bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization and genomic analysis of a lytic Stenotrophomonas maltophilia short-tailed phage A1432 revealed a new genus of the family Mesyanzhinovviridae
Authors: Li Shixia , Xu Man , Yang Deying , Yang Mei , Wu Hejing , Li Xuelian , Yang Changzhou , Fang Zheng , Wu Qingshan , Tan Leitao , Xiao Wei , Weng Qingbei
Published: June 2024

Stenotrophomonas maltophilia (S. maltophilia) is an emerging opportunistic pathogen that exhibits resistant to a majority of commonly used antibiotics. Phages have the potential to serve as an alternative treatment for S. maltophilia infections. In this study, a lytic phage, A1432, infecting S. maltophilia YCR3A-1, was isolated and characterized from a karst cave. Transmission electron microscopy revealed that phage A1432 possesses an icosahedral head and a shorter tail. Phage A1432 demonstrated a narrow host range, with an optimal multiplicity of infection of 0.1. The one-step growth curve indicated a latent time of 10 min, a lysis period of 90 min, a burst size of 43.2 plaque-forming units per cell. In vitro bacteriolytic activity test showed that phage A1432 was capable to inhibit the growth of S. maltophilia YCR3A-1 in an MOI-dependent manner after 2 h of co-culture. BLASTn analysis showed that phage A1432 genome shares the highest similarity (81.46%) with Xanthomonas phage Xoo-sp2 in the NCBI database, while the query coverage was only 37%. The phage contains double-stranded DNA with a genome length of 61,660 bp and a GC content of 61.92%. It is predicted to have 79 open reading frames and one tRNA, with no virulence or antibiotic resistance genes. Phylogenetic analysis using terminase large subunit and DNA polymerase indicated that phage A1432 clustered with members of the Bradleyvirinae subfamily but diverged into a distinct branch. Further phylogenetic comparison analysis using Average Nucleotide Identity, proteomic phylogenetic analysis, genomic network analysis confirmed that phage A1432 belongs to a novel genus within the Bradleyvirinae subfamily, Mesyanzhinovviridae family. Additionally, phylogenetic analysis of the so far isolated S. maltophilia phages revealed significant genetic diversity among these phages. The results of this research will contribute valuable information for further studies on their morphological and genetic diversity, will aid in elucidating the evolutionary mechanisms that give rise to them.
Evolutionary engineering and molecular characterization of cobalt-resistant Rhodobacter sphaeroides
Authors: Atay Güneş , Holyavkin Can , Can Hanay , Arslan Mevlüt , Topaloğlu Alican , Trotta Massimo , Çakar Zeynep Petek
Published: June 2024

With its versatile metabolism including aerobic and anaerobic respiration, photosynthesis, photo-fermentation and nitrogen fixation, Rhodobacter sphaeroides can adapt to diverse environmental and nutritional conditions, including the presence of various stressors such as heavy metals. Thus, it is an important microorganism to study the molecular mechanisms of bacterial stress response and resistance, and to be used as a microbial cell factory for biotechnological applications or bioremediation. In this study, a highly cobalt-resistant and genetically stable R. sphaeroides strain was obtained by evolutionary engineering, also known as adaptive laboratory evolution (ALE), a powerful strategy to improve and characterize genetically complex, desired microbial phenotypes, such as stress resistance. For this purpose, successive batch selection was performed in the presence of gradually increased cobalt stress levels between 0.1–15 mM CoCl2 for 64 passages and without any mutagenesis of the initial population prior to selection. The mutant individuals were randomly chosen from the last population and analyzed in detail. Among these, a highly cobalt-resistant and genetically stable evolved strain called G7 showed significant cross-resistance against various stressors such as iron, magnesium, nickel, aluminum, and NaCl. Growth profiles and flame atomic absorption spectrometry analysis results revealed that in the presence of 4 mM CoCl2 that significantly inhibited growth of the reference strain, the growth of the evolved strain was unaffected, and higher levels of cobalt ions were associated with G7 cells than the reference strain. This may imply that cobalt ions accumulated in or on G7 cells, indicating the potential of G7 for cobalt bioremediation. Whole genome sequencing of the evolved strain identified 23 single nucleotide polymorphisms in various genes that are associated with transcriptional regulators, NifB family-FeMo cofactor biosynthesis, putative virulence factors, TRAP-T family transporter, sodium/proton antiporter, and also in genes with unknown functions, which may have a potential role in the cobalt resistance of R. sphaeroides.
Histoplasmosis in patients living with HIV in Europe: review of literature
Authors: Kontogiannis Dimitra , Di Lorenzo Andrea , Zaçe Drieda , Benvenuto Domenico , Moccione Martina , Muratore Gianmarco , Giacalone Maria L. , Montagnari Giulia , Carnevale Laura , Mulas Tiziana , Coppola Luigi , Campogiani Laura , Sarmati Loredana , Iannetta Marco
Published: June 2024

