bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of growth and contraction in human prostate stromal cells by silencing of NUAK1 and -2, and by the presumed NUAK inhibitors HTH01-015 and WZ4003
Authors: Liu Yuhan , Wang Ruixiao , Huang Ru , Rutz Beata , Ciotkowska Anna , Tamalunas Alexander , Hu Sheng , Trieb Moritz , Waidelich Raphaela , Strittmatter Frank , Stief Christian G. , Hennenberg Martin
Published: April 2023

Background: NUAKs promote myosin light chain phosphorlyation, actin organization, proliferation and suppression of cell death in non-muscle cells, which are critical for smooth muscle contraction and growth. In benign prostatic hyperplasia (BPH), contraction and growth in the prostate drive urethral obstruction and voiding symptoms. However, a role of NUAKs in smooth muscle contraction or prostate functions are unknown. Here, we examined effects of NUAK silencing and the presumed NUAK inhibitors, HTH01-015 and WZ4003 on contraction and growth-related functions in prostate stromal cells (WPMY-1) and in human prostate tissues.

Methods: Effects of NUAK1 and -2 silencing, HTH01-015 and WZ4003 on matrix plug contraction, proliferation (EdU assay, Ki-67 mRNA), apoptosis and cell death (flowcytometry), viability (CCK-8) and actin organization (phalloidin staining) were examined in cultured WPMY-1 cells. Effects of HTH01-015 and WZ4003 on smooth muscle contraction were assessed in organ bath experirments with human prostate tissues.

Results: Effects of silencing were most pronounced on proliferation and cell death, resulting in decreases of proliferation rate by 60% and 70% by silencing of NUAK1 and NUAK2 (compared to scramble siRNA-transfected controls), decreases in Ki-67 by 75% and 77%, while numbers of dead cells after silencing of NUAK1 and NUAK2 amounted to 2.8 and 4.9 fold of scramble-transfected controls. Silencing of each isoform was paralleled by reduced viability, breakdown in actin polymerization, and partial decreases in contractility (maximally 45% by NUAK1 silencing, 58% by NUAK2 silencing). Effects of silencing were mimicked by HTH01-015 and WZ4003, with numbers of dead cells amounting up to 16.1 fold or 7.8 fold with HTH01-015 or WZ4003, compared to solvent-treated controls. Using concentrations of 500 nM, neurogenic contractions of prostate tissues were inhibited partly by HTH01-015 and U46619-induced contractions were inhibited partly by HTH01-015 and WZ4003, while α1-adrenergic and endothelin-1-induced contractions remained unaffected. Using 10 μM, inhibition of endothelin-1-induced contractions by both inhibitors and inhibition of α1-adrenergic contractions by HTH01-015 added to effects seen by 500 nM.

Conclusion: NUAK1 and -2 suppress cell death and promote proliferation in prostate stromal cells. A role in stromal hyperplasia appears possible in BPH. Effects of NUAK silencing are mimicked by HTH01-015 and WZ4003.
Hypolipidemic effect and molecular mechanism of ginsenosides: a review based on oxidative stress
Authors: Jin Wei , Li Chunrun , Yang Shihui , Song Shiyi , Hou Weiwei , Song Yang , Du Quanyu
Published: April 2023

Hyperlipidemia is considered a risk factor for cardiovascular and endocrine diseases. However, effective approaches for treating this common metabolic disorder remain limited. Ginseng has traditionally been used as a natural medicine for invigorating energy or “Qi” and has been demonstrated to possess antioxidative, anti-apoptotic, and anti-inflammatory properties. A large number of studies have shown that ginsenosides, the main active ingredient of ginseng, have lipid-lowering effects. However, there remains a lack of systematic reviews detailing the molecular mechanisms by which ginsenosides reduce blood lipid levels, especially in relation to oxidative stress. For this article, research studies detailing the molecular mechanisms through which ginsenosides regulate oxidative stress and lower blood lipids in the treatment of hyperlipidemia and its related diseases (diabetes, nonalcoholic fatty liver disease, and atherosclerosis) were comprehensively reviewed. The relevant papers were search on seven literature databases. According to the studies reviewed, ginsenosides Rb1, Rb2, Rb3, Re, Rg1, Rg3, Rh2, Rh4, and F2 inhibit oxidative stress by increasing the activity of antioxidant enzymes, promoting fatty acid β-oxidation and autophagy, and regulating the intestinal flora to alleviate high blood pressure and improve the body’s lipid status. These effects are related to the regulation of various signaling pathways, such as those of PPARα, Nrf2, mitogen-activated protein kinases, SIRT3/FOXO3/SOD, and AMPK/SIRT1. These findings suggest that ginseng is a natural medicine with lipid-lowering effects.
Geriatrician-led multidisciplinary team management improving polypharmacy among older inpatients in China
Authors: Song Yi , Chen Lihua , Liu Ying , Xia Xin , Hou Lisha , Wu Jinhui , Cao Li , Mo Li
Published: April 2023

Background/Aim: Polypharmacy is prevalent among older inpatients and associated with adverse outcomes. To determine whether a geriatrician-led multidisciplinary team (MDT) management mode could reduce medications use among older inpatients.

Methods: A retrospective cohort study was conducted in a geriatric department of a tertiary hospital in China with 369 older inpatients, including 190 patients received MDT management (MDT cohort), and 179 patients received usual treatment (non-MDT cohort). The primary outcome was to compare the changes of the amount of medications before and after hospitalization in two cohorts.

