bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of FOLFIRI plus bevacizumab versus FOLFIRI plus cetuximab in RAS-mutant metastatic colorectal cancer: Final update on patients with RAS-mutant metastatic colorectal cancer treated in FIRE-3.
Authors: Weiss Lena , Stintzing Sebastian , Modest Dominik Paul , von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Lerchenmuller Christian A. , Kahl Christoph , Seipelt Gernot , Kullmann Frank , Moehler Markus H. , Scheithauer Werner , Held Swantje , Miller-Phillips Lisa , Stahler Arndt , Jung Andreas , Heinemann Volker
Published: June 2024

3550

Background: Doublet chemotherapy plus bevacizumab is a well-established standard of care in the first-line treatment of RAS-mutant (RASmut) metastatic colorectal cancer (mCRC). The FIRE-3 trial was the first randomized study to compare FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC. Since this trial initially included patients irrespective of RAS mutation status, the present analysis performs an updated evaluation of therapeutic efficacy of targeted therapy with bevacizumab versus cetuximab in RASmut mCRC. Methods: FIRE-3 trial included 752 patients. Initially, pyrosequencing (PSeq) was used to identify RAS mutations. In a subsequent investigation next-generation sequencing (NGS) was applied in 373 available tumors. A 5% mutant allele cutoff was used for both PSeq and NGS both of which were done centrally. Results: Of the 224 RASmut and BRAF wild-type patients, 187 were identified by polymerase chain reaction (PCR) and PSeq, 122 by NGS. 86 tumors were PCR positive and NGS positive (PCR+/NGS+), 36 tumors PCR negative and NGS positive (PCR-/NGS+). In the overall RASmut cohort of 224 patients, no overall survival (OS) benefit was observed when cetuximab was compared to bevacizumab (20.3 months vs 21.1 months; HR 1.028; 95% CI, 0.547-1.583; P=.842). This effect was observed independent of sidedness of primary tumors (PT) for left-sided (21.5 months vs 22.1 months; HR 1.054; 95% CI, 0.763-1.456) and right-sided PT (19.2 months vs 19.5 months; HR 0.931; 95% CI, 0.547-1.583). Conclusions: While cetuximab notably is not effective in RASmut mCRC, this randomized comparison does not provide an indication for superior efficacy of bevacizumab in the first-line treatment of this patient group. Trial identification number: NCT00433927 [clinicaltrials.gov]
Clinicopathological characteristics and survival in metastatic colorectal cancer with short-form APC mutations.
Authors: Osumi Hiroki , Ooki Akira , Fukada Ippei , Yoshino Koichiro , Tamba Mikako , Udagawa Shohei , Fukuoka Shota , Wakatsuki Takeru , Ogura Mariko , Takahari Daisuke , Chin Keisho , Nakamura Yoshiaki , Bando Hideaki , Yoshino Takayuki , Hayashi Naomi , Takahashi Shunji , Yamaguchi Kensei , Seimiya Hiroyuki , Shinozaki Eiji
Published: June 2024

3555

Background: Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli ( APC) gene and plays a key role in tumorigenesis in colorectal cancer (CRC). Tankyrase inhibitors, which cause degradation of β-catenin, are expected to have a promising therapeutic effect for CRC, and the short-form APC mutations predict the sensitivity of CRC cells to tankyrase inhibitors (Tanaka et al. Mol Cancer Ther 2017; Chen et al. Br J Cancer, in press).However, clinicopathological characteristics and survival in metastatic CRC (mCRC) with short-form APCmutations remain unclear. Methods: Patients with mCRC who were treated with chemotherapy between 2010 and 2021 and have tissue or circulating tumor DNA-based next-generation sequencing results were enrolled. Short-form APC mutations were defined as those truncated at amino acid 1,256 or shorter, lacking all seven 20-amino acid repeat (20-AAR) regions. Non-short-form APC mutations were defined as those possess more than one 20-AAR. Short-form and non-short-form heterozygous mutations were classified as non-short-form APC mutations. We confirmed incidence of mCRC with short-form APC mutations and compared clinicopathological characteristics and overall survival (OS) between mCRC patients with short-form and non-short-form APCmutations. Results: Of 177 patients (median age, 56.0 years) included in this study, 44 (25%) and 79 (45%) had short-form and non-short-form APC mutations, respectively. Patients with short-form APC mutations were not likely to have lung metastasis (P = 0.15). Logistic regression multivariate analysis, lung metastasis was related to mCRC patients with short-form APC mutations (Odds ratio: 0.46, P = 0.047). Patients with short-form APC mutations had significantly shorter overall survival (OS) than did those without (n = 133), with a median OS of 34.7 vs 50.5 months ( P Log-rank= 0.035, hazard ratio (HR), 1.59; 95% confidence interval (CI), 1.03-2.45). In multivariate analysis, short-form APC mutation was independent factor related to OS (hazard ratio (HR): 1.68, P = 0.02), as well as the BRAF V600E mutation, liver metastasis and peritoneal metastasis. Conclusions: Short-form APC mutation is more common in mCRC patients without lung metastases and is independently associated with a short prognosis.
Tumor microbiome differences in early-onset versus average-onset pancreatic adenocarcinoma.
Authors: Jayakrishnan Thejus , Sangwan Naseer , Nair Kanika G. , Kamath Suneel Deepak , Patel Mehrie , Joyce Daniel , Walsh Matthew , Simon Robert , Vadehra Deepak , Iyer Renuka V. , Fountzilas Christos , Khorana Alok A.
Published: June 2024

