bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1b study to assess the safety of neoadjuvant trifluridine/tipiracil with concurrent radiation in resectable stage II/III rectal cancer.
Authors: Chen Emerson Yu-sheng , Nabavizadeh Nima , Herzig Daniel , Korngold Elena , Kardosh Adel , Pegna Guillaume Joe , Bensch Kenneth Gregory , Anderson Eric C. , Tsikitis Vassiliki Liana , Lu Kim , Mayo Skye C. , Brinkerhoff Brian , Goodyear Shaun , Wong Melissa , Fahlman Anne , Taber Erin , Vo Johnson , Thomas Charles R. , Lopez Charles D. ,   OHSU Gastrointestinal Cancer Disease Group
Published: January 2023

TPS274 Background: Treatment of locally advanced rectal cancer currently involves tri-modal therapy with pre-operative chemo-radiation (CRT), surgery, and combination chemotherapy. Total neoadjuvant therapy (TNT) is emerging as an important treatment pathway that can increase rates of complete response (CR) leading to better overall outcomes. Novel radio-sensitizing agents may improve rates of CR. Trifluridine/tipiracil (TFD/TPI) is a novel fluoropyrimidine that has demonstrated clinical efficacy in patients with treatment-refractory metastatic colorectal cancer. Importantly, TFD/TPI has superior radio-sensitization in vitro compared to 5-fluorouracil, and we hypothesize that this can improve the tumor response of patients. This phase 1 study assesses the safety and preliminary efficacy of using TFD/TPI for long-course CRT for rectal cancer followed by FOLFOX chemotherapy in the TNT setting. Methods: NCT04104139 is a prospective, dose-finding phase I study using Bayesian Optimal Interval (BOIN) design to determine the maximum tolerated dose (MTD) of TFD/TPI with concurrent standard dose/fractionation radiation for resectable rectal cancer. Adults with previously untreated rectal adenocarcinoma, with clinical stage II (T3-4aN0) and stage III (T1-4aN1+) by MRI and endoscopy are eligible. Patients must first receive CRT with standard radiation (45-50 Gy over 25-28 fractions) followed by up to 8 cycles of standard FOLFOX, or alternatively 5 cycles of CAPOX chemotherapy. During CRT, the first dose level of TFD/TPI is PO 25mg/m2 twice a day from Mon to Fri (5 weekdays) alternating on weeks 1, 3, and 5 concurrent with 5-6 weeks of radiation. The second dose level is 30mg/m2, and third dose level is 35mg/m2. The MTD of TFD/TPI in combination with radiation is the dose corresponding to a dose limiting toxicity (DLT) probability of 30% using the BOIN design with escalation/de-escalation of each dose level occurring in cohorts of 3 participants until a maximum total of 18 participants, sub-total of 12 patients within one dose level, or another stopping rule based on serious toxicities. The primary endpoint is proportion of DLTs for TFD/TPI at MTD. Secondary endpoints include overall tolerability profile, delayed toxicities during FOLFOX, rates of clinical CR, rates of pathologic CR, and correlative biomarkers. The study was activated December 2019 and has accrued 8 of intended 18 patients. Clinical trial information: NCT04104139 .
Trial in progress: A phase 2, multicenter, open-label study of DKN-01 in combination with tislelizumab and chemotherapy as 1L therapy in patients with unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ; DisTinGuish).
Authors: Lee Keun-Wook , Moehler Markus H. , Cunningham David , Wainberg Zev A. , Uronis Hope Elizabeth , Oh Do-Youn , Kim In-Ho , Shim Byoung Yong , Sym Sun Jin , Altura Rachel A , Stilian Melissa C , Parker Elizabeth C , Klempner Samuel J 
Published: January 2023