Results: We reported that MDT management significantly reduced the number of medications used in older inpatients at discharge (at home: n = 7 [IQR: 4, 11] vs at discharge: n = 6 [IQR: 4, 8], p < 0.05). Hospitalization with the MDT management had a significant effect on the change in the amount of medications (F = 7.813, partial-η2 = 0.011, p = 0.005). The discontinuance of medications was associated with polypharmacy at home (OR: 96.52 [95% CI: 12.53-743.48], p < 0.001), and the addition of medications was associated with a diagnosis of chronic obstructive pulmonary disease (COPD) (OR: 2.36 [95% CI: 1.02-5.49], p = 0.046).

Conclusion: The results indicated that the geriatrician-led MDT mode during hospitalization could reduce the number of medications used by older patients. The patients with polypharmacy were more likely to “deprescription” after MDT management, while the patients with COPD were more likely to be under-prescription at home, polypharmacy which could be made up for after MDT management.
Three-year-cohort-study: clinical and cost effectiveness of an inpatient psychiatric rehabilitation
Authors: Awara Mahmoud A. , Downing Laura M. , Edem Dorothy , Lewis Norma , Green Joshua T.
Published: April 2023

Introduction

There has been a resurgence of interest in psychiatric rehabilitation to cater to patients with chronic and complex mental illnesses.

Aims

This study is aimed at examining patients' characteristics and the prevalence of psychiatric and non-psychiatric comorbidity in a local inpatient rehabilitation service, as well as to investigate the impact of the whole-system approach to rehabilitation on future utilization of mental health services and to analyze the cost-effectiveness and quality of this service.

Method

Patients managed over 3 years in a psychiatric rehabilitation inpatient unit were self-controlled; they were retrospectively (pre-rehabilitation) and prospectively (post-rehabilitation) examined for readmission rate, length of stay (LOS), and emergency room (ER) visits. Relevant information was retrieved from Discharge Abstract Database (DAD), Patient Registration System (STAR), and Emergency Department Information System (EDIS). The quality of care in the rehabilitation unit was examined using the Quality Indicator for Rehabilitative Care (QuIRC), and the cost analysis was conducted using data obtained from a single-payer government medical service insurance (MSI) billing system.

Results

Of the 185 patients admitted over the study period, 158 were discharged. There was a significant reduction in readmission rate (64% decrease), LOS (6,585 fewer days spent in hospital), and ER presentations (166 fewer visits) (P < 0.0001), respectively. There were substantial subsequent cost savings in the post-rehabilitation year.

Conclusion and implications for practice

In the 3-year study, an inpatient psychiatric rehabilitation service in Nova Scotia, Canada, resulted in the successful discharge of most patients with severe and persistent mental illness to more socially inclusive environments. It also reduced their post-rehabilitation mental health service utilization, hence greatly enhancing the effectiveness and efficiency of these services.
Impacts of the zero mark-up policy on hospitalization expenses of T2DM and cholecystolithiasis inpatients in SC province, western China: an interrupted time series analysis
Authors: Guo Xirui , Xiao Yao , Liu Huan , Li Qinchuan , Jiang Qian , Liu Chun , Xie Fangqing , Wang Hongju , Yang Fang , Han Xiao , Yang Hengbo , Yang Yong , Ye Yongqin , Gan XiaoHong , Long Enwu
Published: April 2023

Background

Since 2009, a series of ambitious health system reforms have been launched in China, including the zero mark-up drug policy (ZMDP); the policy was intended to reduce substantial medicine expenses for patients by abolishing the 15% mark-up on drugs. This study aims to evaluate the impacts of ZMDP on medical expenditures from the perspective of disease burden disparities in western China.

Method

Two typical diseases including Type 2 diabetes mellitus (T2DM) in internal medicine and cholecystolithiasis (CS) in surgery were selected from medical records in a large tertiary level-A hospital in SC Province. The monthly average medical expenses of patients from May 2015 to August 2018 were extracted to construct an interrupted time series (ITS) model to evaluate the impact of policy implementation on the economic burden.

Results

A total of 5,764 cases were enrolled in our study. The medicine expenses for T2DM patients maintained a negative trend both before and after the intervention of ZMDP. It had declined by 74.3 CNY (P < 0.001) per month on average in the pre-policy period and subsequently dropped to 704.4 CNY (P = 0.028) immediately after the policy. The level change of hospitalization expenses was insignificant (P = 0.197), with a reduction of 677.7 CNY after the policy, while the post-policy long-term trend was significantly increased by 97.7 CNY (P = 0.035) per month contrasted with the pre-policy period. In addition, the anesthesia expenses of T2DM patients had a significant increase in the level under the impact of the policy. In comparison, the medicine expenses of CS patients significantly decreased by 1,014.2 CNY (P < 0.001) after the policy, while the total hospitalization expenses had no significant change in level and slope under the influence of ZMDP. Furthermore, the expenses of surgery and anesthesia for CS patients significantly increased by 320.9 CNY and 331.4 CNY immediately after the policy intervention.