4016

Background: The rise in early-onset gastrointestinal cancers includes an increased risk of pancreatic adenocarcinoma (PDAC), but the underlying pathogenesis is incompletely understood. The tumor microbiome is an increasing focus of research given its impact on tumor pathogenesis and outcomes. We evaluated microbiome profiles in resected specimens from early-onset PDAC (eoPDAC) and average-onset PDAC (aoPDAC). Methods: PDAC specimens were selected consecutively from Cleveland Clinic and Roswell Park Cancer Institute biorepositories and categorized on age at diagnosis ( < 50 years defined as eoPDAC, and > 50 years as aoPDAC). The tissue microbiome was characterized using shotgun metagenomic sequencing. Alpha diversity, denoting the richness and evenness of microbial species within a specific sample, was compared using the Wilcoxon rank-sum test. The differential test of Beta-diversity distances (Bray Curtis distance), representing microbial taxonomic differences between the specimens was performed using Permutational MANOVA. All p-values were adjusted for multiple testing. Results: The study comprised 44 individuals with resected PDAC (24 eoPDAC and 20 aoPDAC). After quality checks, 63 tissue specimens were selected for analysis (13 tumor and 10 adjacent normal specimens for eoPDAC, 20 each of tumor and adjacent normal specimens for aoPDAC). eoPDAC tumor demonstrated significantly higher alpha diversity compared to adjacent normal tissue (P = 0.02) and aoPDAC (P = 0.0062) while aoPDAC did not (tumor vs normal alpha diversity P = 0.31). Beta diversity analysis demonstrated significantly different diversity of genera between all the groups (P < 0.05). Consistent with this finding, the majority of the species - 259/302 (85.8%) in eo vs aoPDAC comparison and 262/366 (71.6%) for eoPDAC vs normal comparison did not overlap. Differential abundance analysis revealed a significant variation of tumor microbiome in eoPDAC vs aoPDAC (P < 0.05). Prevalent bacterial genera (tumor specimens) are listed in the Table. eoPDAC tumor tissues were enriched in Enterobacter, Neisseria,and Escherichia genera, while aoPDAC tumor tissues were enriched in Klebsiella and Bacillus genera. Conclusions: eoPDAC has a distinct microbiome profile compared to aoPDAC. The correlation with several microbial genera associated with pancreatic diseases is a significant finding and warrants further exploration. This is relevant considering the rising incidence of eoPDAC of unknown etiology, and ongoing efforts to develop microbiome-based biomarkers for screening and treatment. [Table: see text]
Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing biliary tract cancer (BTC) and pancreatic cancer (PC): Outcomes from DESTINY-PanTumor02 (DP-02).
Authors: Oh Do-Youn , Lugowska Iwona A. , Stroyakovskiy Daniil , Jung Kyung Hae , Dumas Olivier , Penkov Konstantin , Dechaphunkul Arunee , Oaknin Ana , Kim Seung Tae , Starling Naureen , Chewaskulyong Busyamas , Charonpongsuntorn Chanchai , Doroshow Deborah Blythe , Hsiao Sheng-Yen , Hung Yi-Ping , Jung Lindsey , Kuptsova-Clarkson Nataliya , Michelini Flavia , Puvvada Soham D. , Meric-Bernstam Funda
Published: June 2024

4090

Background: Existing late-line treatment (Tx) options for BTC and PC offer limited long-term benefit. In DP-02, T-DXd showed tumor-agnostic potential, with an objective response rate (ORR) of 37.1% (95% CI 31.3, 43.2) and clinically meaningful survival outcomes in 267 pts with HER2-expressing tumors. Here we report subgroup analyses in the BTC and PC cohorts and characterize pts with an objective response (OR). Methods: This open-label Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic Tx, or without Tx options. The primary endpoint was confirmed ORR by investigator (INV). Secondary endpoints included progression-free survival (PFS) and safety. Exploratory endpoints included efficacy outcomes by HER2 expression. Results: At data cutoff (June 2023), 41 pts with BTC and 25 pts with PC had received T-DXd (median [m] follow up [range]: 6.01 [0.7–29.1] and 4.99 [1.1–27.2] months [mo], respectively); 27 (65.9%) and 18 (72.0%) pts had ≥2 prior Tx regimens, 7 (17.1%) and 2 (8.0%) pts had prior anti-HER2 Tx, and 8 (19.5%) and 18 (72.0%) pts had prior topoisomerase 1 inhibitor Tx, respectively. In pts with BTC and IHC 3+ expression, 9 pts (56.3%; 95% CI 29.9, 80.2; primary tumor locations: n=2 ampulla of Vater; n=2 extrahepatic; n=4 gallbladder; n=1 intrahepatic) had confirmed OR by INV; of these pts, 6 had received ≥2 prior Tx regimens and 4 had PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by central HER2 expression. In pts with BTC and PC, Grade (G) ≥3 drug-related adverse events occurred in 16/41 (39.0%) and 7/25 (28.0%) pts, respectively; adjudicated drug-related interstitial lung disease / pneumonitis occurred in 7/41 (17.1%; n=5 G2; n=1 G3; n=1 G5) and 1/25 (4.0%; n=1 G1) pts, respectively. Conclusions: T-DXd showed clinically meaningful benefit in pts with BTC across primary tumor locations. Low pt numbers limit interpretation of the PC cohort; however, data support further exploration of T-DXd in this population. Safety was consistent with the known profile. These data support T-DXd as a potential Tx for pts with HER2-expressing BTC. Clinical trial information: NCT04482309 . [Table: see text]
Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).
Authors: Lim Kian-Huat , Spencer Kristen Renee , Safyan Rachael A , Picozzi Vincent J. , Varghese Anna M. , Siolas Despina , Perez Kimberly , Clift Sheena , Denis Louis J. , Bhambhani Vijeta , Hill Stacey , Pachter Jonathan A. , Pultar Philippe , Hidalgo Manuel
Published: June 2024

