bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigational drugs services pharmacists education and workflow structure.
Authors: Ayoubi Doaa 
Published: August 2023

169 Background: Per NIH U.S. National Library of Medicine, 428,103 research studies are registered globally as of September 19th, 2022. Each institution must assess its institutional readiness as the complexity and volume of clinical trial increases. Institutional readiness helps assess the capacity of an institution to adopt new technologies and policies to accept, activate, and adjust research despite the complexity of the clinical trial. Clinical research pharmacists help improve the safety and quality of the research by reviewing the scientific literature and medication-related information to develop protocols and evaluate clinical trial feasibility as part of the scientific review committee while performing supportive pharmaceutical review of the protocol, preparation, storage, dispensing, and consulting clinical coordinators and sponsors on the logistics of the trial. Investigational drug service (IDS) also oversees institutional compliance with Good Clinical Practices (GCPs) and Good Manufacturing Practices (GMPs), FDA regulations, and laws. Lack of training for pharmacists, poor safety and quality control, lack of resources, and unstandardized approach to the management of investigational drug products can lead to discrepancy, delay in care, and ultimately, harm to the patient. This study will address the deficiency of institutional readiness to conduct clinical trials with investigational agents and introduce policies and procedures needed to be followed by pharmacists or pharmacy technicians to conduct research. Methods: To explore the challenges in clinical trials and compare work efficiency, work productivity, and growth in the investigational drug service (IDS) pharmacy. This study is conducted at a single-health system compromised of 7 satellite investigational pharmacy from June 2021 to August 2022. Interventions include Epic/Beacon training, CITI training, annual compounding competencies, protocol and procedure development, and Vestigo implementation. Data for inclusion was identified from (where Dr. Ayoubi got data from) were extracted and analyzed. Results: 71% decrease in # of protocols on the priority list to amend protocols. Informatics pharmacists build 190 protocols in one year. Revenue has doubled in one year. Productivity increased as time to verify is reduced by 9.43 minutes to verify an order and time to dispense is reduced by 31.3 min. Number of clinical trials designated to each pharmacist increased from 3-4 to 20 productions per month. Number of investigational drugs ordered increased by 89 last year. Conclusions: Education and Training remain one of the main set back to clinical trials growth, and proper training and education are the pillars to conducting clinical trials in a safe manner and promote growth.
The efficacy of boron neutron capture therapy with folate receptor targeted novel boron carrier in F98 rat brain tumor models.
Authors: Tsujino Kohei , Kawabata Shinji , Kashiwagi Hideki , Kayama Ryo , Fujikawa Yoshiki , Fukuo Yusuke , Hiramastu Ryo , Takami Toshihiro , Miyatake Shin-Ichi , Hu Naonori , Takata Takushi , Tanaka Hiroki , Suzuki Minoru , Nishimura Kai , Nakamura Hiroyuki , Wanibuchi Masahiko 
Published: August 2023

