bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Claudin-1 overexpression with immune exclusion in nasopharyngeal carcinoma and its potential as a novel therapeutic target.
Authors: Yeo Eugenia Li Ling , Ong Enya , Neo Jialing , Chow Wen Min , Tan Kah Min , Tan Janice Ser Huey , Yeong Joe Poh Sheng , Lim Tony Kiat Hon , Hwang Jacqueline Siok Gek , Ng Quan Sing , Soong Yoke Lim , Ang Mei-Kim , Tan Sze Huey , Chua Melvin Lee Kiang , Lim Darren Wan-Teck
Published: August 2023

151

Background: Claudin-1 (CLDN1) is a tight junction protein overexpressed in several cancers, where it is involved in the tumor microenvironment remodeling and stiffening of the tumor-stroma interface. This potentially prevents penetration of tumor infiltrating immune cells, in turn hindering the efficacy of immune checkpoint inhibitors (ICI). Given recent evidence supporting ICI efficacy in nasopharyngeal carcinoma (NPC), we investigated whether CLDN1 is overexpressed in NPC and its association with the tumor immune microenvironment (TME). Methods: 131 NPC patients treated at a single institution were prospectively recruited. TME profiling was performed using deconvolutional methods (CIBERSORT, quanTIseq) on tumor transcriptomes to estimate proportions of immune cell subsets, and expression of immune-related genes and pathways. Transcriptome profiling was performed on tumors with >70% cellularity and normal controls using Illumina Truseq (CA). We stratified tumors by their median CLDN1 expression and compared the immune profile of CLDN1high versus CLDN1low tumors. Cox regression model was used to analyze disease-free survival (DFS) as the primary clinical endpoint. Results: We observed CLDN1 overexpression in NPC versus normal tissues ( P=0.0046) that was independent of known prognostic clinical parameters e.g., TNM-stage and EBV DNA levels. Consistent with our hypothesis, CLDN1 expression was negatively correlated with total immune cell fraction in the tumor ( P<0.001). We observed reduced abundance of most immune subsets in CLDN1high tumors, notably CD8 T cells ( P<0.001), activated CD4 memory T cells ( P<0.001), and M1 and M2 macrophages ( P=0.048 and P<0.001). There was an overall downregulation of both stimulatory and suppressive GO immune-related gene-sets and genes in CLDN1high versus CLDN1low tumors, thereby corroborating our preceding observation of reduced immune infiltration in the TME in CLDN1 overexpressing NPC. Our findings were validated in a published dataset of 113 NPC tumors (Zhang et al., 2017). Of clinical relevance, reduced immune infiltration in the TME was prognostic for DFS; HR of CLDN1high, CD8 T celllow (stratified by median) NPC was 2.1 (95% CI:0.9-5.0) when compared with CLDN1low, CD8 T cellhigh NPC. Conclusions: Here, we report the overexpression of CLDN1 in NPC that is ubiquitous across disease stages and associated with an immune-low TME. This influence on the TME is associated with an inferior outcome of NPC patients. Given the role of the tumor TME in ICI response, our findings provide a rationale for future trials investigating combination of CLDN1 targeting with ICI to reverse this immune exclusion effect, potentially leading to improved outcomes.
Characteristics and prognosis of adolescent and young adult breast cancer.
Authors: Tokumaru Yoshihisa , Okawa Mai , Ando Saki , Niwa Yoshimi , Mori Ryutaro , Matsuhashi Nobuhisa , Futamura Manabu
Published: August 2023

