bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 1/2 study of REGN4336, a PSMAxCD3 bispecific antibody, alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer.
Authors: Kelly William Kevin , Thanigaimani Pradeep , Sun Furong , Seebach Frank A. , Lowy Israel , Sandigursky Sabina , Miller Elizabeth
Published: June 2022

TPS5105

Background: Prostate cancer is the leading cause of new cancer diagnoses and the second most common cause of cancer-related death in American men. Prognosis is especially poor for men with metastatic castration resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA) is highly expressed on malignant prostate tissue but shows limited expression on normal tissue. As such, PSMA is an excellent research target for treatment of mCRPC. REGN4336 is a PSMAxCD3 bispecific antibody designed to facilitate T-cell–mediated killing of PSMA-expressing tumor cells. In preclinical models, REGN4336 demonstrated strong PSMA-dependent antitumor activity that was dose-dependent. Preclinical data also support clinical research into the combination of REGN4336 with cemiplimab (anti–programmed cell death-1) for treating mCRPC. Methods: This is an open-label, Phase 1/2, first-in-human, multicenter dose-escalation study with dose expansion evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of REGN4336 administered subcutaneously alone and in combination with intravenous cemiplimab in patients with mCRPC (NCT05125016). Patients must have received at least two prior lines of systemic therapy approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. In this study, REGN4336 as monotherapy is administered weekly but may be extended to once every 3 weeks following identification of the minimal pharmacologically active dose. REGN4336 in combination with cemiplimab (350 mg) will be administered once every 3 weeks after a 4-week REGN4336 monotherapy lead-in cycle. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate the safety, tolerability, PK, and recommended phase 2 dosing regimen (RP2DR) of REGN4336 alone and in-combination with cemiplimab. Expansion cohort(s) will be enrolled once RP2DRs have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate with REGN4336 alone or in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, PSMA positron emission tomography/computed tomography scans will be performed at predefined timepoints on study. This study is currently open to enrollment. Clinical trial information: NCT03088540.
A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in patients with platinum-sensitive, recurrent ovarian cancer previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial.
Authors: Lee Jung-Yun , Park Junsik , Lee Jae Kwan , Jeong Dae Hoon , Kim Se Ik , Choi Min Chul , Kim Byoung-Gie , Lim Myong Cheol , Park Jeong-Yeol
Published: June 2022

TPS5610

Background: Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi. Methods: The KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate and 4 of planned 44 patients have been enrolled. Clinical trial information: NCT04734665.
FLEX, the 30,000 breast cancer transcriptome project: A platform for early breast cancer research using full-genome arrays paired with clinical data.
Authors: Ma Cynthia X. , Whitworth Pat W. , Vukelja Svetislava J. , Gray Carl R. , Diab Sami , Crozier Jennifer , Berrocal Julian , Habibi Mehran , Brufsky Adam , Maganini Robert , Srkalovic Gordan , Bupathi Manojkumar , Feinstein Trevor , O'Shaughnessy Joyce , Barone Julie , Rehmus Esther Hoogland , Lee Laura A. , Nguyen Holly , Blumencranz Lisa Eileen , Audeh M. William ,   FLEX Investigators Group
Published: June 2022

TPS612

Background: The ongoing, multi-center FLEX trial (NCT03053193) began in the United States in 2017, with the ultimate goal of 30,000 patients enrolled. The primary objective is to create a large-scale collaborative registry of early-stage breast cancer patients that links comprehensive clinical and full genome expression data to reveal new prognostic and/or predictive gene signatures. A key secondary objective of the trial is to enable investigator-initiated studies to explore early-stage breast cancer at a relatively low cost to the investigator. Methods: The prospective FLEX trial enrolls patients aged ≥ 18 years with histologically proven stage I-III breast cancer, with negative or 1-3 positive lymph nodes. Eligible patients have received MammaPrint, with or without BluePrint testing as standard of care, and consent to clinically annotated full transcriptome data collection. The FLEX base study protocol permits investigators to submit their own concept proposal, and upon review and approval by the Research and Scientific Review Committees, investigators interrogate clinical and genomic data from the FLEX database. The 10-year enrollment goal is a minimum of 30,000 patients. Since April 2017, 9,170 patients have been enrolled at over 109 sites in the United States. To date, 38 investigator-initiated substudies have been approved and are in progress, and 28 abstracts have been published in the US scientific congresses. To ensure inclusion of diverse populations, patients from local communities and 11 National Cancer Institute-designated Comprehensive Cancer Centers were included. Our diverse data set is helping meet the needs of historically under-represented patients with breast cancer. Of the self-reported ethnicities within the FLEX database, 65% are White or Caucasian, 8% Black or African American, 4% Latin American, and 2% Asian. There are 5 ongoing FLEX sub studies investigating racial disparities. The molecular profiling and differential gene expression analysis in early-stage breast cancer patients of African American, Asian, Hispanic ancestries helps to provide critical insights that correlate tumor biology with treatment outcomes. FLEX is expanding globally with sites anticipated in multiple European countries. The FLEX trial continues to expedite the discovery and development of novel genomic profiles, bringing precision oncology into the clinic to improve breast cancer management. Clinical trial information: NCT03053193.
A single-arm, phase 2 study of perioperative ipilimumab, nivolumab, and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.
Authors: McArthur Heather L. , Comen Elizabeth Anne , Bryce Yolanda , Solomon Stephen Barnett , Leal Jorge Henrique S. , Abaya Christina DiLauro , Martinez Cristal , Basho Reva K , Park Dorothy J. , McAndrew Philomena , Larkin Brigid , Mills William , Page David B. , Mellinger Staci L. , Fredrich Nicole , Moxon Nicole , Reddy Sangeetha M. , Carter Meredith , Patil Sujata , Norton Larry
Published: June 2022