21 Background: Boron neutron capture therapy (BNCT) is a particle therapy that can be targeted at the cellular level. The most commonly used boron carrier in clinical BNCT is boronophenylalanine (BPA), which is taken up into the tumor cell via L type amino acid transporter (LAT-1). The development of new boron carrier is an important issue, because BNCT using BPA is sometimes ineffective. Focusing on folate receptors that are highly expressed in malignant gliomas, PBC-IP which contained the pteroyl group was developed. The efficacy of BNCT with this drug was evaluated. The efficacy of BNCT using PBC-IP in the F98 rat brain tumor model has been evaluated. Methods: F98 rat glioma cells were used in the in vitro cellular uptake experiment.F98 rat glioma cells were exposed to BPA, sodium borocaptate (BSH), and PBC-IP. F98 rat brain tumor models were used in biodistribution experiment and neutron irradiation experiment. PBC-IP was administered by Convection enhanced delivery (CED). Results: In vitro cellular uptake experiment showed the boron concentration of PBC-IP was much higher than that of BPA and BSH. In vivo biodistribution experiment showed that boron concentration in the tumor using PBC-IP CED was the highest at 3 hours after the termination of 24 h administration. In the in vivo neutron irradiation experiment, significantly difference was observed between BNCT BPA group and combination BNCT (BPA + PBC-IP) group. In addition, long time survivors were observed in BNCT using PBC-IP groups, which were not observed in BNCT BPA groups. Conclusions: This study showed that PBC-IP in combination with BPA may provide the multi-targeted neutron capture therapy, this is because the mechanism of tumor accumulation of PBC-IP is different from that of BPA. In addition, therapeutic strategies targeting folate receptors may be useful, and further research is warranted.
The role of WTX212, an erythrocyte-anti-PD1 antibody conjugate, in anti-tumor activities in tumor models and cancer patients with acquired resistance to immunotherapy.
Authors: Nie Xiaoqian , Liu Yuehua , Xiaofei Gao , Zhang Qi , Xu Li , Huang Yanjie , Yuan Yang , Zheng Jiawei 
Published: August 2023

29 Background: Despite the success of immune-checkpoint blockade (ICB) treatments, a considerable proportion of patients cannot benefit from ICB therapy due to acquired resistance. Recent studies have revealed that successful immunotherapy drives new immune responses arising from peripheral immune system instead of reinvigorating the pre-existing responses in the tumor. Here we designed WTX212, autologous engineered red blood cells (RBCs) conjugated with anti-PD1 antibodies capable of activating the peripheral immune system. We also evaluated its anti-cancer activities in anti-PD1 non-responsive tumor models and a first-in-human (FIH) trial. Methods: The anti-tumor efficacy of WTX212 was evaluated in both PD1 responsive (MC38 colorectal cancer) and non-responsive (KP lung cancer and pB3 breast cancer) mouse tumor models (n=7 / group). Mice were monitored twice a week for clinical signs and tumor sizes. The mechanism of action was investigated in splenectomized mice and by analyzing the biodistribution of WTX212 using a radiolabeling method. The immune landscape was also profiled through cytof mass and scRNA-seq analyses in the spleen, tumor and peripheral blood. The FIH trial (NCT05707325) explores safety, pharmacokinetics and mechanism in cancer patients with acquired resistance to ICB. WTX212 was manufactured by covalently engineering anti-PD1 antibody with RBCs isolated from patients. By 11th April 2023, 3 patients have been enrolled and received at least one dose of WTX212 (20*1010 cells, IV, Q3W). Results: Treatment of WTX212 significantly suppressed tumor growth up to 100% in anti-PD1 responsive and non-responsive tumor models. Unlike antibodies, WTX212 primarily distributed to the spleen and vascular system. The anti-tumor effect of WTX212 was abrogated in corresponding splenectomized mice. Compared to anti-PD1 antibody, single-cell analysis identified the immune landscape remodeling in the spleen from WTX212-treated mice, with down-regulation of PD-L1+ myeloid-derived suppressor cells (MDSCs) and up-regulation of effector CD8+ T cells. In the FIH trial, 3 patients have been administered with total thirteen cycles of WTX212. No treatment-related AEs greater than Grade 2 were observed. WTX212 remained in the peripheral blood day 21 post transfusion. WTX212 rapidly activates peripheral immune systems with decreased MDSCs, Tregs and increased effector T cells in peripheral blood from all patients. The first patient who received six cycles of WTX212 treatment demonstrated stable disease with a 20% reduction at the target lesion. Conclusions: WTX212 demonstrated anti-tumor activities by activating the peripheral immune system to overcome resistance to immunotherapy in both preclinical models and human patients. WTX212 is well-tolerated supporting the future clinical trials. Clinical trial information: NCT05707325 .
Serum-based parameters as distinctive predictive biomarkers in patients with hepatocellular carcinoma undergoing curative radiation therapy.
Authors: Lee Dong-Soo 
Published: August 2023