Conclusion

Our study indicated that the ZMDP has been an effective intervention to reduce the excessive medicine expenses for both researched medical and surgical diseases, but failed to show any long-term advantage. Moreover, the policy has no significant impact on relieving the overall hospitalization burden for either condition.
Different combinations of monensin and narasin on growth performance, carcass traits, and ruminal fermentation characteristics of finishing beef cattle
Authors: Baggio Marcelo , Gouvêa Vinícius N. , Barroso José Paulo R. , Miszura Alexandre A. , Limede Arnaldo C. , Soares Letícia C. B. , Ferraz Marcos Vinicius C. , Vicente Ana Carolina S. , Ferreira Evandro M. , Marques Rodrigo S. , Pires Alexandre V.
Published: April 2023

The objective of this study was to evaluate the effects of different combinations of monensin and narasin on finishing cattle. In Exp. 1, 40 rumen-cannulated Nellore steers [initial body weight (BW) = 231 ± 3.64 kg] were blocked by initial BW and assigned to one of the five treatments as follows: Control (CON): no feed additive in the basal diet during the entire feeding period; Sodium monensin (MM) at 25 mg/kg dry matter (DM) during the entire feeding period [adaptation (days 1–21) and finishing (days 22–42) periods]; Narasin (NN) at 13 mg/kg DM during the entire feeding period (adaptation and finishing periods); Sodium monensin at 25 mg/kg DM during the adaptation period and narasin at 13 mg/kg DM during the finishing period (MN); and narasin at 13 mg/kg DM during the adaptation period and sodium monensin at 25 mg/kg DM during the finishing period (NM). Steers fed MM had lower dry matter intake (DMI) during the adaptation period compared to NM (P = 0.02) but not compared to CON, MM, MN, or NN (P ≥ 0.12). No differences in DMI were observed among the treatments during the finishing (P = 0.45) or the total feeding period (P = 0.15). Treatments did not affect the nutrient intake (P ≥ 0.51) or the total apparent digestibility of nutrients (P ≥ 0.22). In Exp. 2, 120 Nellore bulls (initial BW = 425 ± 5.4 kg) were used to evaluate the effects of the same treatments of Exp. 1 on growth performance and carcass characteristics of finishing feedlot cattle. Steers fed NM had greater DMI during the adaptation period compared to CON, MM, and MN (P ≤ 0.03), but no differences were observed between NM and NN (P = 0.66) or between CON, MM, and NN (P ≥ 0.11). No other differences between treatments were observed (P ≥ 12). Feeding narasin at 13 mg/kg DM during the adaptation period increases the DMI compared to monensin at 25 mg/kg DM, but the feed additives evaluated herein did not affect the total tract apparent digestibility of nutrients, growth performance, or carcass characteristics of finishing cattle.
RET rearrangements are relevant to histopathologic subtypes and clinicopathological features in Thai papillary thyroid carcinoma patients
Authors: Khonrak Thitima , Watcharadetwittaya Sasithorn , Chamgramol Yaovalux , Intarawichian Piyapharom , Deenonpoe Raksawan
Published: April 2023

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The RET gene rearrangements CCDC6::RET and NCOA4::RET are the most common RET gene rearrangements in PTC patients. Different RET::PTC rearrangements are associated with different PTC phenotypes.

Methods: Eighty-three formalin-fixed paraffin-embedded (FFPE) PTC samples were examined. The prevalence and expression levels of CCDC6::RET and NCOA4::RET were determined using semi-quantitative polymerase chain reaction (qRT-PCR). The association of these rearrangements with clinicopathological data was investigated.

Results: The presence of CCDC6::RET rearrangement was significantly associated with the classic subtype and absence of angio/lymphatic invasion (p < 0.05). While NCOA4::RET was associated with the tall-cell subtype, and presence of angio/lymphatic invasion and lymph node metastasis (p < 0.05). Multivariate analysis demonstrated that an absence of extrathyroidal extension and extranodal extension were independent predictive factors for CCDC6::RET, whereas the tall-cell subtype, large tumor size, angioinvasion, lymphatic invasion and perineural invasion were independent predictive factors for NCOA4::RET (p < 0.05). However, the mRNA expression level of CCDC6::RET and of NCOA4::RET were not significantly associated with clinicopathological data.

Conclusion:CCDC6::RET was correlated with an innocent PTC subtype and characteristics, but NCOA4::RET correlated with an aggressive phenotype of PTC. Therefore, these RET rearrangements strongly associated with clinicopathological phenotypes and can be used as predictive markers in PTC patients.
Experimental Study on the Influence of Temperature on the Mechanical Properties of Near-Space Airship Envelopes
Authors: Xie Weicheng , Wang Xiaoliang , Tang Jiwei , Chen Yonglin , Wu Junjie
Published: April 2023

A biaxial tension test considering temperature is crucial to predict the mechanical properties of airship envelopes. However, there is a lack of biaxial tensile test equipment for high- and low-temperature correlation. In this study, a temperature control device suitable for biaxial tension was designed based on the traditional device, and the biaxial tension test of the UN-5100 material in high- and low-temperature environments was realized. In addition, a series of tests were carried out to verify the effectiveness and rationality of the temperature control device. Then, a biaxial tensile test of UN-5100 specimens between −33 °C and 80 °C were carried out and the stress–strain relationship of the UN-5100 specimens under high- and low-temperature environments was obtained. Based on the test data, the elastic modulus and Poisson’s ratio of the UN-5100 specimens at different temperatures were calculated. Finally, the test results showed that the elastic modulus and Poisson’s ratio of the airship envelope were larger at low temperatures, indicating that the capsule is relatively safe at such temperatures. The relationships between the temperature and the mechanical properties of the airship were also summarized.
A Study on a Vitiated Air Heater for a Direct-Connect Scramjet Combustor and Preliminary Test on the Scramjet Combustor Ignition
Authors: Lee Jae-Hyuk , Lee Eun-Sung , Han Hyung-Seok , Kim Min-Su , Choi Jeong-Yeol
Published: April 2023