TPS484 Background: Advanced G/GEJ cancer is a major cause of cancer-related mortality requiring novel therapies. DKN-01 is a humanized mAb that binds and neutralizes DKK1. DKK1 plays a major role in WNT-pathway regulation and is overexpressed in multiple cancers. DKK1 expression is associated with poor prognosis, an immunosuppressive tumor microenvironment, and resistance to chemotherapy in G/GEJ cancer. The non-randomized Part A of DisTinGuish demonstrated durable clinical benefit in patients with G/GEJ adenocarcinoma. Higher response rates were observed in patients with high tumoral DKK1 expression, when DKN-01 was administered in combination with an anti-PD1 mAb, tislelizumab, and chemotherapy1,2. Furthermore, in Part B, durable responses were seen in 2L patients with DKK1-high G/GEJ cancers treated with a chemotherapy-free doublet regimen, DKN-01 plus tislelizumab1. Part C will evaluate the efficacy of this chemoimmunotherapy combination in a randomized fashion in treatment-naïve G/GEJ adenocarcinoma patients. Methods: Part C is an ongoing, global, randomized phase 2 open-label study evaluating DKN-01 in combination with tislelizumab + chemotherapy (CAPOX or mFOLFOX6) vs tislelizumab + chemotherapy in patients with advanced G/GEJ adenocarcinoma. Patients are randomized 1:1 and stratified by DKK1 and PD-L1 expression. Approximately 160 patients will be enrolled from 5 different countries. Key inclusion criteria include patients with HER2 negative, G/GEJ adenocarcinoma who have received no prior systemic treatment in the unresectable locally advanced/metastatic setting and can provide tumor tissue to document PD-L1 CPS and DKK1 expression, as performed at a central lab. Key exclusion criteria include prior treatment with anti-PD1/L1/L2. The primary endpoint is PFS according to RECIST v1.1 as assessed by the investigator in patients with DKK1-high tumors. Key secondary and exploratory end points include PFS, OS, ORR, DoR in patients with tumors with any level of DKK1 expression, as assessed by both investigator and by blinded, central review. Recruitment is ongoing. Clinical trial information: NCT04363801 . References SJ Klempner, et al. DKN-01 and tislelizumab ± chemotherapy as a first-line (1L) and second-line (2L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial. JCO 40, no. 4_suppl, 2022, 292-292.&nbsp; SJ Klempner, et al. DKN-01 and Tislelizumab + Chemotherapy as First-line (1L) Investigational Therapy in Advanced Gastroesophageal Adenocarcinoma (GEA): DisTinGuish Trial. ESMO Annual Meeting September 2022. Clinical trial information: NCT04363801 .
A phase I study of GPC3 targeted CAR-T cell therapy in advanced GPC3-expressing hepatocellular carcinoma (HCC).
Authors: Xie Changqing , Monge B. M. Cecilia , Mabry-Hrones Donna , Coffman Kelley Lauren , Hicks Stephanie , Redd Bernadette , Wood Brad , Highfill Steven , Ho Mitchell , Greten Tim F. 
Published: January 2023

TPS624 Background: The mortality of hepatocellular carcinoma (HCC) is increasing worldwide, but outcome of systemic treatments in advanced HCC is suboptimal. Adoptive T-cell transfer therapy represents a promising field that exploits the ability of T-cells to recognize and eliminate their target. Targeting the tumor-associated antigen glypican- 3 (GPC3) through chimeric antigen receptors (CAR) engineered T cells is a mechanistically rational novel treatment for advanced HCC. This study aims to determine the dose and early signals of GPC3 targeted (CAR)-T cells in advanced GPC3 expressing HCC (NCT05003895). Methods: This phase I first in human dose escalation trial will study the safety and feasibility of CAR (hYP7)- T cells in advanced HCC patients expressing GPC3. Eligibility criteria includes advanced HCC, not candidates for curative interventions, progressed on first line systemic treatment, tumor GPC3 positivity of ³ 25% by IHC, Child-Pugh Class A, ³1 measurable lesion, ECOG 0 or 1, adequate organ and marrow function. ParticipantsÕ T cells collected through leukapheresis will be transduced with a lentivirus encoding the CAR construct to generate CAR expressing T cells. Patients receive a conditioning chemotherapy regimen of cyclophosphamide and fludarabine prior to the infusion of the GPC3 directed CAR-T cells (Table). The trial has a 4-level modified Fibonacci dose escalation with a minimum of 3 patients at each level and a 28-day interval between the first three patients. Response will be assessed by imaging every two months during the first year. Patients undergo close monitoring with safety assessments during the first year and are followed for life. The primary objective is to determine the MTD, DLT, safety and feasibility of anti-GPC3 CAR expressing T- cells in patients with GPC3-expressing advanced HCC. Secondary objectives include best overall response and overall survival. Exploratory objectives are multiple and include studies to evaluate the persistence and peak levels of anti-GPC3 CAR-T cells after infusion. Recruitment began in December 2021 and the two patients at dose level -1 has been treated; the planned sample size is 38 patients. Table 1 Dose Level Anti-GPC3 CAR-T Cyclophosphamide (mg/m2) Fludarabine (mg/m2) Level -1 0.3x106 CAR-T per kg bw 200 30 Level 1 0.3x106 CAR-T per kg bw 300 30 Level 2 1x106 CAR-T per kg bw 300 30 Level 3 3x106 CAR-T per kg bw 300 30. Clinical trial information: NCT05003895 .
Phase II trial of second-line regorafenib in patients with unresectable hepatocellular carcinoma after progression on first-line atezolizumab plus bevacizumab: REGONEXT trial.
Authors: Cheon Jaekyung , Ryoo Baek-Yeol , Kang Beodeul , Chon Hongjae , Yoo Changhoon 
Published: January 2023