48 Background: The aim of this study was to investigate whether serum immune and inflammatory parameters can help to predict the clinical outcomes in patients with unresectable hepatocellular carcinoma (HCC) undergoing curative radiation therapy (RT). Methods: A total of 76 RT courses among 71 patients between January 2014 and April 2019 were analyzed. The following variables were included in the analysis: systemic inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), absolute lymphocyte count, lymphocyte-to-monocyte ratio (LMR), albumin, albumin-to-alkaline phosphatase ratio, RT-related parameters, and levels of total protein, hemoglobin, α- fetoprotein, PIVKA-II, and C-reactive protein. Overall survival (OS), local control (LC), distant control (DC), and intrahepatic control (IHC) rates were calculated using the Kaplan-Meier method, and graphs were compared using the log-rank test. The multivariate Cox model was used to identify independent prognostic factors. The optimal cutoff values for survival separation were decided using the maximal chi-square test. Results: The mean age was 61.4 years, and most patients were men (n = 62, 81.6%). Most of the study population underwent pre-RT TACE/HAIC (n = 74, 97.4%). The median RT fraction number, fractional doses, and biologically equivalent doses by α/β=10 were 12 (range, 4–30), 5 (range, 2–12) Gy and 72.6 (range, 51.5–119) Gy, respectively. With a median follow-up of 12 (range, 3.1–56.7) months, the 1-year OS, LC, DC, and IHC rates were 55.2%, 88.2%, 64.4%, and 50.5%, respectively. In the multivariate analysis, significant independent prognostic indicators were the lowest posttreatment PNI for OS ( P < 0.001), lowest pretreatment LMR for LC ( P = 0.03), and highest posttreatment PLR for DC ( P = 0.006). Conclusions: Distinct serum-based parameters predicted OS, LC, and DC rates. Future research is necessary to confirm our findings.
Impact of pathological response and recurrence pattern on the survival of patients who develop recurrence from neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma (ESCC).
Authors: Chuang Chien Huai , Guo Jhe-Cyuan , Huang Ta-Chen , Wu Tsung-Che , Hsu Chih-Hung 
Published: August 2023

49 Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is one of indicated strategies for locally advanced ESCC. Pathological complete response (pCR) is a well-known favorable prognostic factor. However, whether pCR to nCRT impacts on the post-progression survival (PPS) is not well described before. Methods: We reviewed medical records of four studies evaluating nCRT for locally advanced ESCC between 2000 and 2015 at National Taiwan University Hospital (NCT00154804, NCT01034189, NCT01034332). CRT comprised twice weekly paclitaxel and cisplatin-based regimens and 40Gy radiotherapy in 20 fractions; esophagectomy with lymph node dissection was performed 6 to 8 weeks after completing nCRT. We analyzed the recurrence patterns and PPS between pCR and non-pCR groups. Results: Among 158 patients (pts) receiving nCRT followed by surgery, 85 pts developed recurrence (recurrence rate [RR], 53.8%) with a median follow-up of 110.2 months (mo). Among pts with recurrence, 19 were from pCR group (RR, 33.3%), and 66 from non-pCR group (RR, 65.3%). The median time to recurrence (TTR) were 12.6 and 8.5 mo for pCR and non-pCR group. The patterns of recurrence were summarized in the table. The median PPS in pCR and non-pCR group were 7.9 and 5.3 mo. In pCR group, the median PPS was similar despite different patterns of recurrence. In contrast, the median PPS of non-pCR group was numerically longer in pts with isolated locoregional recurrence and shortest in those with any distant recurrence (10.0 and 4.8 mo). Pts with recurrence more than 12 mo after surgery exhibited longer PPS than those within 12 mo in both groups. Overall, the median PPS of pts of different recurrence pattern or TTR did not differ significantly between two groups. Conclusions: The recurrence patterns may be different in pCR and non-pCR groups. Patients with early recurrence faced a poor prognosis irrespective of pathologic response. Whether pCR status and recurrence impact on PPS in pts receiving nCRT warrants additional studies.[Table: see text]
CRISPincette, and detection of low frequency cancer mutations in ctDNA.
Authors: Kim Jin-Soo , Won Yoon-Ho , Kang ShinJae , Park Taegun , Lee In Seon , Choi Hyun-jeung , Rhee JaeWon , Kim Mi Young , Hur Junseok W , Ye Sunghyeok 
Published: August 2023