Vitiation air heater (VAH) combustion characteristics for a direct-connect scramjet combustor (DCSC) were experimentally studied. The VAH consists of a head, modular chamber, and circular-to-rectangular shape transition (CRST) nozzle. The CRST nozzle transforms the circular cross-sectioned rocket-type VAH into a rectangular cross-sectioned scramjet combustor. The CRST nozzle exit Mach numbers at the top, middle, and bottom were measured using a tungsten wedge. The oblique shock formed by the wedge was captured using Schlieren visualization and recorded with a high-speed camera. The θ-β-M relation showed that the exit Mach number was 2.04 ± 0.04 with a chamber pressure of 1.685 ± 0.07 MPa. With the VAH design point verified, preliminary scramjet combustor ignition tests were conducted. As the fuel was not auto-ignited by the vitiated air, the forced ignition method, in which VAH ignition flame ignites the scramjet fuel, was used. The Schlieren images showed that a cavity shear layer combustion mode was formed and also showed that the forced ignition method could be used as a reference model for the ignitor-ignition method.
CAA-PPI: A Computational Feature Design to Predict Protein–Protein Interactions Using Different Encoding Strategies
Authors: Mewara Bhawna , Sahni Gunjan , Lalwani Soniya , Kumar Rajesh
Published: April 2023

Protein–protein interactions (PPIs) are involved in an extensive variety of biological procedures, including cell-to-cell interactions, and metabolic and developmental control. PPIs are becoming one of the most important aims of system biology. PPIs act as a fundamental part in predicting the protein function of the target protein and the drug ability of molecules. An abundance of work has been performed to develop methods to computationally predict PPIs as this supplements laboratory trials and offers a cost-effective way of predicting the most likely set of interactions at the entire proteome scale. This article presents an innovative feature representation method (CAA-PPI) to extract features from protein sequences using two different encoding strategies followed by an ensemble learning method. The random forest methodwas used as a classifier for PPI prediction. CAA-PPI considers the role of the trigram and bond of a given amino acid with its nearby ones. The proposed PPI model achieved more than a 98% prediction accuracy with one encoding scheme and more than a 95% prediction accuracy with another encoding scheme for the two diverse PPI datasets, i.e., H. pylori and Yeast. Further, investigations were performed to compare the CAA-PPI approach with existing sequence-based methods and revealed the proficiency of the proposed method with both encoding strategies. To further assess the practical prediction competence, a blind test was implemented on five other species’ datasets independent of the training set, and the obtained results ascertained the productivity of CAA-PPI with both encoding schemes.
Identification of the Binding Epitope of an Anti-Mouse CCR6 Monoclonal Antibody (C6Mab-13) Using 1× Alanine Scanning
Authors: Tanaka Tomohiro , Tawara Mayuki , Suzuki Hiroyuki , Kaneko Mika K. , Kato Yukinari
Published: April 2023

CC chemokine receptor 6 (CCR6) is one of the members of the G-protein-coupled receptor (GPCR) family that is upregulated in many immune-related cells, such as B lymphocytes, effector and memory T cells, regulatory T cells, and immature dendritic cells. The coordination between CCR6 and its ligand CC motif chemokine ligand 20 (CCL20) is deeply involved in the pathogenesis of various diseases, such as cancer, psoriasis, and autoimmune diseases. Thus, CCR6 is an attractive target for therapy and is being investigated as a diagnostic marker for various diseases. In a previous study, we developed an anti-mouse CCR6 (mCCR6) monoclonal antibody (mAb), C6Mab-13 (rat IgG1, kappa), that was applicable for flow cytometry by immunizing a rat with the N-terminal peptide of mCCR6. In this study, we investigated the binding epitope of C6Mab-13 using an enzyme-linked immunosorbent assay (ELISA) and the surface plasmon resonance (SPR) method, which were conducted with respect to the synthesized point-mutated-peptides within the 1–20 amino acid region of mCCR6. In the ELISA results, C6Mab-13 lost its ability to react to the alanine-substituted peptide of mCCR6 at Asp11, thereby identifying Asp11 as the epitope of C6Mab-13. In our SPR analysis, the dissociation constants (KD) could not be calculated for the G9A and D11A mutants due to the lack of binding. The SPR analysis demonstrated that the C6Mab-13 epitope comprises Gly9 and Asp11. Taken together, the key binding epitope of C6Mab-13 was determined to be located around Asp11 on mCCR6. Based on the epitope information, C6Mab-13 could be useful for further functional analysis of mCCR6 in future studies.
Automatic Feedback System for X-ray Flux at BL08U1A Soft X-ray Spectromicroscopy Beamline of Shanghai Synchrotron Radiation Facility
Authors: Zhang Chi , Liu Haigang , Wang Chunpeng , Guo Zhi , Zhang Xiangzhi , Xu Zijian , Zhen Xiangjun , Wang Yong , Tai Renzhong
Published: April 2023

