOG performance status ≤ 2 are eligible. Pts with active central nervous system disease and infections were excluded. CPX-351 will be dosed at 100 mg/m2 cytarabine and 44 mg/m2 daunorubicin on days 1, 3, and 5 during induction. Bone marrow biopsy will be performed between days 14-21 to assess response. If needed, re-induction CPX-351 dose will be 44 mg/m2 daunorubicin/100 mg/m2 cytarabine on days 1 and 3. Pts achieving a complete remission (CR) following induction can receive up to 2 cycles of consolidation CPX-351 dosed as cytarabine 65 mg/m2 and daunorubicin 29 mg/m2 on days 1 and 3. The primary endpoint of the study is overall response rates defined as CR and CR with incomplete blood count recovery (CRi)) within 45 days of beginning therapy. Secondary endpoints are duration of response, event-free survival, overall survival, rate of allogeneic stem cell transplant, and adverse events. A maximum of 46 pts will be enrolled at 4 U.S. sites with 5-year follow-up from the start of CPX-351.The study is open and has enrolled 4 pts to date. Clinical trial information: NCT04269213.
Frontline treatment of follicular lymphoma with atezolizumab and obinutuzumab, with and without radiotherapy (The FLUORO study).
Authors: Hawkes Eliza Anne , Manos Kate , Khor Richard , Douglas Genevieve , Lee Sze Ting , Lee Denise , Campbell Belinda , Grobler Anneke , Gilbertson Michael , Palmer Jodie , Chong Geoff 
Published: June 2022

TPS7587 Background: Follicular lymphoma (FL) is the commonest indolent lymphoma, comprising 20% of non-Hodgkin Lymphoma, with approximately 80% of patients (pts) requiring therapy. At present, advanced stage is incurable; most pts require >1 treatment. Overall response rates (ORR) to standard chemoimmunotherapy (bendamustine or CHOP with rituximab or obinutuzumab) approximate 85% with considerable toxicity (grade 3-5 in 69-75%) (Hiddemann 2018). With the FL population predominantly >65 years, 10-year median survival and need for further therapy, efficacious treatments with low toxicity are desirable. PD1/PDL1 axis inhibitors are active in FL. A phase I study of obinutuzumab (O) + atezolizumab (A) induced 57% ORR in pts with rituximab-refractory FL (Palomba 2017). Our phase II ‘1st FLOR’ study, combining nivolumab + rituximab in treatment naïve FL yielded 92% ORR, (54% Complete Response, CR). Toxicity profiles compared favourably with conventional chemotherapy: 41% grade 3-5 events (Hawkes 2021). FL is sensitive to low dose radiotherapy (RT), with abscopal effects reported, and potential to improve treatment efficacy with minimal additional toxicity when combined with PD1/PDL1 inhibitors (Sharabi 2015). This investigator initiated, multicentre single-arm phase II PET-adapted trial aims to assess the response of O + A +/- RT for treatment-naïve FL, reducing treatment-related toxicity using a chemotherapy-free, multi-modality, synergistic regimen. Methods: Eligible pts are >18 years, ECOG 0-2 with untreated, biopsy proven, grade 1-3A stage II-IV FL. Exclusions are significant compressive symptoms, autoimmune disease, pneumonitis and treatment urgency. All pts receive 6 cycles (q21 days) of O 1000mg + A 1200mg (plus O given on days 8 & 15 of cycle 1). Interim PET-CT is performed post cycle 2. Pts with less than CR will undergo RT (4Gy) to residual disease after cycle 3. At end of induction, responding patients will receive maintenance O (up to 12 cycles, 1000mg Q8W). Pts with significant progression will be taken off study. Total follow-up is 2 years post treatment. Primary endpoint is CR rate following 6 x O&A +/- RT. Secondary endpoints include ORR, PFS, OS and adverse events. PET centres are ARTnet accredited with central analysis. An extensive exploratory biomarker substudy is planned. Sample size is 46 according to a Simon’s 2-stage design. If ≥5 positive responses (CR +/- PR) without prohibitive toxicity are seen in the first 15 pts, 31 further pts will be recruited.The trial has currently enrolled 7 pts from 4 Australian sites. Clinical trial information: NCT04962126.
Evaluation of seroprevalence and associated risk factors of Toxoplasmosis in sheep and goats in District Jhang-Pakistan
Authors: Zafar Muhammad Awais , Shafique Muhammad , Zahoor Muhammad Asif , Saqalein Muhammad , Aslam Bilal , Arshad Muhammad Imran , Waheed Usman , Kashif Muhammad 
Published: June 2022