61 Background: Liquid biopsy has emerged as a non-invasive and widely applicable approach in clinical practice for cancer detection and monitoring. Detecting low-frequency mutations in circulating tumor DNA (ctDNA) is crucial for the success of liquid biopsy; however, technical limitations have hindered the detection of low variant allele frequency (VAF) mutations. To address this issue, we developed CRISPincette, a novel method which combines next-generation sequencing with an advanced CRISPR system, GeneCker-Cas9. Methods: CRISPincette was designed to efficiently detect mutant alleles by eliminating abundant wild-type alleles from normal cell-induced cell-free DNA (cfDNA) using CRISPR/Cas9. An engineered CRISPR/Cas9 variant, GeneCker-Cas9, was developed to maintain single-base precision outside the PAM region, enabling efficient discrimination of single-base mutations at all 20 positions within a single guide RNA target sequence. This advanced fidelity significantly improved the accuracy compared to high-specificity SpCas9 variants (SpCas9-HF and eSpCas9). To validate the sensitivity and accuracy of ctDNA detection using CRISPincette, we employed NGS standard materials (Horizon HD776, 778, 779) and assessed the improvement in ctDNA detection sensitivity for EGFR gene mutations (EGFR 19del, EGFR L858R, EGFR T790M). Subsequently, we analyzed the clinical applicability of CRISPincette using plasma samples from 7 non-small cell lung cancer (NSCLC) patients (6 patients with EGFR mutations and 1 patient without EGFR mutations). Results: Our analysis showed an approximately 10 to 30-fold enhancement in the detection sensitivity of EGFR gene mutations. Concordant detection of EGFR mutations was observed in the 6 patients with EGFR mutations using real-time PCR tests in each tissue biopsy, and no EGFR mutation was detected in the patient without the EGFR mutation. This confirmed CRISPincette's high accuracy and sensitivity in detecting low-frequency mutations in ctDNA. Conclusions: The implementation of CRISPincette has significantly improved the accuracy and sensitivity of liquid biopsy, making it a reliable and non-invasive alternative for confirming molecular pathological information in cancer patients. Furthermore, the high accuracy of CRISPincette will be a powerful tool for monitoring treatment and prognosis through the timing of anticancer drug administration. Overall, CRISPincette represents a substantial advancement in liquid biopsy technology, with potential implications for cancer diagnosis, treatment allocation, and monitoring the emergence of resistance.
Dosimetric feasibility of dose-painting radiotherapy for targeting hypoxia in prostate cancer on a novel ring gantry radiotherapy system.
Authors: Feghali Karine , Perennec Tanguy , Oderinde Oluwaseyi M. , Maniyedath Arjun , Moignier Alexandra , Rousseau Caroline , Ferrer Ludovic , Delpon Gregory , Hatt Matthieu , Seroux Yves , Doré Melanie , Supiot Stephane 
Published: August 2023