An online automatic feedback system has been successfully installed and commissioned at the BL08U1A Soft X-ray Spectromicroscopy Beamline of Shanghai Synchrotron Radiation Facility, which can monitor the incident X-ray beam in real time by measuring the blade-edge signals of the exit slit and automatically adjust the elliptical cylindrical mirror parameters to achieve beam calibration and maintain the optimal X-ray flux of the sample. This work provides a comprehensive description of the hardware composition, system implementation, feedback logic, function and software design, system optimization and commission, as well as the online experimental results supported by the system. The experimental results demonstrated that the online automatic feedback system is capable of effectively maintaining the optimal X-ray beam flux for X-ray absorption spectroscopy experiments. Its success can provide valuable technique assistance for the design, construction and optimization of similar systems at various beamlines in synchrotron sources in the future.
Estimation and Analysis of Seasonal Rainfall Distribution and Potential of Türkiye and Its 25 Main Watersheds
Authors: Aksu Hasan Hüseyin
Published: April 2023

In this study, the seasonal rainfall distribution in Türkiye and its 25 main watersheds were estimated, and potentials were calculated and analyzed. Empirical Bayesian kriging (EBK) and ordinary kriging (OK) methods were applied in interpolations. The calculations were made through EBK, which provided the highest estimation accuracy in all seasons. In winter, which is the season with the highest rainfall, Türkiye’s rainfall depth is 208.8 mm, and its volume is 162.87 billion m3. In summer, the season with the lowest rainfall, Türkiye’s rainfall depth is 61.7 mm, and its volume is 48.13 billion m3. The watersheds with the highest rainfall depth are Antalya (480.1 mm) in winter, Ceyhan (222.8 mm) in spring, and East Black Sea in summer (197.5 mm) and autumn (299.7 mm). Conversely, the watersheds with the lowest precipitation depth are Aras (74.9 mm) in winter, Little Meander (16.5 mm) in summer, and Konya in spring (131.3 mm) and autumn (86.2 mm). In summer, rainfall shortage is observed in all watersheds in the Central and Southern parts of Türkiye. As we go from the north to the south, the watersheds’ seasonal rainfall depths and shares become more irregular and variable.
Generalizations of Hardy-Type Inequalities by Montgomery Identity and New Green Functions
Authors: Himmelreich Kristina Krulić , Pečarić Josip , Pokaz Dora , Praljak Marjan
Published: April 2023

In this paper we extend general Hardy’s inequality by appropriately combining Montgomery’s identity and Green functions. Related Grüss and Ostrowski-type inequalities are also derived.
A Comparative Study of Secure Outsourced Matrix Multiplication Based on Homomorphic Encryption
Authors: Babenko Mikhail , Golimblevskaia Elena , Tchernykh Andrei , Shiriaev Egor , Ermakova Tatiana , Pulido-Gaytan Luis Bernardo , Valuev Georgii , Avetisyan Arutyun , Gagloeva Lana A.
Published: April 2023

Homomorphic encryption (HE) is a promising solution for handling sensitive data in semi-trusted third-party computing environments, as it enables processing of encrypted data. However, applying sophisticated techniques such as machine learning, statistics, and image processing to encrypted data remains a challenge. The computational complexity of some encrypted operations can significantly increase processing time. In this paper, we focus on the analysis of two state-of-the-art HE matrix multiplication algorithms with the best time and space complexities. We show how their performance depends on the libraries and the execution context, considering the standard Cheon–Kim–Kim–Song (CKKS) HE scheme with fixed-point numbers based on the Microsoft SEAL and PALISADE libraries. We show that Windows OS for the SEAL library and Linux OS for the PALISADE library are the best options. In general, PALISADE-Linux outperforms PALISADE-Windows, SEAL-Linux, and SEAL-Windows by 1.28, 1.59, and 1.67 times on average for different matrix sizes, respectively. We derive high-precision extrapolation formulas to estimate the processing time of HE multiplication of larger matrices.
Leukocytes Classification for Leukemia Detection Using Quantum Inspired Deep Feature Selection
Authors: Ahmad Riaz , Awais Muhammad , Kausar Nabeela , Tariq Usman , Cha Jae-Hyuk , Balili Jamel
Published: April 2023

Leukocytes, also referred to as white blood cells (WBCs), are a crucial component of the human immune system. Abnormal proliferation of leukocytes in the bone marrow leads to leukemia, a fatal blood cancer. Classification of various subtypes of WBCs is an important step in the diagnosis of leukemia. The method of automated classification of WBCs using deep convolutional neural networks is promising to achieve a significant level of accuracy, but suffers from high computational costs due to very large feature sets. Dimensionality reduction through intelligent feature selection is essential to improve the model performance with reduced computational complexity. This work proposed an improved pipeline for subtype classification of WBCs that relies on transfer learning for feature extraction using deep neural networks, followed by a wrapper feature selection approach based on a customized quantum-inspired evolutionary algorithm (QIEA). This algorithm, inspired by the principles of quantum physics, outperforms classical evolutionary algorithms in the exploration of search space. The reduced feature vector obtained from QIEA was then classified with multiple baseline classifiers. In order to validate the proposed methodology, a public dataset of 5000 images of five subtypes of WBCs was used. The proposed system achieves a classification accuracy of about 99% with a reduction of 90% in the size of the feature vector. The proposed feature selection method also shows a better convergence performance as compared to the classical genetic algorithm and a comparable performance to several existing works.
Therapies beyond Physiological Barriers and Drug Resistance: A Pilot Study and Review of the Literature Investigating If Intrathecal Trastuzumab and New Treatment Options Can Improve Oncologic Outcomes in Leptomeningeal Metastases from HER2-Positive Breast Cancer
Authors: Trifănescu Oana Gabriela , Mitrea Dan , Galeș Laurenția Nicoleta , Ciornei Ana , Păun Mihai-Andrei , Butnariu Ioana , Trifănescu Raluca Alexandra , Motaș Natalia , Toma Radu Valeriu , Bîlteanu Liviu , Gherghe Mirela , Anghel Rodica Maricela
Published: April 2023