16

Background: Adolescent and young adult (AYA)-generation breast cancer has characteristics of high clinicopathological malignancy and poor prognosis compared to cancers of other age groups. In recent advances in cancer research, the tumor microenvironment is involved in cancer invasion. In this study, we investigated the biology of AYA-generation breast cancer and the prognostic effects of the cancer microenvironment in breast cancer patients. Methods: In the current study, we analyzed 2042 breast cancer patients with clinical and intratumoral gene expression data from the open public databases TCGA and METABRIC. Patients aged 15-39 were defined as AYA-generation breast cancer, and patients aged 40-65 as middle-aged breast cancer. Tumor biology and cancer microenvironment were assessed using gene set enrichment analysis (GSEA) and the xCell algorithm. Disease-specific survival (DSS) and disease-free survival (DFS) were used to evaluate the prognosis of AYA-generation breast cancer compared to that of middle-aged and elderly breast cancer. Results: In METABRIC, the proportion of advanced stages was higher in AYA generation breast cancer than in middle-aged and elderly breast cancer (p<0.01). However, this was not the case with TCGA cohort. In the prognostic analysis, AYA-generation breast cancer showed shortened DSS and DFS compared with middle-aged breast cancer only in METABRIC. To clarify the association between prognosis and cancer biology, we performed GSEA. AYA-generation breast cancer enriched cell proliferation-related gene sets such as E2F Targets, G2M Checkpoints, and MYC Targets V1 in METABRIC. The analysis of TCGA also confirmed this result. Interestingly, the infiltration of macrophage M1 (p<0.001) and helper T cell Th1 (p=0.007), which act as tumor suppressors, was significantly higher in AYA generation breast cancer in METABRIC cohort. In TCGA, there was only a tendency for Th1 infiltration to be high in AYA generation breast cancer. Conclusions: AYA-generation breast cancer enriched gene sets associated with cell proliferation which might explain the worse prognosis of AYA-generation breast cancer.
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.
Inhibiting the Glucocorticoid Receptor to Enhance Chemotherapy Response
Authors: Prekovic Stefan , Zwart Wilbert
Published: August 2023

Explaining the biology of how glucocorticoid receptor blockade boosts chemotherapy in ovarian cancer.
Novel Adjuvant Targeted Approach for PTEN-Mutated Choroid Plexus Carcinoma in Adults: Case Report and Literature Review
Authors: Zhang Jackie J. , Rodriguez Quintero Juan C. , Nahm Joshua K. , Bhattacharjee Meenakshi B. , Nunez Luis C. , Riascos Roy F. , Blanco Angel I. , Day Arthur L. , Zhu Jay-Jiguang
Published: August 2023

53-year-old female, with CPC and PTEN mutation by NGS, was successfully treated with everolimus and brain radiation
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

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

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

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

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.
Η επίδραση δυνητικά τροποποιήσιμων επιβαρυντικών παραγόντων στην έκβαση της κύησης σε πληθυσμό της Κεντρικής Μακεδονίας
Authors: Αποστολοπούλου Αικατερίνη
Published: August 2023