TPS617

Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER < 10%, PR < 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 80 pts will be enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686.
A randomized study to measure and enhance the health-related quality of life in patients with cancer receiving immune checkpoint modulators (ME-Q).
Authors: Fonseca Magalhaes Filho Marcos Aurelio , VOON PEI JYE , Carlsson Lindsay , Silver Grace , Hansen Aaron Richard
Published: June 2022

TPS6603

Background: Existing data demonstrate the impact of Immune checkpoint modulators (ICMs) on Health-Related Quality of Life (HRQOL), but this was from studies that used HRQOL tools developed for patients treated with chemotherapy and/or radiation. To address this gap, we developed a toxicity subscale to cover important immune-related adverse events (irAEs) to combine this subscale with the generic FACT-G to measure HRQOL in patients treated with ICMs, the FACT-ICM. This trial proposes to validate the use of the FACT-ICM as a tool for HRQOL measurement and simultaneously to assess the benefit of remote symptom monitoring and management using a new electronic platform developed specifically for patients receiving ICMs. Methods: Participants will be randomized (1:1) before starting their standard of care ICM therapy to either usual care or the monitoring arm. The ME-Q platform uses a web-based application to enable remote monitoring of patient symptoms and HRQOL, allowing all participants enrolled in both the usual care or monitoring arms to complete the FACT-ICM and other questionnaires (DART, Health Resource Utilization, Decision regret scale, post-study system usability questionnaire) at set time points. Patients on the monitoring arm will have their electronic responses sent automatically, and new or significant worsening symptoms of clinical concern will generate an alert to the advanced practicing nurse (APN) responsible for replying to the patient and acting on responses. Via phone or a video teleconference, the nurse will perform a targeted assessment and provide standardized clinical advice and interventions based on well-established clinical algorithms and international guidelines for the management of irAEs. The APN will inform the patient's clinical team about the patient's responses and obtain the treating team's input and agreement on a proposed treatment plan. Patients enrolled in the usual care arm will respond to the questionnaires; however, their responses are not transmitted to their clinical team. The primary objective will be to validate the PRO tool for HRQOL measurement, and the secondary objective is to improve HRQOL in cancer patients receiving ICMs by remote monitoring and symptom management using the ME-Q electronic platform. We estimate that a total sample size of 266 patients (divided into two arms) achieves 90% power to detect an effect size of 0.4 in mean score changes (from baseline to 4 months) between arms using a two-sample t-test with a two-sided significance level of 0.05. Enrolment is to be completed in 2 years.
Assessment of adolescent and young adult oncology patient and provider perspectives in Philadelphia (AYA-4P).
Authors: Terry Christopher , Pomerantz Miriam , Sandos Jodi , Wilde Lindsay
Published: June 2022

TPS6604

Background: The overall cancer incidence continues to increase in adolescent and young adult patients (AYAs), defined by the National Cancer Institute as individuals diagnosed between the ages of 15-39. Both disease biology and psychosocial needs are unique for young adults living with cancer. AYAs are more likely to have challenges related to work, insurance, relationships, fertility and emotional distress. Studies demonstrate that specialized supportive care improves outcomes such as health-related quality of life, mental health, and physical functioning. Most AYA oncology programs are developed without patient input and affiliated with pediatrics. The Sidney Kimmel Cancer Center (SKCC) at Jefferson is an adult oncology group serving over 900 new patients annually between the ages of 18-39, but does not have a formal AYA program. With guidance from patient advocates and other validated tools, a unique survey-based needs assessment was created by SKCC to provide data for the development of a comprehensive, patient-centered model of care for AYAs. Methods: A one-time survey will be administered electronically to participants through Qualtrics. Solicitation from SKCC and the Young Adult Cancer Connection, a local patient advocacy group, will occur via social media and email aggregation. Eligible patients are those who received the majority of their cancer care within 30 miles of Philadelphia between the ages of 18-39. Eligible healthcare providers include current advanced practice providers or physicians who have practiced at SKCC for at least 1 year. There are no hypotheses being tested or primary outcome variables, therefore no sample size calculations were performed. A $10 Amazon card is offered as incentive for the patient-directed survey to improve response rates and reach at least 100 completed surveys. The provider survey includes no completion incentive. Each survey should take no longer than 20 minutes to complete and no follow-up is required. Surveys are multiple choice with a single open-ended, free response question at the end for additional comments. Categorical survey responses will be summarized using frequencies and percentages. Descriptive statistics and data visualization will be used to characterize the patient demographics and summarize awareness, experiences, and priorities of the participants. Primary objectives of the surveys are to assess AYAs’ current perspective of age-specific medical services and psychosocial support in Philadelphia, as well as to assess the knowledge and perspective of providers of the current care and available services for AYAs at SKCC. The secondary objective is to identify patient preferences and areas for improvement. By using the data generated from the surveys, SKCC will be more informed in their patient-centric approach to program development in an effort to improve the overall care for Philadelphia’s AYA oncology community.
Phase 1/2, open-label, dose-escalation, dose-expansion study of menin inhibitor DSP-5336 in adult patients with acute leukemia with and without mixed-lineage leukemia (MLL)-rearrangement (r) or nucleophosmin 1 (NPM1) mutation (m).
Authors: Daver Naval Guastad , Affinito John , Cai Hongliang , Dobrowolska Hanna , Eguchi Ken , Zhang Zijing , Stoudemire Jay , Watanabe Akinobu , Martinez Pablo , Komarnitsky Philip
Published: June 2022