TPS634 Background: Atezolizumab-bevacizumab (Ate/Bev) has demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III trial, and is the new standard of care for first-line treatment of advanced HCC. However, the optimal sequence of therapy after failure of Ate/Bev is unknown. Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumour immunity. Although regorafenib showed survival benefit as subsequent treatment in patients with advanced HCC after progression on sorafenib, the efficacy and safety of regorafenib as subsequent therapy after Ate/Bev has not been investigated yet. Therefore, we designed a phase II trial investigating the efficacy and safety of regorafenib as second-line therapy in patients with advanced HCC who progressed on first-line Ate/Bev. Methods: This is a phase II, multicenter, single-arm study in patients with advanced HCC who had progression on first-line Ate/Bev. Additional key eligibility criteria include with Eastern Cooperative Oncology Group performance status 0–1, Child-Pugh score of 5 or 6, evaluable disease per RECIST v1.1, prior administration of at least 2 cycles of Ate/Bev, and adequate organ function. Key exclusion criteria include fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma, prior regorafenib treatment, clinically significant bleeding within 28 days of enrollment and untreated or symptomatic CNS or leptomeningeal metastasis. Eligible patients will receive oral regorafenib 160 mg daily for 3 weeks of every 4-week cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, time to progression, overall response rate (ORR), disease control rate and safety. ORR and PFS is assessed per RECIST v 1.1. This study is ongoing and 18 of planned 40 patients have been enrolled. This study is prospectively registered at ClinicalTrials.gov, NCT5134532.
Trial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations.
Authors: Tolcher Anthony W. , Park Wungki , Wang Judy S. , Spira Alexander I. , Janne Pasi A. , Lee Ho-Jin , Gill Stanley , LoRusso Patricia , Herzberg Benjamin , Goldman Jonathan W. , Morgensztern Daniel , Berlin Jordan , Kasi Anup , Fujii Hisaki , Pelster Meredith 
Published: January 2023