Η συγκεκριμένη έρευνα αποτελεί μία τυχαιοποιημένη κλινική μελέτη που είχε ως στόχο να αξιολογήσει τις διατροφικές συνήθειες των εγκύων στην περιοχή της Κεντρικής Μακεδονίας και να εξετάσει τη συσχέτισή τους με μαιευτικές επιπλοκές, καθώς και επιπλοκές υγείας της μητέρας και του νεογνού. Η μελέτη περιλάμβανε 1100 έγκυες γυναίκες που προσήλθαν για τακτικό έλεγχο στο πρώτο τρίμηνο της κύησης. Χορηγήθηκαν ερωτηματολόγια κατανάλωσης διατροφικής πρόσληψης και καταγραφής του επιπέδου άσκησης πριν από την εγκυμοσύνη. Στη συνέχεια, οι συμμετέχουσες κατανεμήθηκαν με τυχαίο τρόπο στην ομάδα παρέμβασης είτε στην ομάδα ελέγχου. Η ομάδα παρέμβασης έλαβε διατροφικές συστάσεις και συμβουλές, ενώ η ομάδα ελέγχου όχι. Η επάρκεια της κατανάλωσης μακροθρεπτικών και μικροθρεπτικών συστατικών αξιολογήθηκε με βάση καθιερωμένες συστάσεις. Παρατηρήθηκε ανεπάρκεια στην κατανάλωση βασικών θρεπτικών συστατικών πριν από την εγκυμοσύνη, όπως το φολικό οξύ, η βιοτίνη και το ιώδιο, και αποκλίσεις από τη συνιστώμενη κατανάλωση μακροθρεπτικών συστατικών. Η ομάδα παρέμβασης έδειξε αυξημένη κατανάλωση ιωδίου, φολικού οξέος και πολυακόρεστων λιπαρών οξέων κατά τη διάρκεια της εγκυμοσύνης, ενώ η κατανάλωση κορεσμένων λιπαρών ήταν υψηλότερη στην ομάδα παρέμβασης και η κατανάλωση βιταμίνης D υψηλότερη στην ομάδα ελέγχου. Καταγράφηκε ο επιπολασμός σακχαρώδους διαβήτη κύησης, νεογνών μικρών για την ηλικία κύησης, πρόωρων τοκετών και καισαρικής τομής. Δεν παρατηρήθηκαν σημαντικές διαφορές στην εμφάνιση περιγεννητικών επιπλοκών μεταξύ των ομάδων παρέμβασης και ελέγχου. Η πολυπαραγοντική ανάλυση αποκάλυψε συσχετίσεις μεταξύ της κατανάλωσης θρεπτικών συστατικών και των επιπλοκών όπως ο διαβήτης κύησης, τα μικρά νεογνά για την ηλικία της κύησης και ο τοκετός με καισαρική τομή. Ενώ η παρέμβαση βελτίωσε την ποιότητα της διατροφής, δεν επηρέασε τα ποσοστάπεριγεννητικών επιπλοκών σε σύγκριση με την ομάδα ελέγχου. Η μελέτη τονίζει την ανάγκη για περαιτέρω έρευνα σε αυτόν τον τομέα για την παροχή καλύτερης καθοδήγησης για τις έγκυες γυναίκες.
Researching the teaching of the transversal skill of problem-solving within an English for specific and academic purposes (ESP/EAP) context
Authors: Ξύδης Δημήτριος
Published: August 2023

Ο κύριος στόχος της παρούσας διατριβής είναι να διερευνήσει την ένταξη της ‘εγκάρσιας’ δεξιότητας της επίλυσης προβλημάτων στα πλαίσια της διδασκαλίας των Αγγλικών σε ένα ελληνικό Πανεπιστημιακό τμήμα Logistics (τον τρόπο δηλαδή διδάσκεται από τους καθηγητές των ειδικών μαθημάτων της Διοίκησης των Συστημάτων Εφοδιασμού και βιώνεται από τους φοιτητές), σε συνδυασμό με έρευνα της φύσης της εφαρμογής αυτής της ικανότητας στον σχετικό εργασιακό χώρο, με στόχο την εξαγωγή συμπερασμάτων σχετικά με την επιτυχή ενσωμάτωση αυτής της σημαντικής ‘ήπιας’ δεξιότητας στη διδασκαλία των Αγγλικών για Ειδικούς και Ακαδημαϊκούς Σκοπούς (ESP/EAP), δηλαδή στη διδασκαλία των Αγγλικών για τη Διοίκηση Εφοδιαστικής Αλυσίδας, (κλάδος της διδασκαλίας των Επιχειρηματικών Αγγλικών), εμπλουτίζοντας συγκεκριμένα τον σχετικό σχεδιασμό μαθημάτων Αγγλικών για Ειδικούς και Ακαδημαϊκούς Σκοπούς με αυθεντικό υλικό διδασκαλίας στα πλαίσια συγκεκριμένων και ανάλογων (προσαρμοσμένων στο συγκεκριμένο εκπαιδευτικό περιβάλλον) μεθόδων διδασκαλίας, για την ομαλή μετάβαση των φοιτητών από το περιβάλλον της τριτοβάθμιας εκπαίδευσης στον επαγγελματικό χώρο που έχουν θέσει ως στόχο τους, και την μετέπειτα ενήλικη ζωή τους γενικότερα.
Rapid, Economic, Acetic acid, Papanicolaou (REAP) staining technique analogous to the routine Papanicolaou staining (PAP) technique
Authors: Alone Prachi , Vodithala Sahitya , Vagha Sunita
Published: August 2023