4140

Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]
Quality indicators in the care of patients with rectal cancer in social security in Guatemala: Results of a retrospective population study.
Authors: López Pedro Luis , Castro-Salguero Hugo Raul , Ranero Meneses Jorge Luis , Peralta de León Stefany Jerusa
Published: June 2024

e15518

Introduction: Rectal cancer is a serious condition affecting a significant number of patients worldwide. However, in the Guatemalan population, the epidemiology and clinical characteristics of this disease have not been widely studied. This study aims to address this knowledge gap by retrospectively analyzing patients with rectal cancer treated at the Guatemalan Social Security Institute between 2013 and 2018. Methods: A retrospective analysis of eighty-eight patients with rectal cancer treated at the Guatemalan Social Security Institute during the mentioned period was conducted. Descriptive statistical techniques, such as chi-square, as well as survival analysis using Cox regression and Kaplan-Meier, were employed to assess the relationship between clinical stages, treatments, and overall survival. Results: The mean age at diagnosis was 70 years +/- 20 years, and 71% of the patients were male. At the time of diagnosis, 14.28% of the patients had localized disease, 58.86% had regional spread, and 26.86% had metastatic disease. Patients in clinical stage I showed a 5-year survival rate of 100%, with a p-value < 0.001 and an HR of 0.01. Additionally, the combination of chemotherapy, radiotherapy, and surgery was found to be significantly associated with improved survival, with a p-value of 0.03 and an HR of 0.82. Conclusions: This study provides crucial information on the clinical characteristics and survival of Guatemalan patients with rectal cancer. The findings underscore the importance of early detection and multimodal treatment, including chemoradiotherapy followed by surgery, to improve outcomes in these patients. Sharing these results is essential to promote access to standard treatment and enhance survival outcomes in patients with rectal cancer in Guatemala.
Triplet chemotherapy combined with anti-EGFR treatment in RAS wild-type colon cancer: A network meta-analysis.
Authors: Di Nardo Paola , Giudici Fabiola , Basile Debora , de Scordilli Marco , Torresan Sara , Bortolot Martina , Rota Simone , Foltran Luisa , Guardascione Michela , Fumagalli Arianna , Noto Claudia , Guglielmi Alessandra , Ongaro Elena , Puglisi Fabio
Published: June 2024

e15592

Background: The optimal first-line treatment for RAS wild-type (wt) metastatic colorectal cancer (mCRC) remains undetermined. Recently, several studies have explored the efficacy of first-line treatment regimens, including triplet chemotherapy (CT) combined with an anti-EGFR antibody, in comparison to either doublet CT combined with an anti-EGFR antibody, triplet CT combined with an anti-VEGF treatment, or triplet CT alone. However, none of these trials yielded conclusive results. Hence, we conducted a systematic review and an explorative network meta-analysis (NMA) of the available data. Methods: A systematic review was conducted, encompassing all phase II/III randomized clinical trials (RCTs) that compared a regimen consisting of triplet CT associated with an anti-EGFR treatment against different first-line systemic regimens for RAS-wt mCRC patients. Both pairwise and NMA were performed to establish direct and indirect comparisons of overall response rate (ORR) using a random effects model within the frequentist framework. Results: 7 RCTs (TRIPLETE, VOLFI, TRICE, PANIRINOX, AIO-CELIM2, FOCULM, DEEPER), involving a total of 1283 patients, were included in the analysis. Overall, 4 arms were identified, encompassing all possible combinations of CT, anti-EGFR treatment, and anti-VEGF treatment: arm A (triplet + anti-EGFR), arm B (doublet + anti-EGFR), arm C (triplet alone), and arm D (triplet + anti-VEGF). A benefit was demonstrated for all treatments associated with targeted therapy when compared to triplet alone; no difference was observed among groups A, B and D. Results of selected NMA comparisons are shown in the table 1. Additionally, we conducted a pairwise meta-analysis for ORR, which, due to available comparisons, was only feasible for groups A vs. B, A vs. C, and A vs. D; the results of this analysis confirmed the NMA findings (group A vs. group C, pooled OR: 4.23 (2.06 – 8.68)). Conclusions: Through indirect comparisons, no significant ORR benefit was found for triplet CT associated with anti-EGFR treatment compared to doublet CT combined with anti-EGFR treatment or triplet CT combined with anti-VEGF. All regimens incorporating targeted treatment demonstrated superior performance compared to triplet CT alone. Our findings do not advocate for the routine use of triplet CT associated with anti-EGFR treatment in this patient population; however, we await mature OS data from a few of the trials included in our analysis. [Table: see text]
A first-in-human, phase 1/2 trial of FOG-001, a β-catenin:TCF antagonist, in patients with locally advanced or metastatic solid tumors.
Authors: Papadopoulos Kyriakos P. , Rodon Ahnert Jordi , Khushman Moh'd M. , Sharma Sunil , Pelster Meredith , Cecchini Michael , Kummar Shivaani , Choi Minjung , Akella Lalith V , Garofalo Amanda , Yu Ziyang , Iyer Varsha , Nguyen Marie Huong , Orford Keith W. , Klempner Samuel J.
Published: June 2024