Toxoplasmosis is a zoonotic infection caused by a pathogenic protozoan, Toxoplasma gondii, responsible for huge economic and health losses in developing countries. The current study was conducted to assess the seroprevalence of Toxoplasmosis and associated risk factors in sheep and goats in District Jhang, Punjab, Pakistan. Blood samples (n=400) were collected from both genders of goats (n=219) and sheep (n=181) from four Tehsils of District Jhang alongwith a comprehensive questionnaire to evaluate the risk factors associated with the disease endemicity and spread. For assessing the seroprevalence, the samples were examined using Latex agglutination test. Additional data regarding hygienic conditions, water source, gender, breed, age of animal was also collected on a predesigned questionnaire. The overall seroprevalence of Toxoplasma gondii was found 34.25% (137/400) in District Jhang. Higher seroprevalence was recorded in goats {36.52% (80/219)} as compared to sheep {31.49% (57/181)}, however, it was non-significant (p>0.05). Gender-wise seroprevalence was found 32.59% (44/135) and 35.09% (93/265) in male and female animals, respectively (p>0.05). Further, the association of Toxoplasmosis between different age groups was significantly higher in older animals having age >24 months 42.75% (62/145) than younger animals with age <12 months 26.60% (29/109) and 11-24 months 31.50% (46/146) (p<0.05). The seroprevalence was also higher 40.81% (80/196) in animals drinking water from outdoor water source than in animals drinking from indoor water source 27.94% (57/204) (p<0.05). Moreover, seroprevalence was significantly higher 43.11% (97/225) in animals kept in vicinity of cats than in absence of cats 22.85% (40/175) (p<0.05). However, reproductive status, breeds, flock size had non-significant impact on the prevalence of T. gondii. Thus, it is concluded that the presence of cats near animals, larger flock size, older age of animals, and poor hygienic conditions are main risk factors of Toxoplasmosis in sheep and goats and these could be a potential threat of infection for livestock industry and public health.
Three-dimensional structure determination of gold nanotriangles in solution using X-ray free-electron laser single-particle analysis
Authors: Nakano Miki , Miyashita Osamu , Joti Yasumasa , Suzuki Akihiro , Mitomo Hideyuki , Niida Yoshiya , Yang Ying , Yumoto Hirokatsu , Koyama Takahisa , Tono Kensuke , Ohashi Haruhiko , Yabashi Makina , Ishikawa Tetsuya , Bessho Yoshitaka , Ijiro Kuniharu , Nishino Yoshinori , Tama Florence 
Published: June 2022

X-ray free-electron lasers (XFELs) have allowed the imaging of nanoscale samples in near-physiological conditions. To achieve three-dimensional (3D) nanostructural reconstruction, many challenges need to be addressed, such as sample delivery for data collection and data processing of noisy diffraction patterns. Here, we provided a demonstration of the 3D structure reconstruction of a gold nanoparticle from XFEL diffraction data measured at the SPring-8 Angstrom Compact Free-Electron Laser using microliquid enclosure arrays (MLEAs) sample holders. MLEAs enable in-solution measurements, however, they induce a significant amount of background noise. Thus, we performed a series of data analyses to identify the diffraction patterns suitable for 3D reconstruction as well as nonhit patterns to estimate the background noise. The background subtraction from the data significantly improved the quality of the restored structure, with the resolution estimated to be 5 nm using Fourier shell correlation. Our paper has revealed the notable potential of XFEL imaging using MLEAs in combination with the developed data-analysis protocol.
Quantifying the impact of ecological memory on the dynamics of interacting communities
Authors: Khalighi Moein , Sommeria-Klein Guilhem , Gonze Didier , Faust Karoline , Lahti Leo 
Published: June 2022

Ecological memory refers to the influence of past events on the response of an ecosystem to exogenous or endogenous changes. Memory has been widely recognized as a key contributor to the dynamics of ecosystems and other complex systems, yet quantitative community models often ignore memory and its implications.
Recent modeling studies have shown how interactions between community members can lead to the emergence of resilience and multistability under environmental perturbations. We demonstrate how memory can be introduced in such models using the framework of fractional calculus. We study how the dynamics of a well-characterized interaction model is affected by gradual increases in ecological memory under varying initial conditions, perturbations, and stochasticity.
Our results highlight the implications of memory on several key aspects of community dynamics. In general, memory introduces inertia into the dynamics. This favors species coexistence under perturbation, enhances system resistance to state shifts, mitigates hysteresis, and can affect system resilience both ways depending on the time scale considered. Memory also promotes long transient dynamics, such as long-standing oscillations and delayed regime shifts, and contributes to the emergence and persistence of alternative stable states. Our study highlights the fundamental role of memory in communities, and provides quantitative tools to introduce it in ecological models and analyse its impact under varying conditions.
Strain design optimization using reinforcement learning
Authors: Sabzevari Maryam , Szedmak Sandor , Penttilä Merja , Jouhten Paula , Rousu Juho 
Published: June 2022