The current research compared classical Papanicolaou stain with REAP (Rapid, Economic, Acetic Acid Papanicolaou) stain to evaluate staining character, range, charge virtue, and sustaining of stain. The PAP Stain is the standard dye in support of shielding cell study for any cell study and is used in various research centers with several reductions. In certainty, PAP Stain has lowered squamous cell carcinoma incidence by 70%, particularly within wealthy provinces with effectively-designed broadcasting systems. But the stain has gone through several changes, moving from the uncreative formal mechanism -> gradual REAP PAP staining in which staining duration level is decreased, it improves the quality, it is cost-effective, easily available, and ethyl alcohol is temporarily superseded with 1% ethanoic acid in advanced nations with guarding programs with careful planning. It has been used to access FNAC (fine needle aspiration cytology). Because of its precise nuclear and nucleoli staining, PAP staining of FNAC and fluid smears is a trustworthy stain. FNAC is a straightforward, speedy, and reliable pre-operative assessment and diagnosis process that has sparked advancements in dyeing technology which utilizes minimal coloring count with a clear cell framework. Around 40 minutes are needed for the standard methodology for traditional PAP Stain. REAP Stain was developed to address this, improving quality while cutting staining time to about one minute. This study's objective was to evaluate the value of the Rapid-Pap stain utilizing quantifiable investigation. The effectiveness of cytoplasmic and nuclear staining, stain preservation, value, and overall course of action for the two techniques—conventional PAP stain and REAP stain—were collated. When compared to traditional Papanicolaou, REAP stain offers a good, quick, and affordable replacement for the screening of cells. The REAP technique also does a superb job for the maintenance of stains.
Targeting for Long-Term Outcomes
Authors: Yang Jeremy , Eckles Dean , Dhillon Paramveer , Aral Sinan
Published: August 2023

Decision makers often want to target interventions so as to maximize an outcome that is observed only in the long term. This typically requires delaying decisions until the outcome is observed or relying on simple short-term proxies for the long-term outcome. Here, we build on the statistical surrogacy and policy learning literatures to impute the missing long-term outcomes and then approximate the optimal targeting policy on the imputed outcomes via a doubly robust approach. We first show that conditions for the validity of average treatment effect estimation with imputed outcomes are also sufficient for valid policy evaluation and optimization; furthermore, these conditions can be somewhat relaxed for policy optimization. We apply our approach in two large-scale proactive churn management experiments at The Boston Globe by targeting optimal discounts to its digital subscribers with the aim of maximizing long-term revenue. Using the first experiment, we evaluate this approach empirically by comparing the policy learned using imputed outcomes with a policy learned on the ground-truth, long-term outcomes. The performance of these two policies is statistically indistinguishable, and we rule out large losses from relying on surrogates. Our approach also outperforms a policy learned on short-term proxies for the long-term outcome. In a second field experiment, we implement the optimal targeting policy with additional randomized exploration, which allows us to update the optimal policy for future subscribers. Over three years, our approach had a net-positive revenue impact in the range of $4–$5 million compared with the status quo.

This paper was accepted by Eric Anderson, marketing.

Funding: This work was supported by Boston Globe Media.

Supplemental Material: The online appendix and data are available at https://doi.org/10.1287/mnsc.2023.4881 .
The Importance of Advance Care Plans in the Care Home
Authors: Croft Joanne , Cobb Jade , Williams Jacqui
Published: August 2023

Through the use of case studies, this article explains the purpose and importance of the use of advance care plans in care homes and the potential consequences of not having an advance care plan in place regarding the care of individual residents. It explores reasons why they may not be completed or used effectively, and considers why the design of the advance care plan is important and needs to be specific for care home use.
Tiny Capsule to Aid Disease Diagnosis
Authors: Knight Helen
Published: August 2023

Sonopill will take ultrasound images and reduce need for painful surgery
Pulmonary Arterial Hypertension in Hyperthyroidism: Age, Ethnic, and Gender Disparities
Authors: Sacerdote Alan , Dave Paulomi , Inoue Taiga , Bahtiyar Gul , Peynado Heidi , Navarro Victor , Cohen Ronny , L’Eplattanier Mark , Fenteany Gabriel
Published: August 2023

Objective: Pulmonary arterial hypertension (PAH) affects 2.6% of adults and 36% of people with chronic obstructive pulmonary disease (COPD). Several case reports and small case series suggested a hyperthyroidism-PAH association.