TPS3175

Background: The Wnt/β-catenin pathway is a frequently activated oncogenic pathway and a well-described driver of many cancers. FOG-001 is designed to be a first-in-class direct inhibitor of β-catenin that blocks β-catenin’s interaction with the T-cell factor (TCF) family of transcription factors. Preclinical studies have indicated FOG-001 can cause tumor growth inhibition and regression by disrupting β-catenin-dependent signaling. FOG-001 is unique from previously reported Wnt/β-catenin pathway modulators as it is designed to directly inhibit TCF transcription factor and β-catenin interaction, the most downstream node in the Wnt pathway. It is hypothesized FOG-001 will abrogate the hyperactivation of the Wnt pathway that is driven by most known pathway mutations. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Parts 1a and 1b) and dose-expansion (Part 2) study is evaluating the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of FOG-001 in patients with advanced or metastatic solid tumors. Patients with the following tumor types are eligible: microsatellite stable (MSS) colorectal cancer (CRC) or any solid tumor with documented Wnt pathway activating mutation (WPAM) (Part 1a), MSS CRC only (Part 1b) and MSS CRC, gastric/gastroesophageal (GEJ) cancer, non-small cell lung cancer (NSCLC), and any solid tumors with documented WPAM in Part 2. Patients must have received ≥1 prior systemic anticancer therapy(ies) and be ineligible for curative surgery or curative chemoradiation. In Part 1, FOG-001 is administered at escalating doses via intravenous (IV) infusion on Days 1, 8, 15, and 22 of each 4-week cycle; additional dosing regimens may be explored. After selection of the preliminary recommended Phase 2 dose(s) (pRP2D) and regimen(s) in Part 1, the following cohorts will be enrolled to receive FOG-001 at the pRP2D in Part 2: (2a) MSS CRC; (2b) NSCLC with documented WPAM in adenomatous polyposis coli (APC) or β-catenin; (2c) gastric/GEJ cancer with documented WPAM in APC or β-catenin; and (2d) solid tumors with ≥1 documented WPAM in any predefined Wnt pathway genes. The primary endpoints are safety/tolerability (Parts 1 and 2), and also preliminary antitumor activity (objective response rate) (Part 2). Secondary endpoints are PK, PD, and additional antitumor activity assessments. Enrollment in Part 1 is ongoing. Clinical trial information: NCT05919264 .
Pilot study of CBX-12 pharmacodynamics in patients with advanced solid tumors.
Authors: Shin Sarah , O'Sullivan Coyne Geraldine Helen , Rubinstein Larry V. , Takebe Naoko , Wright John Joseph , Wilsker Deborah , Ferry-Galow Katherine V. , Karlovich Chris Alan , Anderson Larry , Kuhlmann Laura , Parchment Ralph E. , Doroshow James H. , Chen Alice P.
Published: June 2024

TPS3187

Background: Topoisomerase 1 (TOP1) inhibitors effectively kill a diverse range of tumor cells but have limited clinical utility due to severe off-target toxicities. Targeted therapeutic strategies have been developed to circumvent these limitations, although there remains an unmet need for antigen-agnostic tumor targeting. CBX-12 is a peptide conjugate that uses a novel pH-low insertion peptide (pHLIP) linked to TOP1 inhibitor exatecan to selectively target the low-pH tumor microenvironment and deliver the payload intracellularly. Recently published results of the first-in-human study of CBX-12 (NCT04902872) demonstrated single-agent activity in 4 patients, including a complete response in a patient with ovarian cancer. The predominant reported toxicity was myelosuppression with the most common grade 3/4 treatment-related adverse event being neutropenia in 28.6% of patients. Here we report our new pharmacodynamic (PD) biomarker-driven pilot study of CBX-12 in patients with advanced solid tumors. The primary objective of this study is to assess the effects of CBX-12 on biomarkers of DNA damage response (DDR) in biopsy specimen to establish the degree and duration of CBX-12 target engagement. The secondary objectives are to assess the effects of CBX-12 on TOP1 molecular response; determine any association between tumor TOP1 levels, DDR modulation, and plasma exatecan levels; evaluate the effect of CBX-12 on CD8+ T cell infiltration and activation in the tumor microenvironment; assess the objective response rate using RECIST v 1.1; and assess safety and tolerability of CBX-12. The planned PD endpoints aim to confirm and further enrich knowledge of the mechanisms underlying response or resistance to CBX-12 treatment, and guide future complementary treatment combination strategies. The study results may also help identify future patient populations likely to benefit from CBX-12 treatment. Methods: CBX-12 will be administered intravenously once weekly in 28-day cycles at the recommended phase 2 dose. Mandatory biopsies will be collected at baseline, 24-36 hours post first dose, and on cycle 3 day 1 to assess both short- and long-term effects of CBX-12 on the tumor. Mandatory research blood samples will be collected at specified timepoints for pharmacokinetic, circulating tumor cell, and cell-free DNA analyses. Clinical trial information: NCT05691517 .
A first-in-human (FIH), phase 1/2, dose-escalation, dose-optimization, and dose-expansion study of PARP1-selective inhibitor IMP1734 in participants with advanced solid tumors.
Authors: Sonpavde Guru P. , Call Justin A , Falchook Gerald Steven , Garmezy Benjamin , Rasco Drew W. , Liu Lan , Niu Tiantian , He Jenna , Zhang Congcong , Kochan Jarema , Rebello Sam , Russo Giuseppe , Chen Viola , Krishnan Suba
Published: June 2024