Leptomeningeal metastases (LM) are a rare but rapidly fatal complication defined by the spread of tumor cells within the leptomeninges and the subarachnoid space, found in approximately 10% of patients with HER2-positive breast cancers. This pilot study evaluated the efficacy of local treatment with intrathecal Trastuzumab (IT) added to systemic treatment. The oncologic outcome of 14 patients with HER2-positive LM is reported. Seven received IT, and seven received standard of care (SOC). The mean number of IT cycles administered was 12.14 ± 4.00. The response rate to CNS after IT treatment + SOC was 71.4%, and three patients (42.8%) obtained durable responses lasting more than 12 months. The median progression-free survival (mPFS) after LM diagnosis was six months, and the median overall survival (mOS) was ten months. The mean values of the PFS in favor of IT therapy (10.6 mo vs. 6.6 mo) and OS (13.7 vs. 9.3 mo) suggest a non-negligible investigation direction in the sense of exploiting intrathecal administration as a possible treatment modality in these patients. Adverse events reported were local pain related to intrathecal administration and one case of arachnoiditis, hematoma, and CSF fistulae. Intrathecal administration of Trastuzumab, alongside systemic treatment and radiotherapy, might improve oncologic outcomes in LM HER2-positive breast cancer with manageable toxicity.
Telemedical Consultations in Palliative Care: Benefits through Knowledge Exchange and Intercollegiate Collaboration—Findings from the German oVID Project
Authors: Bückmann Andreas , Bernhardt Florian , Eveslage Maria , Storck Michael , Thölking Gerold , Buss Helga , Domagk Dirk , Juhra Christian , Lenz Philipp
Published: April 2023

(1) Background: As the number of people receiving specialized palliative care (PC) continues to rise, there is a need to ensure the transfer of this expertise from university-based PC departments to primary care hospitals without such in-house access. The present study examines the potential of telemedicine to bridge these gaps. (2) Methods: This is a prospective multi-center feasibility trial. All physicians were appropriately pre-equipped and instructed to conduct telemedical consultations (TCs), which took place within fixed meetings or on-call appointments either related or unrelated to individual patients (allowing TCs also for educational and knowledge exchange purposes). (3) Results: An inquiry for participation was submitted to 11 hospitals, with 5 external hospitals actively cooperating. In the first study section, a total of 57 patient cases were included within 95 patient-related TCs during 80 meetings. Other university disciplines were involved in 21 meetings (26.2%). Therapy adjustments resulted following 25 of 71 affected TCs (35.2%). In 20 cases (21.1%), an on-site consultation at the university hospital was avoided, and in 12 cases (12.6%), a transfer was avoided. Overall, TCs were considered helpful in resolving issues for 97.9% of the cases (n = 93). Yet, technical problems arose in about one-third of all meetings for at least one physician (36.2%; n = 29). Besides, in the second study section, we also conducted 43 meetings between physicians for education and knowledge exchange only. (4) Conclusions: Telemedicine has the potential to transfer university expertise to external hospitals through simple means. It improves collaboration among physicians, may prevent unnecessary transfers or outpatient presentations, and is thus likely to lower costs.
The Membrane Protein Sortilin Is a Potential Biomarker and Target for Glioblastoma
Authors: Marsland Mark , Dowdell Amiee , Faulkner Sam , Gedye Craig , Lynam James , Griffin Cassandra P. , Marsland Joanne , Jiang Chen Chen , Hondermarck Hubert
Published: April 2023

Glioblastoma (GBM) is a devastating brain cancer with no effective treatment, and there is an urgent need for developing innovative biomarkers as well as therapeutic targets for better management of the disease. The membrane protein sortilin has recently been shown to participate in tumor cell invasiveness in several cancers, but its involvement and clinical relevance in GBM is unclear. In the present study, we explored the expression of sortilin and its potential as a clinical biomarker and therapeutic target for GBM. Sortilin expression was investigated by immunohistochemistry and digital quantification in a series of 71 clinical cases of invasive GBM vs. 20 non-invasive gliomas. Sortilin was overexpressed in GBM and, importantly, higher expression levels were associated with worse patient survival, pointing to sortilin tissue expression as a potential prognostic biomarker for GBM. Sortilin was also detectable in the plasma of GBM patients by enzyme-linked immunosorbent assay (ELISA), but no differences were observed between sortilin levels in the blood of GBM vs. glioma patients. In vitro, sortilin was detected in 11 brain-cancer-patient-derived cell lines at the anticipated molecular weight of 100 kDa. Interestingly, targeting sortilin with the orally bioavailable small molecule inhibitor AF38469 resulted in decreased GBM invasiveness, but cancer cell proliferation was not affected, showing that sortilin is targetable in GBM. Together, these data suggest the clinical relevance for sortilin in GBM and support further investigation of GBM as a clinical biomarker and therapeutic target.
Tumor Organoid and Spheroid Models for Cervical Cancer
Authors: Kutle Ivana , Polten Robert , Hachenberg Jens , Klapdor Rüdiger , Morgan Michael , Schambach Axel
Published: April 2023