Design: Retrospective chart review.

Methods: We undertook a retrospective chart review (1982–2018) to assess PAH prevalence in a multi-ethnic convenience sample of hyperthyroid adults with multiple etiologies. We calculated associations of pulmonary artery maximum systolic pressure (PSAPmax) with subject age, and maximum serum triiodothyronine (T3) and thyroxine (T4), free T3, and T4, minimum serum thyroid-stimulating hormone (TSH), and thyroid antibody titers, comparing PAH prevalence and the odds of being undiagnosed as to hyperthyroidism etiology by gender and ethnicity/race.

Results: We found a high prevalence of PAH in hyperthyroid people, like that reported for people with COPD. We found no significant association between PSAPmax and any thyroid function test or thyroid antibody titer. As reported more recently in the general population, PSAPmax significantly correlated with age in hyperthyroid people. There was no significant disparity in the prevalence of PAH among White, non-Hispanic Black, and Latinx hyperthyroid people or between genders. The percentage of patients whose hyperthyroidism etiology was undiagnosed was high with significant disparity only between non-Hispanic Black and White people and between men and women. PAH was common in hyperthyroid subjects with any hyperthyroidism etiology.

Conclusions: 2D-echocardiography should be performed in all hyperthyroid people because PAH is common, especially in older people because of their co-morbidities and poorer prognoses. Further research is needed regarding demographic disparities in being undiagnosed as to hyperthyroidism etiology.

Principal Verdicts/Significance Statement: We reconfirmed the high PAH incidence in hyperthyroidism, previously reported, but profoundly under-recognized by physicians, to patients’ detriment. Further, we found that the shift in the general PAH population from younger to older individuals is mirrored in hyperthyroid people with PAH. This is concerning because older people have more co-morbidities and worse prognoses, necessitating early, effective intervention. PAH was present with diverse hyperthyroidism etiologies, suggesting that it is multicausal, resulting from autoimmunity, thyroid hormone excess, and goitrous upper airway obstruction and should be considered, regardless of etiology. Our observations that many subjects had no established hyperthyroidism etiology and that males and Blacks were likelier to be undiagnosed are concerning, warranting further study.
A review of the genus Asyndetus Loew, 1869 (Diptera: Dolichopodidae) from Iran and neighbouring countries with the description of three new species
Authors: GRICHANOV IGOR YA. , GILASIAN EBRAHIM
Published: August 2023

Three new long-legged fly species, Asyndetus alborzensis sp. nov., A. persicus sp. nov. and A. karkhehensis sp. nov. from Iran are described and illustrated. Asyndetus alborzensis sp. nov. is remarkable in having matt-black frons and face; A. persicus sp. nov. is the third Palaearctic species with two ventral combs of long black bristles on male abdominal sternite 5; A. karkhehensis sp. nov. male is peculiar in distinctly broken apical part of wing vein M1+2; vein dm-m present, and hind tarsus with only one claw. Asyndetus longicornis collected from the Mangrove habitats (Asalouyeh, Bushehr province) is newly recorded from Iran. Asyndetus chaetifemoratus and A. separatus are excluded from the fauna of Iran. A check list and identification key to 19 Asyndetus species of Iran and neighbouring countries are compiled for the first time.
Changes in neurotransmitter levels, brain structural characteristics, and their correlation with PANSS scores in patients with first-episode schizophrenia
Authors: Xu Xian-Jia , Liu Tang-Long , He Liang , Pu Ben
Published: August 2023