TPS3191

Background: PARP inhibitors (PARPi) selectively kill tumor cells harboring genetic mutations in critical DNA repair genes (e.g., BRCA1/2). While several approved nonselective PARPi have provided robust anti-tumor activity, they are associated with significant hematologic toxicities that limit dose intensity and clinical benefit. Drugs that selectively inhibit PARP1 but spare PARP2 may improve the risk-benefit profile for this class of therapies by retaining anti-tumor activity while avoiding PARP2-related toxicities. IMP1734 (EIK1003) is a potent PARP1-selective inhibitor that inhibits tumor growth in nonclinical models and may widen the therapeutic index in tumors where non-selective PARPi have demonstrated efficacy. Methods: Study EIK1003-001 (IMP1734-101) is a global, multi-center, Phase 1/2 study evaluating the safety and potential antitumor activity of IMP1734 in participants with advanced solid tumors. The study has 3 parts: Part 1 (FIH; Dose Escalation), Part 2 (Dose Optimization), and Part 3 (Dose Expansion at the recommended dose for expansion [RDE]). Part 1 of this study is currently enrolling and consists of dose escalation of IMP1734 in study participants with advanced/recurrent/metastatic ovarian, breast, or prostate cancer with suspected deleterious/deleterious mutations in a pre-specified panel of homologous recombination repair (HRR) genes (n = 70). Eligible participants must be ≥ 18 years of age, have histologically or cytologically confirmed tumors as indicated in each study part, and at least 1 RECIST v1.1-measurable lesion and/or pre-specified serum tumor-specific marker. All participants must have a deleterious or suspected deleterious mutation in select HRR genes. Primary endpoints include safety and tolerability (evaluation of dose-limiting toxicities and determining the maximum tolerated dose, maximum achievable dose, and RDE). Secondary endpoints include evaluation of the pharmacokinetic parameters of IMP1734 and measures of efficacy, including overall response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints include analysis of pharmacodynamic biomarkers, serial ctDNA measurements, and patient quality-of-life measures. This study opened on 11 Dec 2023. Clinical trial information: NCT06253130 .
Correlation between the structural phase transition and magnetic properties of sol-gel synthesized
nanoparticles
Authors: Jharwal Swati , Verma Vivek Kumar , Kumar Arvind
Published: June 2024

The La2CoFeO6 (LCFO) nanoparticles were synthesized using the sol-gel method and calcined at 600

, 800

, and 1000

. The X-ray diffraction data confirm the successful formation of LCFO nanoparticles. The crystallite size was observed to increase from ∼13 nm to ∼26 nm as the calcination temperature rose. Detailed Rietveld analysis revealed the coexistence of both orthorhombic (Pnma: S.G. 62) and rhombohedral (

: S.G. 167) phases in the LCFO samples. A two-phase Rietveld refinement demonstrated a structural phase transition (from Pnma to

) as the calcination temperature increased. FESEM micrographs exhibited a granular morphology for the LCFO nanoparticles, and the grain size was observed to increase with the elevated calcination temperature. Magnetization curves illustrated an increase in magnetization with a decrease in crystallite size or a reduction in calcination temperature for LCFO nanoparticles. At higher calcination temperatures, the rhombohedral phase displayed significant antisite disorder, resulting in the disruption of long-range ferromagnetic ordering in the material and a subsequent decrease in maximum magnetization.
Brown Gathering
Authors: Leon Adrian de
Published: June 2024

Through a sustained engagement with The Precarious Life of the Parol, an installation art exhibition by the Filipinx artist Diane Williams, this essay theorizes “brown gathering”: a quotidian practice of archiving that mobilizes the kinship networks of minoritarian subjects as an affective and circulatory infrastructure of collecting, preserving, and (re)signifying the objects of brown life. Brown gathering simultaneously attests to the intimacies of state violence and the practices of minoritarian subjects. In Parol, named after a Filipinx Christmas ornament of Spanish and native origin, Williams turns toward this curatorial practice of making art with trash objects as a way to reckon with the archival absences of Philippine history. This investigation of Williams’s pieces, all made from trash objects that her family donated to her, concerns three categories: skeletal frames (wood and wire), used to explore archives of excess and mess; plastics, used to speak about the temporality of diaspora; and discarded food containers (SPAM cans and sauce mixes), used to theorize the politics of the brown body. These objects, like the brown subjects that signify them, are testaments to the ongoing plunder of empire and to what empire jettisons around the world.
PLETHORA transcription factors promote early embryo development through induction of meristematic potential
Authors: Kerstens Merijn , Galinha Carla , Hofhuis Hugo , Nodine Michael , Pardal Renan , Scheres Ben , Willemsen Viola
Published: June 2024