Histoplasma capsulatum (var. capsulatum Hcc and duboisii Hcd), is a dimorphic fungus that causes histoplasmosis. It usually affects people coming from endemic areas, causing a variety of clinical manifestations up to progressive disseminated histoplasmosis (PDH), especially among people living with HIV (PLWH). We conducted a systematic review to assess histoplasmosis burden of PLWH in Europe. The review follows PRISMA guidelines, with protocol registered in PROSPERO (CRD42023429779). Seventy-eight articles were selected, including 109 patients (32 women). On overall, median age was 37 years. Forty-six patients were Americans, 39 Africans, 17 Europeans, 5 Asians, in 2 cases nationality was not specified. Cases were mainly diagnosed in Italy (28.4%), France (17.3%) and Spain (17.4%), with a north–south gradient. Six cases lacked epidemiologic links with endemic areas. Concerning CDC HIV staging at diagnosis, the information was available for 60 PLWH (55%) and all subjects were at stage C3 except for two subjects at stage B3. PDH was the AIDS-presenting illness in 39 patients. Most patients had a PDH (80.7%); other common extrapulmonary forms were isolated cutaneous histoplasmosis (7.3%), or lymphatic localization (2.7%). In 30 cases, the diagnosis was made by analyzing only one sample. For the remaining 79 cases, multiple samples were collected from each patient. Regarding the biological sample more frequently used for the diagnosis of histoplasmosis, bronchoalveolar lavage sample was taken from 39 patients, and tested positive in 51.3% of cases; 36 patients underwent a skin biopsy which was positive in 86.1% of cases and 28 patients performed bone-marrow biopsy, which led to the diagnosis of histoplasmosis in 92.9% of cases. The identification of Histoplasma capsulatum was available in 97 PLWH through examination of different samples: Hcc and Hcd were identified in 89 and 8 PLWH, respectively. Concerning therapies, 67.9% were treated with liposomal amphotericin B, 18.3% with itraconazole, 10 died pre-treatment. The overall mortality rate was 23.6%. Non-survivors exhibited more frequently gastrointestinal symptoms (p = 0.017), while cutaneous signs correlated with better survival (p = 0.05). Untreated patients faced higher mortality (p < 0.001). Histoplasmosis should be considered amongst opportunistic infection in PLWH, even in Europe, especially if patients originate from or have travelled to endemic areas.

Systematic review registration: The registration number is CRD42023429779.
Emerging role of exosomal microRNA in liver cancer in the era of precision medicine; potential and challenges
Authors: El Hayek Tarek , Alnaser-Almusa Osama Abdulwahab , Alsalameh Sulaiman Mamoun , Alhalabi Maya Taofik , Sabbah Ahmad Nedal , Alshehri Eman Abdullah , Mir Tanveer Ahmad , Mani Naresh Kumar , Al-Kattan Khaled , Chinnappan Raja , Yaqinuddin Ahmed
Published: June 2024