TPS7066

Background: DSP-5336, a menin MLL interaction inhibitor, elicited antitumor activity in MLL–r or NPM1m acute leukemia models in vitro and in vivo. An open-label, single-arm, phase 1/2 study (NCT04988555) will evaluate the safety and efficacy of DSP-5336 and determine the recommended phase 2 dose (RP2D) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL). Methods: Patients aged ≥18 y with R/R AML, ALL, or acute leukemia of ambiguous lineage after ≥1 line of standard therapy, ECOG PS 0–2, and adequate organ function are eligible. Patients will receive DSP-5336 twice daily for 28 d/cycle. In phase 1, there will be two parallel escalation cohorts: patients who do not receive concomitant azole antifungal medication and patients who receive antifungal azoles (ie, posaconazole, voriconazole, or fluconazole); 21–30 patients will be enrolled during phase 1 into multiple ascending dose levels. Dose escalation will use a Bayesian logistic regression model. Phase 2 will enroll two arms: R/R AML with MLL –r and R/R AML with NPM1m (10 –20 patients/arm). Patients will be treated at the RP2D to evaluate clinical activity and safety. Clinical trial information: NCT04988555. [Table: see text]
A phase 1/2 study of REGN5093-M114, a METxMET antibody-drug conjugate, in patients with mesenchymal epithelial transition factor (MET)-overexpressing NSCLC.
Authors: Drilon Alexander E. , Awad Mark M. , Gadgeel Shirish M. , Villaruz Liza C , Sabari Joshua K. , Perez Javier , Daly Christopher , Patel Shraddha , Li Siyu , Seebach Frank A. , Lowy Israel , Magnan Heather D. , Rietschel Petra
Published: June 2022

TPS8593

Background: MET, also called hepatocyte growth factor receptor (HGFR), is a high-affinity transmembrane protein receptor for HGF. MET is overexpressed in various malignancies, including non-small cell lung cancer (NSCLC). MET overexpression can accompany MET exon 14 alteration or de novo/acquired MET amplification. REGN5093-M114 is an antibody drug conjugate composed of a novel linker-payload (M114, carrying the maytansine derivative M24, a potent inhibitor of microtubule assembly) covalently bound to lysine residues on a MET-targeting human IgG4p bispecific antibody, REGN5093. In preclinical models of MET overexpressing cancers, REGN5093-M114 demonstrated significant dose-dependent antitumor activity. Methods: This is an open label, phase 1/2, first-in-human, multicenter dose-escalation study with cohort expansion evaluating REGN5093-M114 in patients with MET-overexpressing NSCLC (NCT04982224). Patients must have advanced stage NSCLC for which there are no approved therapies available expected to confer clinical benefit, with tumor overexpressing MET (≥75% tumor cell staining at 2+) as centrally confirmed by immunohistochemistry. For the expansion phase, patients must have at least one lesion that is measurable by RECIST 1.1. REGN5093-M114 will be administered intravenously once every 3 weeks over 30 minutes until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal. The primary objectives in dose escalation are to evaluate safety, tolerability, PK, and maximum tolerated dose and/or recommended phase 2 dosing regimen of REGN5093-M114. PKs will include the assessment of REGN5093-M114, total antibody, and payload M24 concentrations. The primary objective in dose expansion is to assess preliminary anti-tumor activity of REGN5093-M114 in MET-overexpressing NSCLC as measured by the objective response rate. The secondary objectives of both phases of the study include an evaluation of treatment durability, and the immunogenicity of REGN5093-M114. This study is currently open to enrollment. Clinical trial information: NCT04982224.
Phase 2 study of tarlatamab, a DLL3-targeting, half life–extended, bispecific T-cell engager (HLE BiTE)immuno-oncology therapy, in relapsed/refractory small cell lung cancer (SCLC).
Authors: Ramalingam Suresh S. , Ahn Myung-Ju , Akamatsu Hiroaki , Blackhall Fiona Helen , Borghaei Hossein , Hummel Horst-Dieter , Johnson Melissa Lynne , Reck Martin , Zhang Yiran , Jandial Danielle , Cheng Sunfa , Paz-Ares Luis G.
Published: June 2022