Plants are dependent on divisions of stem cells to establish cell lineages required for growth. During embryogenesis, early division products are considered to be stem cells, whereas during post-embryonic development, stem cells are present in meristems at the root and shoot apex. PLETHORA/AINTEGUMENTA-LIKE (PLT/AIL) transcription factors are regulators of post-embryonic meristem function and are required to maintain stem cell pools. Despite the parallels between embryonic and post-embryonic stem cells, the role of PLTs during early embryogenesis has not been thoroughly investigated. Here, we demonstrate that the PLT regulome in the zygote, and apical and basal cells is in strong congruence with that of post-embryonic meristematic cells. We reveal that out of all six PLTs, only PLT2 and PLT4/BABY BOOM (BBM) are expressed in the zygote, and that these two factors are essential for progression of embryogenesis beyond the zygote stage and first divisions. Finally, we show that other PLTs can rescue plt2 bbm defects when expressed from the PLT2 and BBM promoters, establishing upstream regulation as a key factor in early embryogenesis. Our data indicate that generic PLT factors facilitate early embryo development in Arabidopsis by induction of meristematic potential.
The retromer and retriever systems are conserved and differentially expanded in parabasalids
Authors: Shinde Abhishek Prakash , Kučerová Jitka , Dacks Joel Bryan , Tachezy Jan
Published: June 2024

Early endosomes sort transmembrane cargo either for lysosomal degradation or retrieval to the plasma membrane or the Golgi complex. Endosomal retrieval in eukaryotes is governed by the anciently homologous retromer or retriever complexes. Each comprises a core tri-protein subcomplex, membrane-deformation proteins and interacting partner complexes, together retrieving a variety of known cargo proteins. Trichomonas vaginalis, a sexually transmitted human parasite, uses the endomembrane system for pathogenesis. It has massively and selectively expanded its endomembrane protein complement, the evolutionary path of which has been largely unexplored. Our molecular evolutionary study of retromer, retriever and associated machinery in parabasalids and its free-living sister lineage of Anaeramoeba demonstrates specific expansion of the retromer machinery, contrasting with the retriever components. We also observed partial loss of the Commander complex and sorting nexins in Parabasalia but complete retention in Anaeramoeba. Notably, we identified putative parabasalid sorting nexin analogs. Finally, we report the first retriever protein localization in a non-metazoan group along with retromer protein localization in T. vaginalis.
O COMPORTAMENTO DE COMPRA NO NATAL E O ATO DE PRESENTEAR
Authors: Carvalho João Vitor , Valadares Gustavo Clemente , Manoel Iuri dos Santos , Campos Alyce Cardoso , Carvalho João Francisco Sarno , Silva Sheldon William
Published: June 2024

Este artigo teve como objetivo analisar o comportamento de compra de presentes de natal e as principais motivações para presentear apresentadas pelos consumidores da região de São Sebastião do Paraíso – MG. Como proposta de pesquisa, acredita-se que o Natal é uma ocasião em que as pessoas são contagiadas por um momento de gratidão, carinho e afeto, em que a doação de presentes é uma forma de demonstrar seus sentimentos. Para obtenção dos dados, foi realizada uma pesquisa quantitativa com questionário aplicado a 125 participantes. As evidências coletadas mostraram que a principal motivação para se presentear durante essa época do ano é a manutenção dos relacionamentos afetivos com a família. Os pressupostos levantados sobre o ato de presentear (dádiva, reciprocidade, ocasião, simbolismo, função do ato de presentear e ritual) se mostraram presentes nesta festividade, em que se observam os sentimentos de agradecimento e prazer ao presentear.
Predictive Ability of Self-Care and Psychological Flow in Occupational Stress Among Nurses
Authors: Salem Almahaireh Abdallah , Suhail  Shawaqfeh Baha'
Published: June 2024

Background The nursing workforce is crucial in healthcare systems worldwide and contributes to community well-being. also, Nurses experience numerous psychological, social, emotional, and behavioral shocks and challenges in their work. In Jordan, 43% of doctors and nurses suffer from high levels of burnout, around 55% experience high levels of emotional exhaustion, and 33% of doctors and nurses suffer from high levels of psychological pressure and job stress. Others found that 70% of nurses experience stress. these issues can be reduced by practicing self-care and psychological flow which impact in work-related tasks which are important in effectively addressing occupational stress healthily and soundly. This study aims to determine predictive ability of self-care and psychological flow in occupational stress among nurses Methods This study follows the quantitative technique. sample consisting of 476 nurses in Amman Jordan was chosen. Three scales were developed to meet the study objectives: Occupational stress scale, Self-care scale, and psychological flow scale. Results The study results indicate that self-care and psychological flow levels were low, while the occupational stress level was high. Also, there are a predictive ability of self-care and psychological flow in occupational stress among nurses. Conclusions This study shows that of self-care and psychological flow predict occupational stress among nurses, which helps us to manage the occupational stress among them by giving them self-care and psychological flow practices and healing time.
Ultrasound imaging and guidance in the management of myofascial pain syndrome: a narrative review
Authors: Wu Wei-Ting , Chang Ke-Vin , Ricci Vincenzo , Özçakar Levent
Published: June 2024