Exosomal microRNAs (miRNAs) have great potential in the fight against hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related death worldwide. In this study, we explored the various applications of these small molecules while analyzing their complex roles in tumor development, metastasis, and changes in the tumor microenvironment. We also discussed the complex interactions that exist between exosomal miRNAs and other non-coding RNAs such as circular RNAs, and show how these interactions coordinate important biochemical pathways that propel the development of HCC. The possibility of targeting exosomal miRNAs for therapeutic intervention is paramount, even beyond their mechanistic significance. We also highlighted their growing potential as cutting-edge biomarkers that could lead to tailored treatment plans by enabling early identification, precise prognosis, and real-time treatment response monitoring. This thorough analysis revealed an intricate network of exosomal miRNAs lead to HCC progression. Finally, strategies for purification and isolation of exosomes and advanced biosensing techniques for detection of exosomal miRNAs are also discussed. Overall, this comprehensive review sheds light on the complex web of exosomal miRNAs in HCC, offering valuable insights for future advancements in diagnosis, prognosis, and ultimately, improved outcomes for patients battling this deadly disease.
A method for the analysis of the oligomerization profile of the Huntington’s disease-associated, aggregation-prone mutant huntingtin protein by isopycnic ultracentrifugation
Authors: Bonavita Raffaella , Di Martino Rosaria , Cortone Giuseppe , Prodomo Antonello , Di Gennaro Mariagrazia , Scerra Gianluca , Panico Valentino , Nuzzo Silvia , Salvatore Marco , Williams Sarah V. , Vitale Fulvia , Caporaso Maria Gabriella , D’Agostino Massimo , Pisani Francesca M. , Fleming Angeleen , Renna Maurizio
Published: June 2024

Conformational diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases as well as ataxias and fronto-temporal disorders, are part of common class of neurological disorders characterised by the aggregation and progressive accumulation of mutant proteins which display aberrant conformation. In particular, Huntington’s disease (HD) is caused by mutations leading to an abnormal expansion in the polyglutamine (poly-Q) tract of the huntingtin protein (HTT), leading to the formation of inclusion bodies in neurons of affected patients. Furthermore, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of mutant HTT to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. There is still no successful strategy to treat HD. In addition, the current understanding of the biological processes leading to the oligomerization and aggregation of proteins bearing the poly-Q tract has been derived from studies conducted on isolated poly-Q monomers and oligomers, whose structural properties are still unclear and often inconsistent. Here we describe a standardised biochemical approach to analyse by isopycnic ultracentrifugation the oligomerization of the N-terminal fragment of mutant HTT. The dynamic range of our method allows one to detect large and heterogeneous HTT complexes. Hence, it could be harnessed for the identification of novel molecular determinants responsible for the aggregation and the prion-like spreading properties of HTT in the context of HD. Equally, it provides a tool to test novel small molecules or bioactive compounds designed to inhibit the aggregation of mutant HTT.
Exploring the neural and behavioral correlates of cognitive telerehabilitation in mild cognitive impairment with three distinct approaches
Authors: Caminiti Silvia Paola , Bernini Sara , Bottiroli Sara , Mitolo Micaela , Manca Riccardo , Grillo Valentina , Avenali Micol , De Icco Roberto , Capellari Sabina , Carlesimo Giovanni Augusto , Venneri Annalena , Tassorelli Cristina
Published: June 2024

Background

Currently, the impact of drug therapies on neurodegenerative conditions is limited. Therefore, there is a strong clinical interest in non-pharmacological interventions aimed at preserving functionality, delaying disease progression, reducing disability, and improving quality of life for both patients and their caregivers. This longitudinal multicenter Randomized Controlled Trial (RCT) applies three innovative cognitive telerehabilitation (TR) methods to evaluate their impact on brain functional connectivity reconfigurations and on the overall level of cognitive and everyday functions.

Methods

We will include 110 participants with mild cognitive impairment (MCI). Fifty-five participants will be randomly assigned to the intervention group who will receive cognitive TR via three approaches, namely: (a) Network-based Cognitive Training (NBCT), (b) Home-based Cognitive Rehabilitation (HomeCoRe), or (c) Semantic Memory Rehabilitation Training (SMRT). The control group (n = 55) will receive an unstructured home-based cognitive stimulation. The rehabilitative program will last either 4 (NBTC) or 6 weeks (HomeCoRe and SMRT), and the control condition will be adapted to each TR intervention. The effects of TR will be tested in terms of Δ connectivity change, obtained from high-density electroencephalogram (HD-EEG) or functional magnetic resonance imaging at rest (rs-fMRI), acquired before (T0) and after (T1) the intervention. All participants will undergo a comprehensive neuropsychological assessment at four time-points: baseline (T0), within 2 weeks (T1), and after 6 (T2) and 12 months (T3) from the end of TR.