In recent years, because of the growing desire to improve the noninvasiveness and safety of tumor treatments, sonodynamic therapy has gradually become a popular research topic. However, due to the complexity of the therapeutic process, the relevant mechanisms have not yet been fully elucidated. One of the widely accepted possibilities involves the effect of reactive oxygen species. In this review, the mechanism of reactive oxygen species production by sonodynamic therapy (SDT) and ways to enhance the sonodynamic production of reactive oxygen species are reviewed. Then, the clinical application and limitations of SDT are discussed. In conclusion, current research on sonodynamic therapy should focus on the development of sonosensitizers that efficiently produce active oxygen, exhibit biological safety, and promote the clinical transformation of sonodynamic therapy.
Standardization of apple cancellation test for neglect patients in Korea: An observational study
Authors: Jang Woo-Hyuk , Jang Jong-Sik
Published: August 2023

In recent years, because of the growing desire to improve the noninvasiveness and safety of tumor treatments, sonodynamic therapy has gradually become a popular research topic. However, due to the complexity of the therapeutic process, the relevant mechanisms have not yet been fully elucidated. One of the widely accepted possibilities involves the effect of reactive oxygen species. In this review, the mechanism of reactive oxygen species production by sonodynamic therapy (SDT) and ways to enhance the sonodynamic production of reactive oxygen species are reviewed. Then, the clinical application and limitations of SDT are discussed. In conclusion, current research on sonodynamic therapy should focus on the development of sonosensitizers that efficiently produce active oxygen, exhibit biological safety, and promote the clinical transformation of sonodynamic therapy.
Meta-analysis of outcomes from drug-eluting stent implantation in infrapopliteal arteries
Authors: Li Ming-Xuan , Tu Hai-Xia , Yin Meng-Chen
Published: August 2023

In recent years, because of the growing desire to improve the noninvasiveness and safety of tumor treatments, sonodynamic therapy has gradually become a popular research topic. However, due to the complexity of the therapeutic process, the relevant mechanisms have not yet been fully elucidated. One of the widely accepted possibilities involves the effect of reactive oxygen species. In this review, the mechanism of reactive oxygen species production by sonodynamic therapy (SDT) and ways to enhance the sonodynamic production of reactive oxygen species are reviewed. Then, the clinical application and limitations of SDT are discussed. In conclusion, current research on sonodynamic therapy should focus on the development of sonosensitizers that efficiently produce active oxygen, exhibit biological safety, and promote the clinical transformation of sonodynamic therapy.
Acute hepatitis of unknown etiology in an adult female: A case report
Authors: Dass Lucinda , Pacia Alexandra Marie Malabanan , Hamidi Mahgol
Published: August 2023

In recent years, because of the growing desire to improve the noninvasiveness and safety of tumor treatments, sonodynamic therapy has gradually become a popular research topic. However, due to the complexity of the therapeutic process, the relevant mechanisms have not yet been fully elucidated. One of the widely accepted possibilities involves the effect of reactive oxygen species. In this review, the mechanism of reactive oxygen species production by sonodynamic therapy (SDT) and ways to enhance the sonodynamic production of reactive oxygen species are reviewed. Then, the clinical application and limitations of SDT are discussed. In conclusion, current research on sonodynamic therapy should focus on the development of sonosensitizers that efficiently produce active oxygen, exhibit biological safety, and promote the clinical transformation of sonodynamic therapy.
Zimberelimab plus chemotherapy as the first-line treatment of malignant peritoneal mesothelioma: A case report and review of literature
Authors: Peng Xiao-Dong , You Zhen-Yu , He Lian-Xiang , Deng Qi
Published: August 2023

In recent years, because of the growing desire to improve the noninvasiveness and safety of tumor treatments, sonodynamic therapy has gradually become a popular research topic. However, due to the complexity of the therapeutic process, the relevant mechanisms have not yet been fully elucidated. One of the widely accepted possibilities involves the effect of reactive oxygen species. In this review, the mechanism of reactive oxygen species production by sonodynamic therapy (SDT) and ways to enhance the sonodynamic production of reactive oxygen species are reviewed. Then, the clinical application and limitations of SDT are discussed. In conclusion, current research on sonodynamic therapy should focus on the development of sonosensitizers that efficiently produce active oxygen, exhibit biological safety, and promote the clinical transformation of sonodynamic therapy.