TPS8603

Background: SCLC is characterized by rapid growth and early development of metastases. Platinum-based first-line chemotherapy is associated with a high initial response rate; however, disease recurrence is common. Delta-like ligand 3 (DLL3) is a Notch ligand that is upregulated and aberrantly expressed on the cell surface in most SCLC, making it a compelling therapeutic target. Tarlatamab is an HLE BiTE immuno-oncology therapy designed to bind DLL3 on target cancer cells and CD3 on T cells, forming a cytolytic synapse inducing T cell activation and expansion and T cell-dependent killing of tumor cells. Interim results of an ongoing first-in-human study in patients with relapsed/refractory SCLC (NCT03319940) show preliminary evidence for tarlatamab efficacy in pretreated patients with confirmed partial responses in 20% of patients and duration of response of 8.7 months (Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4–8, 2021; Virtual). Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 27% of patients and TRAEs resulted in discontinuation in 5% of patients. This promising efficacy/safety profile supports further study of tarlatamab in SCLC. Methods: NCT05060016 is a phase 2, open-label study evaluating tarlatamab in patients with relapsed/refractory SCLC after two or more lines of prior treatment. Part 1 is a dose characterization phase in which subjects will be randomized 1:1 to two active doses of tarlatamab. Part 2 will continue enrollment for the selected target dose only based on interim analysis of Part 1. Key eligibility criteria include adults with histologically or cytologically confirmed SCLC whose disease progressed/recurred after two or more lines of prior treatment including at least 1 platinum-based regimen (including a PD-L1 inhibitor, if standard of care, with certain exceptions per protocol), treated brain metastases, ECOG performance status ≤1, and life expectancy ≥ 12 weeks in the opinion of the investigator. The primary endpoint for the primary analysis is ORR per RECIST 1.1 as assessed by blinded independent central review. Secondary objectives are to evaluate antitumor activity by additional measures (duration of response, progression-free survival, disease control rate and duration, overall survival), safety and tolerability, immunogenicity, and pharmacokinetics. Sites in North America, Asia and Europe are participating in the trial with subjects already enrolled and enrollment ongoing. Clinical trial information: NCT05060016.
A biomarker-guided Bayesian response-adaptive phase II trial for metastatic melanoma: The Personalized Immunotherapy Platform (PIP) trial design.
Authors: Lo Serigne N. , Gide Tuba Nur , Gonzalez Maria , Silva Ines , Menzies Alexander M. , Carlino Matteo S. , Scolyer Richard A. , Heritier Stephane , Wilmott James S. , Long Georgina V.
Published: June 2022

TPS9599

Background: Anti-PD1-based immunotherapies have been approved for many cancer types and are now a standard therapy for advanced melanoma. Despite this, ̃50% of advanced melanoma patients (pts) fail to respond or eventually progress after response. It is therefore critical to identify pts with a low likelihood of response to anti-PD1-based therapy and efficiently assess activity of rationally-selected alternative novel immunotherapies. Methods: We designed this investigator-initiated phase II PIP-Trial to evaluate two consecutive biomarker testing platforms, followed by the activity of rationally selected 5 novel agents in pts with advanced melanoma. Two separate pt populations are included: Part-A) treatment-naïve pts predicted to be resistant to either anti-PD-1 alone or combined with ipilimumab using Biomarker Test-1); and Part-B) pts who had progressed on 1 prior line of PD1-based therapy. Part-A) is a Bayesian adaptive multi-arm multi-stage design using response adaptive randomisation after a burn-in period where pts are randomised to the existing arms with equal probability. From then on, regular interim analyses will be carried out with the objective to either drop poorly performing arms or continue. Part-B) is an open platform without control that combined a selection and an expansion phase to identify best novel agent(s) as second-line therapy. Expansion phase decisions will be based on enrichment for biomarker Test-2. Dropping an arm occurs when the posterior probability of observing a clinically significant effect on the primary outcome (i.e. 6-month RECIST objective response rate (ORR)) is low. The operational characteristics of the design were investigated through simulations considering 4 plausible scenarios with 40% ORR in the control arm (anti-PD1 + Anti-CTLA4). Simulations were based on the upcoming R package BATS. Part-A has at least 85% power to detect a 30% absolute improvement in ORR with respect to the control arm (with a max N = 216 – Table below). Part-B will be able to select two promising treatments in the expansion phase and formally test their efficacy against a minimum ORR of 25% at 80% power (max N = 150). [Table: see text]
Reliability of Drug History to Verify Androgen Abuse in Men
Authors: Shankara-Narayana Nandini , Brooker Lance , Goebel Catrin , Speers Naomi , Handelsman David J
Published: June 2022

Context

Clinical evaluations that require excluding androgen abuse, a secretive, illicit activity, rely on the drug history, but its veracity for androgen abuse has neither been verified nor has any objective corroborating laboratory test been validated.