Discussion

The results of this RCT will identify a potential association between improvement in performance induced by individual cognitive TR approaches and modulation of resting-state brain connectivity. The knowledge gained with this study might foster the development of novel TR approaches underpinned by established neural mechanisms to be validated and implemented in clinical practice.

Clinical trial registration: [https://classic.clinicaltrials.gov/ct2/show/NCT06278818], identifier [NCT06278818].
Tactile stimulation of young WAG/Rij rats prevents development of depression but not absence epilepsy
Authors: Balikci Aymen , Eryilmaz Ugur , Guler Vildan Keles , Ilbay Gul
Published: June 2024

Investigations in Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats that are susceptible to genetic absence epilepsy have demonstrated that environmental modifications affect absence seizures. Previously, we showed that neonatal tactile stimulations produce disease-modifying effect on genetically determined absence epilepsy and associated depression in Wag/Rij rats. The study presented here examined the effect of TS during late ontogenesis (adolescence and young adulthood) on epilepsy and depression outcomes in this genetically epileptic rat strain. On postnatal day (PND) 38, male WAG/Rij rats randomly were assigned to either the tactile stimulation (TS), handled or control group (unhandled) with 8 animals in each group. Following a 7-day adaptation period to their new surroundings, the animals were submitted to tactile stimulation from PND 45 to PND 90, five days per week, for 5 min daily. The tactile-stimulated rat was removed from its cage, placed on the experimenter’s lap, and had its neck and back gently stroked by the researcher. The handled rats were taken to another cage and left alone for 5 min daily from PND 45 to PND 90. The control rats were left undisturbed in their home cage, except for regular cage cleaning. After PND 90, all rats were left undisturbed until behavioral testing and EEG recording. When the animals were 7 months old, they were subjected to the sucrose consumption test (SCT) and the forced swimming test (FST). Electroencephalogram (EEG) recordings were made at 8 months of age in order to measure electroencephalographic seizure activity, thus, the spike–wave discharges (SWDs). Tactile-stimulated rats showed increased sucrose consumption and number of approaches to the sucrose solution in the SCT when compared with the handled and control rats. In the FST, rats in TS group showed lower immobility time and greater immobility latency, active swimming time and diving frequency than the handled and control rats. The duration and the number of seizures were not different amongst the groups. The data obtained suggest that TS in young rats is able to prevent depression in WAG/Rij rats.
The effects of reward and punishment on the performance of ping-pong ball bouncing
Authors: Yin Cong , Wang Yaoxu , Li Biao , Gao Tian
Published: June 2024

Introduction

Reward and punishment modulate behavior. In real-world motor skill learning, reward and punishment have been found to have dissociable effects on optimizing motor skill learning, but the scientific basis for these effects is largely unknown.

Methods

In the present study, we investigated the effects of reward and punishment on the performance of real-world motor skill learning. Specifically, three groups of participants were trained and tested on a ping-pong ball bouncing task for three consecutive days. The training and testing sessions were identical across the three days: participants were trained with their right (dominant) hand each day under conditions of either reward, punishment, or a neutral control condition (neither). Before and after the training session, all participants were tested with their right and left hands without any feedback.

Results

We found that punishment promoted early learning, while reward promoted late learning. Reward facilitated short-term memory, while punishment impaired long-term memory. Both reward and punishment interfered with long-term memory gains. Interestingly, the effects of reward and punishment transferred to the left hand.