73 Background: This study aimed at demonstrating the dosimetric feasibility of tumoral and hypoxia-guided dose escalated radiation therapy in prostate cancer on a novel ring gantry system TPS, based on conventionally fractionated and hypofractionated regimens. Methods: Three patients who underwent external-beam RT for intermediate-risk prostate cancer in the PAIR prostate study and had pre-therapeutic F-MISO PET uptake in the tumor, were selected. The GTV and the hypoxic region (biological tumor volume [BTV]) within the PTV on F-MISO PET uptake were delineated. IMRT planning based on three different prescriptions was performed: 1) Standard fractionation (SF)- 77Gy/35 fractions (fx) to PTV, with a boost to 95Gy and 118Gy in 35 fx to the GTV and to the hypoxic region defined by F-MISO PET, respectively, 2) moderate hypofractionation (MH)- 60 Gy/20 fx with a boost to 67Gy and 91Gy in 20 fx to the GTV and to the hypoxic region, respectively, and 3) high hypofractionation (HH)- 40 Gy/5 fx with a boost to 50Gy in 5 fx to the GTV and as high as possible to the hypoxic region (SBRT). Planning was performed on the research version of the RefleXion treatment planning system (X1-TPS). Results: The average size of the GTV and BTV was 6.03±2.05 cc, and 1.90±1.64 cc, respectively. For the SF regimen, the average D98% and D2% to the PTV, GTV and BTV were 71.33±0.15 Gy and 110.43±8.57 Gy; 91.43±1.12 Gy and 108.53± 10.29 Gy; and 112.33±3.54 Gy, and 121.37±1.31 Gy, respectively. For the MH and HH techniques, the average D98% to the PTV was 56.13±0.51 Gy, and 37.03± 1.81 Gy, and the average D2% was 85.53±8.52 Gy, and 58.47±1.90 Gy. In addition, the average D98%, and D2% to the GTV was 65.67±0.15 Gy, and 80.27±10.20 Gy using the MH treatment technique, while the average D98%, and D2% to the BTV was 85.87±5.00 Gy, and 94.9±1.15 Gy, respectively. Also, for the HH treatment planning method, the average D98%, and D2% to the GTV was 50.33±3.79 Gy, and 57.23±4.75 Gy, while the average D98%, and D2% to the BTV was 54.57±3.67 Gy and 61.00±2.17 Gy, respectively. The average D50% of Bladder, Rectum, and Femoral heads was 12.28±11.39 Gy, 26.09±5.89 Gy, and 11.44±2.92 Gy, while the average V15Gy was 43.07±18.68%, 72.39±8.81 %, and 23.43±20.44%, respectively. Conclusions: This study showed the dosimetric feasibility of dose-escalating the tumor and the hypoxic region in patients with prostate cancer on the RefleXion X1 TPS without compromising the OARs dose limits.
Diagnostic performance of a novel radiomic model for predicting post-treatment prostate cancer recurrence: A comparison to CAPRA and MSKCC nomograms.
Authors: Huynh Linda My , Taylor Olivia , Marasco Jacob , Wang Shuo , Baine Michael 
Published: August 2023

76 Background: mpMRI-derived radiomic features have been shown to capture sub-visual patterns for quantitative characterization of tumor phenotype. We seek to compare the diagnostic performance of a mpMRI-based radiomic model to currently available nomograms for prediction of post-radical prostatectomy (RP) biochemical recurrence (BCR). Methods: mpMRI was obtained from 76 patients who had underwent RP for treatment of localized PCa. All patients had ≥2 years follow-up and those with neo-adjuvant or adjuvant treatment were excluded. Radiomic analysis and cross-validation of mpMRI features yielded features significantly correlated with BCR, defined as two consecutive serum PSA≥0.2ng/ml. These features were aggregated to construct a radiomic model, which was compared to the risk scores generated by inputting patients’ clinicodemographic features into the USCF Cancer of the Prostate Risk Assessment (UCSF-CAPRA) score and Memorial Sloan Kettering Cancer Center (MSKCC) Pre-Radical Prostatectomy nomogram. The performance of each model was compared utilizing receiver-operator curve (ROC) analysis and area under the curve (AUC) was reported. Results: In feature extraction and ranking, six radiomic features were determined to be important and non-redundant in predicting PCa recurrence (least material condition, gray-level non-uniformity, shape-elongation, shape-sphericity, first-order skewness). These features were aggregated into the radiomic model and repeated five-fold cross validation yielded a model with AUC of 0.95±0.06, 33% sensitivity, and 100% specificity. UCSF-CAPRA and MSKCC nomograms yielded AUC of 0.72±0.07 and 0.82±0.07, respectively. Conclusions: The mpMRI-derived radiomic model performed well when compared to the UCSF-CAPRA score and MSKCC Pre-Radical Prostatectomy nomogram. Future projects will incorporate patient demographics and disease characteristics available at the time of initial PCa diagnosis to improve the radiomic model accuracy.
A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane
Authors: Wills Rachel C. , Doyle Colleen P. , Zewe James P. , Pacheco Jonathan , Hansen Scott D. , Hammond Gerald R. V. 
Published: August 2023