Objective

In a high-risk population, to (a) validate the drug history of androgen abuse objectively using state-of-the-art World Anti-Doping Agency–accredited antidoping laboratory urine mass spectrometry tests and (b) to determine what biochemical tests best distinguish androgen abuse from nonuse in this population.

Methods

Urine samples from current (n = 41) and past (n = 31) androgen abusers and nonusers (n = 21) were analyzed by comprehensive mass spectrometry-based detection tests for androgens and related drugs (ARD).

Results

No prohibited ARDs were identified among nonusers. Current users had a median of 5 (range 1-13) drugs detected comprising 176 ARDs among 220 drug identifications. Past users had a median of 1 (range 0-9) drugs detected comprising 21 ARDs among 43 drugs. Negative predictive value was high (>0.8) for those denying drug usage while positive predictive value was good (>0.6) for both those reporting currently using (current) and not using (nonusers plus past users) ARD. Serum luteinizing hormone (LH) alone had high, but imperfect, discriminatory power (89%) to distinguish between current and noncurrent androgen use.

Conclusions

We demonstrates that a negative drug history in a high-risk group has high reliability and that even a single suppressed serum LH exhibits high discrimination for objectively detecting androgen abuse.
Transgender Girls Grow Tall: Adult Height Is Unaffected by GnRH Analogue and Estradiol Treatment
Authors: Boogers Lidewij Sophia , Wiepjes Chantal Maria , Klink Daniel Tatting , Hellinga Ilse , van Trotsenburg Adrianus Sarinus Paulus , den Heijer Martin , Hannema Sabine Elisabeth
Published: June 2022

Context

Transgender adolescents can receive gonadotropin-releasing hormone analogues (GnRH) and gender-affirming hormone therapy (GAHT), but little is known about effects on growth and adult height. This is of interest since height differs between sexes and some transgender girls wish to limit their growth.

Objective

This work aims to investigate the effects of GnRHa and GAHT on growth, and the efficacy of growth-reductive treatment.

Methods

This retrospective cohort study took place at a specialized tertiary gender clinic. A total of 161 transgender girls were treated with GnRHa and estradiol at a regular dose (2 mg) or high growth-reductive doses of estradiol (6 mg) or ethinyl estradiol (EE, 100-200 µg). Main outcome measures included growth, adult height, and the difference from predicted adult height (PAH) and target height.

Results

Growth velocity and bone maturation decreased during GnRHa, but increased during GAHT. Adult height after regular-dose treatment was 180.4 ± 5.6 cm, which was 1.5 cm below PAH at the start GnRHa (95% CI, 0.2 cm to 2.7 cm), and close to target height (–1.1 cm; 95% CI, –2.5 cm to 0.3 cm). Compared to regular-dose treatment, high-dose estradiol and EE reduced adult height by 0.9 cm (95% CI, –0.9 cm to 2.8 cm) and 3.0 cm (95% CI, 0.2 cm to 5.8 cm), respectively.

Conclusion

Growth decelerated during GnRHa and accelerated during GAHT. After regular-dose treatment, adult height was slightly lower than predicted at start of GnRHa, likely due to systematic overestimation of PAH as described in boys from the general population, but not significantly different from target height. High-dose EE resulted in greater reduction of adult height than high-dose estradiol, but this needs to be weighed against possible adverse effects.
The cellular function of ROP GTPase prenylation is important for multicellularity in the moss Physcomitrium patens
Authors: Bao Liang , Ren Junling , Nguyen Mary , Slusarczyk Arkadiusz Slawomir , Thole Julie M. , Martinez Susana Perez , Huang Jinling , Fujita Tomomichi , Running Mark P.
Published: June 2022

A complete picture of how signaling pathways lead to multicellularity is largely unknown. Previously, we generated mutations in a protein prenylation enzyme, GGB, and showed that it is essential for maintaining multicellularity in the moss Physcomitrium patens. Here, we show that ROP GTPases act as downstream factors that are prenylated by GGB and themselves play an important role in the multicellularity of P. patens. We also show that the loss of multicellularity caused by the suppression of GGB or ROP GTPases is due to uncoordinated cell expansion, defects in cell wall integrity and the disturbance of the directional control of cell plate orientation. Expressing prenylatable ROP in the ggb mutant not only rescues multicellularity in protonemata but also results in development of gametophores. Although the prenylation of ROP is important for multicellularity, a higher threshold of active ROP is required for gametophore development. Thus, our results suggest that ROP activation via prenylation by GGB is a key process at both cell and tissue levels, facilitating the developmental transition from one dimension to two dimensions and to three dimensions in P. patens.
Orb-dependent polyadenylation contributes to PLP expression and centrosome scaffold assembly
Authors: Fang Junnan , Lerit Dorothy A.
Published: June 2022