Myofascial pain syndrome (MPS) is a common musculoskeletal disorder characterized by muscle pain, tenderness, and trigger points. Ultrasonography has emerged as a key tool for diagnosing and treating MPS owing to its ability to provide precise, minimally invasive guidance. This review discusses the use of ultrasonography in various approaches to evaluate and manage MPS. Studies have shown that shear-wave sonoelastography can effectively assess muscle elasticity and offer insights into trapezius stiffness in patients with MPS. Ultrasound-guided interfascial hydrodissection, especially with visual feedback, has demonstrated effectiveness in treating trapezius MPS. Similarly, ultrasound-guided rhomboid interfascial plane blocks and perimysium dissection for posterior shoulder MPS have significantly reduced pain and improved quality of life. The combination of extracorporeal shockwave therapy with ultrasound-guided lidocaine injections has been particularly successful in reducing pain and stiffness in trapezius MPS. Research regarding various guided injections, including dry needling, interfascial plane blocks, and fascial hydrodissection, emphasizes the importance of ultrasonography for accuracy and safety. Additionally, ultrasound-guided delivery of local anesthetics and steroids to the quadratus lumborum muscle has shown lasting pain relief over a 6-month period. Overall, these findings highlight the pivotal role of ultrasonography in the assessment and treatment of MPS.
Mącznica lekarska Arctostaphylos uva-ursi (L.) Spreng. – potencjał terapeutyczny oraz zastosowanie w medycynie i kosmetologii
Authors: Zoń Aleksandra , Bacler-Żbikowska Barbara
Published: June 2024

Należąca do rodziny wrzosowatych zimozielona krzewinka mącznica lekarska Arctostaphylos uva-ursi (L.) Spreng. jest cenną rośliną leczniczą, z której pozyskuje się liść Uvae ursi folium. Zawarte w tym surowcu substancje czynne wykazują m.in. działanieprzeciwbakteryjne, przeciwutleniające i przeciwzapalne. Dzięki wysokiej zawartości arbutyny, awonoidów oraz kwasów fenolowych liść mącznicy jest szeroko wykorzystywany w leczeniu m.in. bakteryjnych zakażeń układu moczowo-płciowego, a także trądziku pospolitego. Liczne badania wskazują także na możliwość wykorzystania substancji pozyskiwanych z mącznicy w terapii nowotworów, chorób neurodegeneracyjnych czy też cukrzycy. Dodatkowo, ze względu na zdolność do rozjaśniania skóry przez arbutynę, liść mącznicy lekarskiej używany jest także w kosmetologii, m.in. do produkcji kosmetyków na przebarwienia skóry. Rosnące zapotrzebowanie na surowiec oraz brak możliwości jego pozyskiwania ze źródeł naturalnych doprowadziło do poszukiwania nowych alternatywnych metod jego pozyskiwania. Wśród najważniejszych wymienia się metody mikrobiologiczne oraz biotechnologiczne. W poniższej publikacji przedstawiono najważniejsze informacje dotyczące charakterystyki oraz występowania mącznicy lekarskiej, a także składu chemicznego, właściwości oraz potencjalnego zastosowania terapeutycznego opisywanej rośliny.
Wartość odżywcza i prozdrowotna zbóż bezglutenowych
Authors: Zarzecka Krystyna , Ginter Agnieszka , Mystkowska Iwona
Published: June 2024

W pracy przedstawiono charakterystykę wybranych gatunków zbóż niezawierających białek glutenowych z podaniem zawartości składników odżywczych i związków bioaktywnych oraz produktów zbożowych stosowanych przez konsumenta. Omówiono białka glutenowe i znaczenie diety bezglutenowej. Podkreślono, że bezglutenowe produkty zbożowe zawierają mniej składników mineralnych, witamin z grupy B i błonnika i z tego powodu dieta bezglutenowa powinna być wzbogacana nie tylko o pseudozboża, ale też o inne produkty naturalnie bezglutenowe, takie jak: warzywa i owoce, oleje roślinne, nasiona roślin strączkowych, jaja, nieprzetworzone mięso i ryby, mleko i naturalne produkty mleczne. Bezpieczne produkty można kupić nie tylko w Polsce, ale i w całej Europie i są one oznaczone graficznie licencjonowanym znakiem Przekreślonego Kłosa.
Arquitectura, investigación, proyecto y obra
Authors: Añón Abajas Rosa Mª , Ramos Carranza Amadeo , Torres Pérez María Elena
Published: June 2024

Este libro reúne una serie de reflexiones sobre proyectos de recuperación de arquitecturas y espacios públicos varios como viviendas, equipamientos o paisajes. Los proyectos y obras expuestos por profesores e investigadores de diferentes universidades de México, Argentina y España tienen en común el afán por reivindicar la importancia que tiene la arquitectura en la actualidad, abordando problemas y dando a conocer alternativas posibles que deben propiciar soluciones técnicas más sostenible. La mayoría de las casi treinta aportaciones está escrita en primera persona por los propios arquitectos de los proyectos y obras, justificando las decisiones adoptadas a partir de las circunstancias que convergen en cada una de las intervenciones.
Elicitación visual y narrativa histórica en la educación. Un estudio del retrato de Alfried Krupp por Arnold Newman.
Authors: Calviño-Santos Guillermo
Published: June 2024

Este artículo explora el uso de la foto-elicitación en la educación artística mediante el análisis del retrato de Alfried Krupp por Arnold Newman. Se discute cómo esta técnica puede fomentar el pensamiento crítico y la comprensión visual en estudiantes de secundaria y universitarios, ofreciendo una metodología para aplicar el análisis semiótico y la narrativa visual en contextos educativos y presentado una propuesta de aplicación en el aula. La investigación se basa en la metodología artográfica, integrando la perspectiva del educador como artista, investigador y profesor. La foto-elicitación, así entendida, logra desarrollar un proceso de investigación artísticoeducativo, que favorece la compresión de la fotografía como artefacto cultural, empodera al alumnado como creador de narrativas visuales y le sensibiliza respecto a las manifestaciones artísticas contemporáneas.
Migración involuntaria y reasentamiento: asuntos pendientes en la agenda política y legislativa de adaptación al cambio climático en Colombia
Authors: Castro-Buitrago Erika , Vélez-Echeverri Juliana , Madrigal-Pérez Mauricio
Published: June 2024