TPS764 Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 ubiquitin ligase proteins. In preclinical studies, ASP3082 selectively degraded the KRAS G12D-mutated protein and showed growth inhibitory activity in KRAS G12D-mutated cancer cells but not in KRAS -wildtype cancer cells. Notable antitumor effects of ASP3082 have been demonstrated when intravenously administered weekly in mice xenografted with KRAS G12D-mutated cancer cells. Methods: This first-in-human, open-label, multicenter, phase 1 study evaluates the safety and tolerability of ASP3082 in patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer or other solid tumors. Participants with unresectable, locally advanced, or metastatic solid tumor malignancy with documented KRAS G12D mutation are eligible for enrollment. Part 1 consists of dose-escalation cohorts of 3−12 patients receiving intravenous administration of ASP3082 in a 21-day cycle. Part 2 consists of random assignment of ≤20 patients into 2 cohorts with different ASP3082 dose levels to determine the recommended phase 2 dose. Additional tumor-specific expansion cohorts may enroll ≤20 participants per tumor type. Primary endpoints will evaluate safety and tolerability as noted by dose-limiting toxicities, adverse events, serious adverse events, laboratory test results, electrocardiograms, vital signs, physical exams, and Eastern Cooperative Oncology Group performance status. Secondary endpoints will evaluate objective response rate, duration of response, disease control rate per Response Evaluation Criteria in Solid Tumors version 1.1, pharmacokinetics of single and repeated doses of ASP3082, and changes in KRAS G12D in tumor samples. Exploratory objectives will evaluate potential biomarkers that may correlate with treatment outcomes. Tumor assessment follow-up will continue for ≤45 weeks or until progressive disease. Enrollment in Cohort 1 is complete, and enrollment to Cohort 2 began in September 2022. Clinical trial information: NCT05382559 .
Migration as a Vector of Economic Losses From Disaster-Affected Areas in the United States
Authors: DeWaard Jack , Fussell Elizabeth , Curtis Katherine J. , Whitaker Stephan D. , McConnell Kathryn , Price Kobie , Soto Michael , Anampa Castro Catalina 
Published: January 2023

Abstract
We introduce the consideration of human migration into research on economic losses from extreme weather disasters. Taking a comparative case study approach and using data from the Federal Reserve Bank of New York/Equifax Consumer Credit Panel, we document the size of economic losses attributable to migration from 23 disaster-affected areas in the United States before, during, and after some of the most costly hurricanes, tornadoes, and wildfires on record. We then employ demographic standardization and decomposition to determine if these losses primarily reflect changes in out-migration or the economic resources that migrants take with them. Finally, we consider the implications of these losses for changing spatial inequality in the United States. While disaster-affected areas and their populations differ in their experiences of and responses to extreme weather disasters, we generally find that, relative to the year before an extreme weather disaster, economic losses via migration from disaster-affected areas increase the year of and after the disaster, these changes primarily reflect changes in out-migration (vs. the economic resources that migrants take with them), and these losses briefly disrupt the status quo by temporarily reducing spatial inequality.
Undue Burdens: State Abortion Laws in the United States, 1994–2022
Authors: Roth Louise Marie , Lee Jennifer Hyunkyung 
Published: January 2023

Abstract
State laws have influenced access to abortion in the 50 years since Roe v. Wade. The 2022 Dobbs decision returned questions about the legality of abortion to the states, which increased the importance of state laws for abortion access. The objective of this study is to illustrate trends in abortion-restrictive and abortion-supportive state laws using a unique longitudinal database of reproductive health laws across the United States from 1994 to 2022. This study offers a descriptive analysis of historical trends in state-level pre-viability abortion bans, abortion method bans, efforts to dissuade abortion, TRAP (targeted regulation of abortion providers) laws, other laws that restrict reproductive choice, and laws that expand abortion access and support reproductive health. Data sources include state statutes (from Nexis Uni) and secondary sources. The data reveal that pre-viability bans, including gestation-based bans and total bans, became significantly more prevalent over time. Other abortion-restrictive laws increased from 1994 to 2022, but states also passed a growing number of laws that support reproductive health. Increasing polarization into abortion-restrictive and abortion-supportive states characterized the 1994–2022 period. These trends have implications for maternal and infant health and for racial/ethnic and income disparities.
Clinical observation on the treatment of ankle fracture with buttress plate and traditional internal fixation and its effect on GQOLI-74 score and Baird-Jackson score
Authors: Lin Zhen , Gao Lian-yun , Ruan Kang-ming , Guo Deng-bing , Chen Yan-hua , Liu Qing-ping 
Published: January 2023