As the microtubule-organizing centers of most cells, centrosomes engineer the bipolar mitotic spindle required for error-free mitosis. Drosophila Pericentrin-like protein (PLP) directs formation of a pericentriolar material (PCM) scaffold required for PCM organization and microtubule-organizing center function. Here, we investigate the post-transcriptional regulation of Plp mRNA. We identify conserved binding sites for cytoplasmic polyadenylation element binding (CPEB) proteins within the Plp 3′-untranslated region and examine the role of the CPEB ortholog Oo18 RNA-binding protein (Orb) in Plp mRNA regulation. Our data show that Orb interacts biochemically with Plp mRNA to promote polyadenylation and PLP protein expression. Loss of orb, but not orb2, diminishes PLP levels in embryonic extracts. Consequently, PLP localization to centrosomes and its function in PCM scaffolding are compromised in orb mutant embryos, resulting in genomic instability and embryonic lethality. Moreover, we find that PLP overexpression restores centrosome scaffolding and rescues the cell division defects caused by orb depletion. Our data suggest that Orb modulates PLP expression at the level of Plp mRNA polyadenylation and demonstrates that the post-transcriptional regulation of core, conserved centrosomal mRNAs is crucial for centrosome function.
Anna's hummingbird (Calypte anna) physiological response to novel thermal and hypoxic conditions at high elevations
Authors: Spence Austin R. , LeWinter Hannah , Tingley Morgan W.
Published: June 2022

Many species have not tracked their thermal niches upslope as predicted by climate change, potentially because higher elevations are associated with abiotic challenges beyond temperature. To better predict whether organisms can continue to move upslope with rising temperatures, we need to understand their physiological performance when subjected to novel high-elevation conditions. Here, we captured Anna's hummingbirds – a species expanding their elevational distribution in concordance with rising temperatures – from across their current elevational distribution and tested their physiological response to novel abiotic conditions. First, at a central aviary within their current elevational range, we measured hovering metabolic rate to assess their response to oxygen conditions and torpor use to assess their response to thermal conditions. Second, we transported the hummingbirds to a location 1200 m above their current elevational range limit to test for an acute response to novel oxygen and thermal conditions. Hummingbirds exhibited lower hovering metabolic rates above their current elevational range limit, suggesting lower oxygen availability may reduce performance after an acute exposure. Alternatively, hummingbirds showed a facultative response to thermal conditions by using torpor more frequently and for longer. Finally, post-experimental dissection found that hummingbirds originating from higher elevations within their range had larger hearts, a potential plastic response to hypoxic environments. Overall, our results suggest lower oxygen availability and low air pressure may be difficult challenges to overcome for hummingbirds shifting upslope as a consequence of rising temperatures, especially if there is little to no long-term acclimatization. Future studies should investigate how chronic exposure and acclimatization to novel conditions, as opposed to acute experiments, may result in alternative outcomes that help organisms better respond to abiotic challenges associated with climate-induced range shifts.
Bivalves maintain repair when faced with chronically repeated mechanical stress
Authors: Crane R. L. , Denny M. W.
Published: June 2022

Even though mollusks' capacity to repair shell damage is usually studied in response to a single event, their shells have to defend them against predatory and environmental threats throughout their potentially multi-decadal life. We measured whether and how mollusks respond to chronic mechanical stress. Once a week for 7 months, we compressed whole live California mussels (Mytilus californianus) for 15 cycles at ∼55% of their predicted one-time breaking force, a treatment known to cause fatigue damage in shells. We found mussels repaired their shells. Shells of experimentally stressed mussels were just as strong at the end of the experiment as those of control mussels that had not been experimentally loaded, and they were more heavily patched internally. Additionally, stressed shells differed in morphology; they were heavier and thicker at the end of the experiment than control shells but they had increased less in width, resulting in a flatter, less domed shape. Finally, the chronic mechanical stress and repair came at a cost, with stressed mussels having higher mortality and less soft tissue than the control group. Although associated with significant cost, mussels' ability to maintain repair in response to ongoing mechanical stress may be vital to their survival in harsh and predator-filled environments.
Mild hypoxia exposure impacts peripheral serotonin uptake and degradation in Gulf toadfish (Opsanus beta)
Authors: Sebastiani John , Sabatelli Allyson , McDonald M. Danielle
Published: June 2022