Engineered microbial cells present a sustainable alternative to fossil-based synthesis of chemicals and fuels. Cellular synthesis routes are readily assembled and introduced into microbial strains using state-of-the-art synthetic biology tools. However, the optimization of the strains required to reach industrially feasible production levels is far less efficient. It typically relies on trial-and-error leading into high uncertainty in total duration and cost. New techniques that can cope with the complexity and limited mechanistic knowledge of the cellular regulation are called for guiding the strain optimization.
In this paper, we put forward a multi-agent reinforcement learning (MARL) approach that learns from experiments to tune the metabolic enzyme levels so that the production is improved. Our method is model-free and does not assume prior knowledge of the microbe’s metabolic network or its regulation. The multi-agent approach is well-suited to make use of parallel experiments such as multi-well plates commonly used for screening microbial strains.
We demonstrate the method’s capabilities using the genome-scale kinetic model of Escherichia coli, k-ecoli457, as a surrogate for an in vivo cell behaviour in cultivation experiments. We investigate the method’s performance relevant for practical applicability in strain engineering i.e. the speed of convergence towards the optimum response, noise tolerance, and the statistical stability of the solutions found. We further evaluate the proposed MARL approach in improving L-tryptophan production by yeast Saccharomyces cerevisiae, using publicly available experimental data on the performance of a combinatorial strain library.
Overall, our results show that multi-agent reinforcement learning is a promising approach for guiding the strain optimization beyond mechanistic knowledge, with the goal of faster and more reliably obtaining industrially attractive production levels.
Proactive strategies to optimize engagement of Black, Hispanic/Latinx, transgender, and nonbinary individuals in a trial of a novel agent for HIV pre-exposure prophylaxis (PrEP)
Authors: Cespedes Michelle , Das Moupali , Hojilla J. Carlo , Blumenthal Jill , Mounzer Karam , Ramgopal Moti , Hodge Theo , Torres Thiago S. , Peterson Charles , Shibase Senzokuhle , Elliott Ayana , Demidont A. C. , Callaghan Larkin , Watson C. Chauncey , Carter Christoph , Kintu Alex , Baeten Jared M. , Ogbuagu Onyema 
Published: June 2022

IntroductionBlack and Hispanic/Latinx cisgender men who have sex with men (MSM), transgender women, transgender men, and gender nonbinary (TGNB) individuals have been historically underrepresented in HIV pre-exposure prophylaxis (PrEP) clinical trials. There is an urgent need for ongoing engagement with communities that have been the most impacted by HIV and diverse representation in clinical trials. Here we describe strategic approaches undertaken in the PURPOSE 2 trial to optimize engagement of underrepresented individuals.Methods and resultsPURPOSE 2 is an ongoing Phase 3 trial evaluating the safety and efficacy of lenacapavir as PrEP in cisgender MSM and TGNB individuals. In PURPOSE 2, we used a multipronged approach aimed at enriching participation of underrepresented individuals. We conducted a review to identify evidence-informed recommendations from literature, engaged with stakeholders, and established the Global Community Advisory and Accountability Group (GCAG) to represent the needs of the community. Insights from stakeholders and GCAG members resulted in an expansion of the study population to include transgender men, gender nonbinary persons, and adolescents, and evaluation of population-specific outcomes. Feedback from stakeholders and GCAG members also informed investigator and site selection; these were selected based on prior experience working with persons from diverse racial, ethnic and gender identities, and estimates of local HIV incidence. Site selection was also expanded to include community-based clinics with services tailored towards Black, Hispanic/Latinx, and TGNB populations. We established a study-wide recruitment goal of 50% Black MSM and 20% Hispanic/Latinx MSM in US sites and 20% transgender women globally. Site-specific recruitment goals were also developed based on local demographics and HIV incidence. Mandatory trainings included Good Participatory Practice guidelines, gender inclusivity, and antiracism.ConclusionWhile further work is needed to achieve equitable representation, the strategies we describe may serve as a framework for future clinical trials.Trial registrationClinical Trial Number:NCT04925752.
Identifying leaks in the STEM recruitment pipeline among sexual and gender minority US secondary students
Authors: Xavier Hall Casey D. , Wood Christine V. , Hurtado Manuel , Moskowitz David A. , Dyar Christina , Mustanski Brian 
Published: June 2022

PurposeResearch establishes the critical need to address the underrepresentation of women and racial/ethnic minorities in science, technology, engineering, and mathematics (STEM). While emergent research addresses similar challenges for sexual and gender minorities (SGM), this research remains scant and focuses on adult experiences. This analysis examines subgroup differences and the impact of bullying on STEM engagement outcomes among a national sample of SGM secondary students in the U.S.MethodThis report provides descriptive and multivariable regression analysis of national survey data (n = 539) on the experiences of pre-college students who identify as SGM, including the effects of within-school anti-SGM bullying on STEM identity, perceptions of STEM climate, and STEM intentions.ResultsRoughly 50% of the sample intended to enter a STEM field (compared to 25% in previous general samples). Bullying in school was negatively associated with STEM identity and perceptions of STEM climate. Sense of belonging is positively associated with perceptions of STEM climate and STEM intentions. Being non-binary and being a transgender man were associated with decreased sense of belonging and negative perception of STEM climate.ConclusionThis report is the first to identify factors influencing STEM engagement among SGM secondary students and suggests that issues of STEM engagement are already present in adolescence. Moreover, the findings also establish the relationship between anti-SGM bullying and STEM outcomes highlighting the importance of this marginalization experience. Future research should further examine sub-group differences and the persistence of these effects. These findings highlight the need for research and intervention addressing STEM outcomes in SGM populations.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03511131.