ABSTRACT
The lipid molecule phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] controls all aspects of plasma membrane (PM) function in animal cells, from its selective permeability to the attachment of the cytoskeleton. Although disruption of PI(4,5)P2 is associated with a wide range of diseases, it remains unclear how cells sense and maintain PI(4,5)P2 levels to support various cell functions. Here, we show that the PIP4K family of enzymes, which synthesize PI(4,5)P2 via a minor pathway, also function as sensors of tonic PI(4,5)P2 levels. PIP4Ks are recruited to the PM by elevated PI(4,5)P2 levels, where they inhibit the major PI(4,5)P2-synthesizing PIP5Ks. Perturbation of this simple homeostatic mechanism reveals differential sensitivity of PI(4,5)P2-dependent signaling to elevated PI(4,5)P2 levels. These findings reveal that a subset of PI(4,5)P2-driven functions might drive disease associated with disrupted PI(4,5)P2 homeostasis.
An Easy Method of obtaining Methaemoglobin Crystals for Microscopic Examination
Authors: Halliburton W. D. 
Published: August 2023

ABSTRACT
Methæmoglobin is a derivative of the red colouring matter of the blood, concerning which a number of theories have been held. According to Sorby,1 it is more highly oxygenated than oxyhaemoglobin; that is, it is a per-oxyhæmoglobin. Hoppe-Seyler,3 on the other hand, regards it as a sub-oxyhæmoglobin, as it can be obtained under conditions which remove at least part of the oxygen of oxyhaemoglobin. According to both these views, however, the oxygen is regarded as being more firmly combined with the haemoglobin than in the case of oxyhæmoglobin.
Note on the Blood-Corpuscles of the Two-Toed Sloth, Cholœpus Didactylus
Authors: Rolleston Professor 
Published: August 2023

ABSTRACT
MR. H. N. Moseley, of Exeter College, called my attention a few days ago to the appearance of nucleation which a slide of the dried blood-corpuscles of the Two-toed Sloth, Cholœpus didactylus, presented under a quarter-of-an-inch object-glass of Powell and Lealand’s. I had a short time before met with a statement in the recently published second part of Dr. Kühne’s ‘Lehrbuch der Physiologischen Chemie,’ p. 195,‡ to the effect that only some mammals, the sloth and the camel, possessed nucleated blood-corpuscles. And this coincidence determined me to use such means as we had at our disposal for settling a point as to which all recent authorities were, as far as my knowledge went, opposed to Dr. Kühne.
On-demand Triplet-sensitized Photoswitching of Arylazopyrazoles
Authors: Morikawa Masa-aki , Mizuno Miko , Harada Naoyuki , Kimizuka Nobuo 
Published: August 2023

Abstract
Triplet-sensitized Z-to-E photoisomerization of arylazopyrazole derivatives was achieved with red-light excitation of Pd(II) meso-tetraphenyltetrabenzoporphyrin (PdTPTBP) in deaerated DMSO solution. The triplet energy gap between the sensitizer and the arylazopyrazoles affects the apparent rate of Z-to-E photoisomerization. On-demand photoswitching of arylazopyrazoles proceeds facilely and reversibly with almost 100% efficiency despite the endothermic triplet energy transfer processes.