Discussion

The results show that reward and punishment have different effects on real-world motor skill learning. The effects change with training and transfer readily to novel contexts. The results suggest that reward and punishment may act on different learning processes and engage different neural mechanisms during real-world motor skill learning. In addition, high-level metacognitive processes may be enabled by the additional reinforcement feedback during real-world motor skill learning. Our findings provide new insights into the mechanisms underlying motor learning, and may have important implications for practical applications such as sports training and motor rehabilitation.
The ethical significance of user-control in AI-driven speech-BCIs: a narrative review
Authors: van Stuijvenberg O. C. , Samlal D. P. S. , Vansteensel M. J. , Broekman M. L. D. , Jongsma K. R.
Published: June 2024

AI-driven brain-computed interfaces aimed at restoring speech for individuals living with locked-in-syndrome are paired with ethical implications for user’s autonomy, privacy and responsibility. Embedding options for sufficient levels of user-control in speech-BCI design has been proposed to mitigate these ethical challenges. However, how user-control in speech-BCIs is conceptualized and how it relates to these ethical challenges is underdetermined. In this narrative literature review, we aim to clarify and explicate the notion of user-control in speech-BCIs, to better understand in what way user-control could operationalize user’s autonomy, privacy and responsibility and explore how such suggestions for increasing user-control can be translated to recommendations for the design or use of speech-BCIs. First, we identified types of user control, including executory control that can protect voluntariness of speech, and guidance control that can contribute to semantic accuracy. Second, we identified potential causes for a loss of user-control, including contributions of predictive language models, a lack of ability for neural control, or signal interference and external control. Such a loss of user control may have implications for semantic accuracy and mental privacy. Third we explored ways to design for user-control. While embedding initiation signals for users may increase executory control, they may conflict with other aims such as speed and continuity of speech. Design mechanisms for guidance control remain largely conceptual, similar trade-offs in design may be expected. We argue that preceding these trade-offs, the overarching aim of speech-BCIs needs to be defined, requiring input from current and potential users. Additionally, conceptual clarification of user-control and other (ethical) concepts in this debate has practical relevance for BCI researchers. For instance, different concepts of inner speech may have distinct ethical implications. Increased clarity of such concepts can improve anticipation of ethical implications of speech-BCIs and may help to steer design decisions.
Primary retroperitoneal müllerian adenocarcinoma: a case report
Authors: Feng Xiaohui , Zhang Ping , Gao Feng
Published: June 2024

A 45-year-old woman presented with right hip pain for a month. Imaging results revealed that the left peritoneal mass was accompanied by metastases of the right sciatic branch, lung, and retroperitoneal lymph nodes. A biopsy of the left peritoneal mass was performed. The pathological morphology demonstrated clear cell adenocarcinoma. Immunohistochemical staining revealed a positive expression of keratin7 and PAX8 and a negative expression of keratin20, GCDFP-15, ER, PR, WT1, CDX2, villin, TTF-1, napsin-A, vimentin, calretinin, and GATA3. Finally, the diagnosis of primary retroperitoneal müllerian adenocarcinoma (PRMA) was confirmed. PRMA is a very rare type of primary retroperitoneal tumor. PRMA should be considered for the retroperitoneal mass.
A good response to anti-PD-1 monoclonal antibody plus SBRT in a patient with PD-L1-negative recurrent advanced esophageal cancer: a long-term follow-up case report of a possible abscopal effect
Authors: Hai Tao , Liu Jia , Lai Jialu , Zhou Lin
Published: June 2024

There are limited treatment options for recurrent advanced esophageal squamous cell carcinoma. A good response with a possible abscopal effect was observed in a patient with programmed death-ligand 1 (PD-L1)-negative recurrent advanced esophageal squamous cell carcinoma treated with an anti-PD-1 monoclonal antibody plus stereotactic body radiotherapy (SBRT). A 66-year-old male patient was diagnosed with recurrent advanced esophageal squamous cell carcinoma with multiple lung metastases (13 metastatic nodules in total) four months after completing radical radiotherapy plus concurrent and consolidated chemotherapy, and PD-L1 expression in the primary esophageal tumor was negative. This patient received 25 cycles of camrelizumab (an anti-PD-1 monoclonal antibody) in total plus upfront SBRT for two metastatic nodules, which was administered after the first cycle of camrelizumab. After this combined treatment, for most nontarget nodules, an obvious volume decrease and fuzzy change were observed, including two nodules that completely vanished. At the end of follow-up, the progression-free survival and duration of response of this patient were 34 months and 32 months, respectively. This case report indicated that an anti-PD-1 monoclonal antibody combined with SBRT was a promising therapeutic strategy for recurrent esophageal squamous cell carcinoma even in patients with negative PD-L1 expression.
Comparison of 18F-DCFPyL and 68Ga-PSMA-11 for 177Lu-PSMA-617 therapy patient selection
Authors: Yadav Surekha , Kim Sarasa T. , Tuchayi Abuzar Moradi , Jiang Fei , Morley Amanda , Saelee Rachelle , Wang Yingbing , Juarez Roxanna , Lawnh-Heath Courtney , Koshkin Vadim S. , Hope Thomas A.
Published: June 2024