Plasma serotonin (5-hydroxytryptamine, 5-HT) homeostasis is maintained through the combined processes of uptake (via the 5-HT transporter SERT, and others), degradation (via monoamine oxidase, MAO) and excretion. Previous studies have shown that inhibiting SERT, which would inhibit 5-HT uptake and degradation, attenuates parts of the cardiovascular hypoxia reflex in gulf toadfish (Opsanus beta), suggesting that these 5-HT clearance processes may be important during hypoxia exposure. Therefore, the goal of this experiment was to determine the effects of mild hypoxia on 5-HT uptake and degradation in the peripheral tissues of toadfish. We hypothesized that 5-HT uptake and degradation would be upregulated during hypoxia, resulting in lower plasma 5-HT, with uptake occurring in the gill, heart, liver and kidney. Fish were exposed to normoxia (97.6% O2 saturation, 155.6 Torr) or 2 min, 40 min or 24 h mild hypoxia (50% O2 saturation, ∼80 Torr), then injected with radiolabeled [3H]5-HT before blood, urine, bile and tissues were sampled. Plasma 5-HT levels were reduced by 40% after 40 min of hypoxia exposure and persisted through 24 h. 5-HT uptake by the gill was upregulated following 2 min of hypoxia exposure, and degradation in the gill was upregulated at 40 min and 24 h. Interestingly, there was no change in 5-HT uptake by the heart and degradation in the heart decreased by 58% within 2 min of hypoxia exposure and by 85% at 24 h. These results suggest that 5-HT clearance is upregulated during hypoxia and is likely driven, in part, by mechanisms within the gill and not the heart.
The Serum Total and Lipid-Bound Sialic Acid with Hematological-Biochemical Parameter Levels in Dogs with Dirofilariosis
Authors: Kesici Hasan , Değer Yeter , Oguz Bekir , Özdek Uğur
Published: June 2022

The present study was planned to investigate the potential changes in the levels of serum total sialic acid (TSA), lipid-bound sialic acid (LSA) and hematological-biochemical parameters in the dogs naturally infected by Dirofilaria immitis. The patient group included the 7 dogs clinically and parasitologically (Modified Knott and PCR) diagnosed with Dirofilaria immitis while 7 healthy dogs were assigned as the control group. The biochemical parameters, blood gas parameters and hematological parameters were tested in the blood samples taken properly according to the guidelines from all the study animals using modular auto-analyser, blood gas analyser and automated blood count devices, respectively. Serum TSA and LSA levels were measured spectrophotometrically using Sydow and Katapodis methods, respectively. Compared with the healthy group, the dogs diagnosed with dirofilariosis were found to have significantly increased levels of serum troponin, triglycerides, VLDL, LDL, BUN, urea and creatinine and enzymatic activities of CK-MB, ALT, AST, ALP and LDH, and statistically significantly decreased levels of cholesterol and HDL (p<0.05). The increases in levels of total protein and total bilirubin, and enzymatic activity of CK were found statistically insignificant (p>0.05). A significantly decreased level of RBC and a significantly increased level of WBC was determined in the dogs with dirofilariosis (p<0.05). The decreases in the levels of Hct and Hb were found statistically insignificant (p>0.05). The differential blood count test of the dogs with dirofilariosis indicated statistically significantly increased eosinophil count (p<0.05). The increases in the neutrophil and basophil counts, and the decreases in the lymphocyte and monocyte counts were detected to be statistically insignificant (p>0.05). In the dogs with dirofilariosis, the decreases in the levels of pCO2, HCO3 and BE as the venous blood gas parameters were detected to be statistically significant (p<0.05). The decreases in the levels of pH and pO2 were determined to be insignificant (p>0.05). The levels of serum TSA and LSA of the dogs with dirofilariosis were found statistically significantly higher than the healthy group (p<0.05). As a conclusion, statistically significant differences were identified between the dogs with dirofilariosis and healthy dogs in terms of sialic acid levels and certain biochemical, venous blood gas and hematological parameters. On the other hand, the present study is the first to investigate the serum sialic acid levels in the dogs with dirofilariosis.
Postoperative pain assessment with concurrent administration of intraperitoneal tramadol and incisional lidocaine following ovariohysterectomy in dogs
Authors: Peysokhan Mohsen , Sabiza Soroush , Ronagh Ali , Razi Jalali Mohammad
Published: June 2022

This study aimed to assess postoperative pain with concurrent administration of intraperitoneal tramadol and incisional lidocaine following ovariohysterectomy in dogs. A group of twenty mixed breed female dogs, aged 1–2 years, weighing 19.5 ± 0.8 kg were used. Initially, dogs were sedated with intramuscular administration of acepromazine 1%. Anaesthesia was induced with diazepam (0.5 mg/kg) and ketamine (10 mg/kg) and maintained with 1.5% Isoflurane. Ketoprofen (2 mg/kg) was administered intravenously immediately before surgery. Five minutes before midline incision, saline (0.2 ml/kg) was administered to the muscles and subcutaneous space around the incision in the tramadol-saline (TS) group. Also, in the tramadol-lidocaine (TL) group, lidocaine 2% with epinephrine (1.5 mg/Kg) was administered. Ovariohysterectomy was performed and before closing the linea alba, tramadol (4 mg/kg) was splashed on the abdominal viscera in both groups. Cortisol, vital signs and pain scoring systems were evaluated at different time points. Heart rate, respiratory rate and rectal temperature changes were not significant between groups. Cortisol level showed a significant difference between groups at 1, 3 and 6 hours after surgery (p≤0.05). Both UMPS and CMPS-SF pain scores in the TL group were significantly lower than the TS group at 30 minutes, 1, 3 and 6 hours after surgery (p≤0.05) and also at 12 hours after surgery (p≤0.05). It seems that intraperitoneal administration of tramadol (4 mg/kg) along with administration of incisional lidocaine with epinephrine (1.5 mg/kg) is recommended following ovariohysterectomy in dogs.
Effect of the locational relationship between the 1st wave dominant follicle and the corpus luteum on conception rate after embryo transfer: data analysis of 297 embryo transfers from a commercial embryo production program
Authors: Goto Akira , Hayama Koh , Urakawa Manami , Oono Yoshio , Hazano Ken , Kayano Mitsunori , Haneda Shingo , Nakada Ken , Matsui Motozumi
Published: June 2022