Objective: To explore the curative effect of buttress plate and traditional internal fixation in the treatment of ankle fracture, so as to provide potential reference for the clinical treatment of this disease.
Methods: This is a clinical comparative study. The subjects of this study were one hundred patients with ankle fracture treated in Mindong Hospital Affiliated to Fujian Medical University from January 2019 to December 2021. Enrolled patients were randomly divided into the control group and the experimental group. Patients in the control group were treated with traditional internal fixation, and those in the experimental group were provided with buttress plate. Patients were compared in several aspects such as the comprehensive quality of life assessment questionnaire (GQOLI-74), Baird-Jackson score and postoperative complications.
Results: The experimental group showed improved Baird-Jackson score after treatment, significantly higher fracture healing rate than that of the control group three months after treatment. Besides, there was no significant difference in the complications between the two groups, with good prognosis after timely treatment.
Conclusion: Internal fixation with buttress plate has obvious advantages in the treatment of ankle fractures, which can effectively improve the quality of life and promote the rapid healing of fractures. It is worthy of clinical promotion and application.
doi: https://doi.org/10.12669/pjms.39.2.6876
How to cite this: Lin Z, Gao L, Ruan K, Guo D, Chen Y, Liu Q. Clinical observation on the treatment of ankle fracture with buttress plate and traditional internal fixation and its effect on GQOLI-74 score and Baird-Jackson score. Pak J Med Sci. 2023;39(2):---------. doi: https://doi.org/10.12669/pjms.39.2.6876
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Computer-aided drug design approaches applied to screen natural product’s structural analogs targeting arginase in Leishmania spp
Authors: Barazorda-Ccahuana Haruna Luz , Goyzueta-Mamani Luis Daniel , Candia Puma Mayron Antonio , Simões de Freitas Camila , de Sousa Vieria Tavares Grasiele , Pagliara Lage Daniela , Ferraz Coelho Eduardo Antonio , Chávez-Fumagalli Miguel Angel 
Published: January 2023

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics–generalized Born surface area (MM–GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions and hydrogen bonds enhancing enzyme–ligand coupling. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated.
Optimizing the Airflow Velocity Combinations Acting on Male Parent Rows for Hybrid Rice Pollination
Authors: Xi Te , Sun Lunqing , Wang Yongwei , Li Dongfang , Shanno Fake , Yao Fuqiang , Wang Jun 
Published: January 2023

HighlightsThe effect of airflow velocity on pollen distribution was investigated under a large-scale planting mode. The response surface model between pollen distribution and airflow velocity was constructed.Multi-objective optimization of airflow velocity combinations was carried out using a genetic algorithm.The optimal airflow velocity ranges of the male parents are from 22.4 to 24 m/s, 23.1 to 27 m/s, and 23.5 to 24.1 m/s.Abstract. Pollination is the key link in hybrid rice seed production. The pneumatic pollination method can significantly improve pollination efficiency under large-scale planting mode. To investigate the effect of airflow velocity on pollen distribution in hybrid rice pollination, the velocities of airflow acting on different male parent rows were taken as the experimental factors. The pollen amount in per view and the variation rate of pollen distribution in female parent rows were used as experimental indices. Field experiments were carried out using a self-made pneumatic pollination experimental platform. The results showed that when the airflow acted on the male parents in the first and second rows of the adjacent female parent, the pollen dissemination distance was short when the airflow velocity was low, and the pollen was mainly deposited in the area near the male parents. With the increase in airflow velocity, the peak pollen amount in per view in the female parent rows gradually moved away from the male parent rows. But they are all in the female parent rows of the effective area. The total amount of pollen also increased. Due to the blocking effect of the outer male parent row, the pollen dissemination was restricted when the airflow alone acted on the third male parent row. The effect of airflow velocity on pollen distribution was not obvious. The experimental results of different airflow velocities acting on the parent row alone are used as the basis. The objective functions of pollen amount, distribution variation rate, and airflow velocities of each male parent row were established by response surface methodology. The multi-objective optimization of airflow velocity combinations was carried out by a genetic algorithm. The pollen distribution under different air velocity combinations was obtained. When the optimal airflow velocity ranges of the male parents in rows 1, 2, and 3 are 22.4 to 24 m/s, 23.1 to 27 m/s, and 23.5 to 24.1 m/s, respectively, pollination is uniform and sufficient. The research results can provide a basis for the development of pneumatic pollinators and the optimization of working parameters under large-scale planting mode. Keywords: Multi-objective parameter optimization, Pneumatic pollination machinery, Response surface modeling, Rice pollination.