El propósito de este capítulo es establecer las debilidades de la política nacional, de la legislación y de la gestión de riesgos de desastres en el tratamiento de la migración involuntaria y los procesos de reasentamiento por casusas asociadas al cambio climático en Colombia. Para ello presentaremos una breve exposición de los compromisos internacionales adquiridos por el Estado y la necesidad de establecer un marco jurídico garante de los derechos de las personas que migran, la mayoría por causas hidrometeorológicas, y como consecuencia de la deficiente gestión del riesgo de desastres (Organización Internacional para las Migraciones, 2015, p. 10) y la falta de planeación para la adaptación al cambio climático. Este trabajo es el resultado de una investigación de corte jurídico-dogmático, exploratorio y analítico, basado en la revisión de diferentes fuentes documentales (políticas, normas jurídicas, jurisprudencia, informes oficiales internos y de entidades internacionales, y doctrina).
A guide to back pain
Authors: Noakes Amy
Published: June 2024

In this article, Amy Noakes looks at back pain, a leading cause of morbidity and sickness absence in healthcare workers
THE FRACTURE ANKLE IMPLANT REVIEW (FAIR) STUDY: A NATIONAL MULTICENTRE RETROSPECTIVE REVIEW OF IMPLANTS, FIXATION METHODS, AND OUTCOMES IN FIBULA FIXATION IN ANKLE FRACTURES
Authors: Fishley W. , Morrison R. , Baldock T. , Hilley A. , Baker P. , Townshend D.
Published: June 2024

Background

In fixation of the fibula in ankle fractures, AO advocate using a lag screw and one-third tubular neutralisation plate for simple patterns. Where a lag screw cannot be placed, bridging fixation is required. A local pilot service evaluation previously identified variance in use of locking plates in all patterns with significant cost implications. The FAIR study aimed to evaluate current practice and implant use across the United Kingdom (UK) and review outcomes and complication rates between different fibula fixation methods.

Method

The study was supported by CORNET, the North East trainee research collaborative, and BOTA. Data was collected using REDCap from 22 centres in the UK retrospectively for a one-year period between 1st January 2019 and 31st December 2019 on injury mechanism, fracture characteristics, comorbidities, fixation and complications. Follow-up data was collected to at least two-years from the time surgery.

Results

1448 ankle fractures which involved fixation of the fibula were recorded; one-third tubular plate was used in 866 (59.8%) cases, a locking plate in 463 (32.0%) cases and other methods in 119 (8.2%) cases. There was significant difference between centres (p<0.001) in implant type used. Other factors associated with implant type were age, diabetes, osteoporosis, open fractures, fracture pattern and the presence of comminution. Incidence of lateral wound breakdown was higher in locking plates than one-third tubular plates (p<0.05). There was no significant difference in infection, non-union, fixation failure or removal of metalware.

Conclusion

There is significant variation in practice in the UK in implant use for fixation of the fibula in ankle fractures. Potentially unnecessary use of locking plates, where a one-third tubular shows equivalent outcomes, incurs additional cost and may increase the risk of lateral wound breakdown. We would encourage surgeons with high locking plate usage to evaluate their own unit's practice against this data.
DELTOID LIGAMENT RECONSTRUCTION IN ANKLE FRACTURES: DOES IT PREVENT PES PLANUS?
Authors: Aamir J. , Huxley T. , Clarke M. , Dalal N. , Johnston A. , Rigkos D. , Kutty J. , Gunn C. , Condurache C. , McKeever D. , Gomaa A. , Mason L.
Published: June 2024

Introduction

Deltoid ligament reconstruction (DLR) is an important factor in the consideration of pes planus deformity. There is little evidence in the literature determining whether DLR could mitigate the risk of patients acquiring flat foot postoperatively following deltoid ligament injury.

Aim

Our objective was to establish if there was a difference in pes planus deformity in patients who underwent DLR during their ankle fracture fixation compared to those who did not.

Methods

A retrospective analysis of post-operative weight bearing radiographs was performed of patients who underwent ankle fracture fixation. Inclusion criteria were confirmed deltoid instability presurgery without medial malleolar fracture and post operative weightbearing radiographs at least 6 weeks post-fixation. Patients were categorised into no deltoid ligament reconstruction (nDLR) and having DLR. Radiographic pes planus parameters involved Meary's Angle assessment. Other fracture morphology was classified.

Results

A total 723 ankle fractures were screened. 122 patients were included for further analysis. There were 94 patients in the nDLR group and 28 patients in DLR group. The mean Meary's Angle was 15.81 (95% CI 14.06, 17.56) degrees in the nDLR group and −.2 (95% CI −3.86, 3.82) in the DLR group. This was statistically significant (p<.001). There was no significant difference in medial clear space measurements (2.90mm v 3.19mm, p = 0.145). There were significantly more pes planus patients in the nDLR than the DLR group (p<.001, 90.5% vs 25%).

Conclusion

In this study there was significantly greater pes planus parameters in patients not undergoing DLR. Patients undergoing DLR had on average normal parameters, whilst those not undergoing DLR had on average severe pes planus. The benefits of DLR are not only maintaining ankle stability but maintaining medial arch integrity, and this should be taken into account in a future study on DLR.