The ovarian structures identified at the time of ET are important for the selection of recipients. In previous report, the first-wave dominant follicle, located ipsilateral to the corpus luteum on the ovary, was associated with reduced conception rate after artificial insemination. Thus, a similar locational relationship may affect conception rate during embryo transfer. Data from 297 transfers of fresh embryos to virgin heifers were analyzed aiming to check the effect of first-wave dominant follicle location in relation to the corpus luteum on conception rate using a multivariable logistic regression model with six confounders. The location of the first-wave dominant follicle in relation to the corpus luteum location had no significant effect on conception rate, suggesting that it is not necessary to consider the firstwave dominant follicle size and location in the ovaries for recipient selection.
The biological potential of a product containing Pythium oligandrum against Uncinaria stenocephala (Railliet, 1884) larvae
Authors: Luca Iasmina , Imre Mirela , Ilie Marius Stelian , Oprescu Ion , Dărăbuş Gheorghe
Published: June 2022

Pythium oligandrum is an oomycete commonly used in the biological control of plant and vegetable pests. In veterinary medicine is used to treat dermatophytosis produced by Microsporum canis. It acts as an antagonist, negatively influencing the development of other fungi. Through hydrolytic enzymes, such as kinase and cellulase, it destroys the cell wall and the internal cytoplasmic content. Many fungi are considered nematophagous. This potential has not been exploited for Pythium oligandrum, which is why in this study the potential larvicidal action against Uncinaria stenocephala larvae was investigated.Ecosin® product, which contains P. oligandrum and other excipients, was used. A solution was prepared according to manufacturer. The Uncinaria stenocephala larvae were exposed to this substance and the action was investigated after 7 days. The results obtained showed 37.23% larval reduction.Being an eco-friendly product, further studies are needed to improve the protocol for its use in cleaning spaces and surfaces in veterinary clinics, where various parasitic forms (larvae or eggs) are found.
Identification of the Nosema spp., a microsporidian parasite isolated from the honey bees (Apis mellifera) and its association with honey bee colony losses in apiaries of Iran
Authors: Moeini Sahar , Malekifard Farnaz , Tavassoli Mousa
Published: June 2022

The aim of this study was to determine the Nosema species by microscopic and molecular method and its association with honeybee colony losses (Colony Collapse Disorder) in apiaries of Urmia, Northwest of Iran. For this purpose, honeybee samples were collected from 840 colonies kept in 120 apiaries in five different location of Urmia. The specimens were examined for the presence of Nosema spores. After DNA isolation, the 16S rRNA gene was evaluated using multiplex PCR. Total infection prevalence with the microscopic evaluation was 32% while in PCR test was 58.2%. Nosema positive samples were evaluated by PCR sequencing. Based on the results of PCR, all identified cases were N. ceranae. The obtained sequences were transferred to GenBank/NCBI (samples accession numbers MT001887 and MT001893). The results showed the prevalence of Colony Collapse Disorder like symptoms in the studied honeybee colonies were 13.33%. N. ceranae was detected by PCR in 20.28 % of honeybee colonies with Colony Collapse Disorder like signs. Our findings showed that there was a significant relation between Colony Collapse Disorder and presence of N. ceranae. The results of this study concluded that N. ceranae is the only specie that affects the honeybees which may have an important role in the occurrence of collapse of bee families and depopulation of hives in this area.
A mini-review of toxicokinetics and toxicity of heavy metals in marine and freshwater fish
Authors: Mehouel Fetta , Fowler Scott W.
Published: June 2022

The aquatic environment continues to be polluted by anthropogenic activities that cause heavy metals contamination of fish. These trace metals contaminants are present in abundance in the aquatic environment because their inputs also originate from several natural processes. In addition, they are bioaccumulative, persistent and non-biodegradable over time. Therefore the present mini-review accounts for to assesses the bio-kinetics and known effects of the heavy metals and their toxicity in fish. Among the most toxic metals are arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg), and they have been the primary focus of many aquatic ecotoxicological studies in recent years. According to the previous studies analyzed; heavy metals bioaccumulate in the body of fish, whose kinetic activity depends on the metal and also varies from one fish species to another, and can cause irregular and sometimes devastating effects in different organs and systems of the body, acute or chronic, depending on the duration of exposure and the dose of metal assimilated through water or food. Metal uptake can affect all life stages of fish, and these effects are a function of the concentration of the metal in the surrounding environment, its chemical form and also the type of the water in which it lives; fresh or marine.