Cervical cancer is one of the most common malignant diseases in women worldwide. Despite the global introduction of a preventive vaccine against the leading cause of cervical cancer, human papillomavirus (HPV) infection, the incidence of this malignant disease is still very high, especially in economically challenged areas. New advances in cancer therapy, especially the rapid development and application of different immunotherapy strategies, have shown promising pre-clinical and clinical results. However, mortality from advanced stages of cervical cancer remains a significant concern. Precise and thorough evaluation of potential novel anti-cancer therapies in pre-clinical phases is indispensable for efficient development of new, more successful treatment options for cancer patients. Recently, 3D tumor models have become the gold standard in pre-clinical cancer research due to their capacity to better mimic the architecture and microenvironment of tumor tissue as compared to standard two-dimensional (2D) cell cultures. This review will focus on the application of spheroids and patient-derived organoids (PDOs) as tumor models to develop novel therapies against cervical cancer, with an emphasis on the immunotherapies that specifically target cancer cells and modulate the tumor microenvironment (TME).
Definitive Chemoradiation Associated with Improved Survival Outcomes in Patients with Synchronous Oligometastatic Esophageal Cancer
Authors: Matoska Thomas , Banerjee Anjishnu , Shreenivas Aditya , Jurkowski Lauren , Shukla Monica E. , Gore Elizabeth M. , Linsky Paul , Gasparri Mario , George Ben , Johnstone Candice , Johnstone David , Puckett Lindsay L.
Published: April 2023

Background: The study of oligometastatic esophageal cancer (EC) is relatively new. Preliminary data suggests that more aggressive treatment regimens in select patients may improve survival rates in oligometastatic EC. However, the consensus recommends palliative treatment. We hypothesized that oligometastatic esophageal cancer patients treated with a definitive approach (chemoradiotherapy [CRT]) would have improved overall survival (OS) compared to those treated with a purely palliative intent and historical controls. Methods: Patients diagnosed with synchronous oligometastatic (any histology, ≤5 metastatic foci) esophageal cancer treated in a single academic hospital were retrospectively analyzed and divided into definitive and palliative treatment groups. Definitive CRT was defined as radiation therapy to the primary site with ≥40 Gy and ≥2 cycles of chemotherapy. Results: Of 78 Stage IVB (AJCC 8th ed.) patients, 36 met the pre-specified oligometastatic definition. Of these, 19 received definitive CRT, and 17 received palliative treatment. With a median follow-up of 16.5 months (Range: 2.3–95.0 months), median OS for definitive CRT and palliative groups were 90.2 and 8.1 months (p < 0.01), translating into 5-year OS of 50.5% (95%CI: 32.0–79.8%) vs. 7.5% (95%CI: 1.7–48.9%), respectively. Conclusions: Oligometastatic EC patients treated with definitive CRT benefited from that approach with survival rates (50.5%) that vastly exceeded historical standards of 5% at 5 years for metastatic EC. Oligometastatic EC patients treated with definitive CRT had significantly improved OS compared to those treated with palliative-only intent within our cohort. Notably, definitively treated patients were generally younger and with better performance status versus those palliatively treated. Further prospective evaluation of definitive CRT for oligometastatic EC is warranted.
Proof-of-Concept for Liquid Biopsy Disease Monitoring of MYC-Amplified Group 3 Medulloblastoma by Droplet Digital PCR
Authors: Stepien Natalia , Senfter Daniel , Furtner Julia , Haberler Christine , Dorfer Christian , Czech Thomas , Lötsch-Gojo Daniela , Mayr Lisa , Hedrich Cora , Baumgartner Alicia , Aliotti-Lippolis Maria , Schned Hannah , Holler Johannes , Bruckner Katharina , Slavc Irene , Azizi Amedeo A. , Peyrl Andreas , Müllauer Leonhard , Madlener Sibylle , Gojo Johannes
Published: April 2023

Background: Liquid biopsy diagnostic methods are an emerging complementary tool to imaging and pathology techniques across various cancer types. However, there is still no established method for the detection of molecular alterations and disease monitoring in MB, the most common malignant CNS tumor in the pediatric population. In the presented study, we investigated droplet digital polymerase chain reaction (ddPCR) as a highly sensitive method for the detection of MYC amplification in bodily fluids of group 3 MB patients. Methods: We identified a cohort of five MYC-amplified MBs by methylation array and FISH. Predesigned and wet-lab validated probes for ddPCR were used to establish the detection method and were validated in two MYC-amplified MB cell lines as well as tumor tissue of the MYC-amplified cohort. Finally, a total of 49 longitudinal CSF samples were analyzed at multiple timepoints during the course of the disease. Results: Detection of MYC amplification by ddPCR in CSF showed a sensitivity and specificity of 90% and 100%, respectively. We observed a steep increase in amplification rate (AR) at disease progression in 3/5 cases. ddPCR was proven to be more sensitive than cytology for the detection of residual disease. In contrast to CSF, MYC amplification was not detectable by ddPCR in blood samples. Conclusions: ddPCR proves to be a sensitive and specific method for the detection of MYC amplification in the CSF of MB patients. These results warrant implementation of liquid biopsy in future prospective clinical trials to validate the potential for improved diagnosis, disease staging and monitoring.
Naxitamab Combined with Granulocyte-Macrophage Colony-Stimulating Factor as Consolidation for High-Risk Neuroblastoma Patients in First Complete Remission under Compassionate Use—Updated Outcome Report
Authors: Mora Jaume , Castañeda Alicia , Gorostegui Maite , Varo Amalia , Perez-Jaume Sara , Simao Margarida , Muñoz Juan , Garraus Moira , Larrosa Cristina , Salvador Noelia , Lavarino Cinzia , Krauel Lucas , Mañe Salvador
Published: April 2023

Naxitamab is an anti-GD2 antibody approved for the treatment of relapsed/refractory HR-NB. We report the survival, safety, and relapse pattern of a unique set of HR-NB patients consolidated with naxitamab after having achieved first CR. Eighty-two patients were treated with 5 cycles of GM-CSF for 5 days at 250 μg/m2/day (−4 to 0), followed by GM-CSF for 5 days at 500 μg/m2/day (1–5) and naxitamab at 3 mg/kg/day (1, 3, 5), on an outpatient basis. All patients but one were older than 18 months at diagnosis and had stage M; 21 (25.6%) pts had MYCN-amplified (A) NB; and 12 (14.6%) detectable MRD in the BM. Eleven (13.4%) pts had received high-dose chemotherapy and ASCT and 26 (31.7%) radiotherapy before immunotherapy. With a median follow-up of 37.4 months, 31 (37.8%) pts have relapsed. The pattern of relapse was predominantly (77.4%) an isolated organ. Five-year EFS and OS were 57.9% (71.4% for MYCN A) 95% CI = (47.2, 70.9%); and 78.6% (81% for MYCN A) 95% CI = (68.7%, 89.8%), respectively. EFS showed significant differences for patients having received ASCT (p = 0.037) and pre-immunotherapy MRD (p = 0.0011). Cox models showed only MRD as a predictor of EFS. In conclusion, consolidation with naxitamab resulted in reassuring survival rates for HR-NB patients after end-induction CR.
Radiotherapy—Dose Escalated for Large Volume Primary Tumors—And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck—A Randomized Phase II Trial
Authors: Mercke Claes , Wickart-Johansson Gun , Sjödin Helena , Farrajota Neves da Silva Pedro , Alexandersson von Döbeln Gabriella , Margolin Gregori , Jonmarker Jaraj Sara , Carstens Hanna , Berglund Anders , Lax Ingmar , Hellström Mats , Hammarstedt-Nordenvall Lalle , Friesland Signe
Published: April 2023

The leading cause of death for patients with HPV associated squamous cell carcinoma of the head and neck (SCCHN) after treatment with chemoradiotherapy (CRT) nowadays is peripheral metastasis. This study investigated whether induction chemotherapy (IC) could improve progression free survival (PFS) and impact on relapse pattern after CRT. Methods: Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18–75 years, an ECOG performance status 0–1, and adequate organ functions. Results: From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4–92.8) in arm A and 78.4% (95% CI 69.5–88.3) in arm B (HR 1.39, 95% CI 0.69–2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. Conclusions: PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.
A Pilot Study of Lung Clearance Index as a Useful Outcome Marker in the Follow-Up of Pediatric Patients with Non-Cystic Fibrosis Bronchiectasis?
Authors: Alkoussa Wael , Hanssens Laurence , Sputael Valerie , De Lucia Frederico , Quentin Christine
Published: April 2023

The forced expiratory volume in one second (FEV1) is regularly used for the follow-up of patients with non-cystic fibrosis bronchiectasis (nCF-BE). The lung clearance index (LCI), measured by the multiple breath washout test, has been recently proposed as a lung function measure and a potential tool more sensitive than the FEV1 measured by spirometry in assessing airway changes seen on imaging. While several data have been endorsed as a useful endpoint in clinical trials of patients with early or mild CF lung disease and as the main outcome measure in clinical trials with CFTR modulators in children and adolescents with CF, few data are available in the context of non-CF bronchiectasis. The aim of this pilot study was to compare the LCI with the FEV1 as well as the forced vital capacity (FVC), the forced expiratory flow at 25–75% of the FVC (FEF 25–75%), and chest imaging based on the modified Reiff score in patients with primary ciliary dyskinesia (PCD) and non-CF, non-PCD bronchiectasis (PCD-BE and nCFnPCD-BE). Additionally, we compared each test’s duration and the preferred technique. Twenty children were included; nine had PCD-BE and eleven had nCFnPCD-BE. The median age was twelve years (ages ranging between five and eighteen years). The median LCI was seven while the median z-scores of the FEV1, FVC, and FEF 25–75% were −0.6, 0, and −0.9, respectively. No significant associations or correlations were observed between LCI, spirometric parameters, or the modified Reiff score. However, nearly half of the population (n = 9) had an abnormal LCI, while only 10% had an abnormal FEV1. A total of 75% of children preferred MBW, despite it lasting five times longer than spirometry. In this paper, the authors suggest that LCI might be useful in a cohort of pediatric patients with PCD-BE and nCFnPCD-BE for detecting early lung function changes during their follow-up. Additionally, MBW seems to be preferred by patients. These data may encourage further studies on this topic.