Purpose

68Ga-PSMA-11 is recommended for the selection of patients for treatment in the package insert for 177Lu-PSMA-617. We aimed to compare imaging properties and post-treatment outcomes from radioligand therapy (RLT) of patients selected with 68Ga-PSMA-11 and 18F-DCFPyL.

Methods

We retrospectively evaluated 80 patients undergoing PSMA RLT, who had pretreatment imaging using either 68Ga-PSMA-11 or 18F-DCFPyL. For both groups, we compared the biodistribution and lesion uptake and the PSA response to treatment.

Results

Both agents had comparable biodistribution. Patients initially imaged with 18F-DCFPyL had a higher PSA response (66% vs. 42%), and more patients had a PSA50 response (72% vs. 43%) compared to patients imaged with 68Ga-PSMA-11.

Conclusion

18F-DCFPyL and 68Ga-PSMA-11 had comparable biodistribution and lesion uptake. Patients imaged with 18F-DCFPyL demonstrated clinical benefit to PSMA RLT comparable to those imaged with 68Ga-PSMA-11, and either agent can be used for screening patients.
What are the needs in oral antitumor therapy? An analysis of patients’ and practitioners’ preferences
Authors: Hester Anna , Henze Franziska , Debes Anna Marie , Schubert Charlotte Leonie , Koenig Alexander , Harbeck Nadia , Wuerstlein Rachel
Published: June 2024

Background

Since the European approval of CDK4/6 inhibitors in 2016, the treatment of patients with hormone-receptor-positive, HER2-negative metastatic breast cancer has changed significantly. Compared with chemotherapy, endocrine-based therapy has different treatment regimens and is associated with new side effects. Oral therapy aims for optimal drug efficacy and long treatment times while maintaining maximum independence and quality of life resulting in the conservation of medical staff resources.

Methods

A monocentric analysis of therapy preferences of practitioners (25 nurses and physicians) and patients (11 on endocrine monotherapy, 17 on endocrine-based therapy, and 14 on intravenous chemotherapy) was performed using specific questionnaires. Preferences were assessed using a four-point Likert scale or bidirectional response options.

Results

All patients were highly supportive of oral therapy (mean agreement score on the Likert scale 1.3, p < 0.001 vs. all other options) and a consultation interval of 4 weeks (2.0, p = 0.015 vs. 3 weeks). Practitioners also preferred oral therapy (1.4) and visits every 4 weeks (1.6). In general, patients on oral therapies reported higher compatibility of their therapy with daily life than patients on chemotherapy (1.6 and 1.7 vs. 2.6, p = 0.006). Outpatient oncology is the main source of information for all patients, mainly in case of side effects (2.0) and open questions (1.8). Regarding oral antitumor therapy regimens, patients do not show a significant preference for a specific regimen, while practitioners prefer a continuous regimen (1.6) over a 21/7 regimen (21 days on and 7 days off therapy, 2.5). Patients are likely to accept mild side effects (e.g., neutropenia, diarrhea, polyneuropathy, fatigue) and would still adhere to their initial choice of regimen (continuous or 21/7). Only when side effects occur with a severity of CTCAE grade 3 do patients prefer the regimen in which the side effects occur for a shorter period of time.

Conclusion

Patients and practitioners prefer oral antitumor therapy—both continuous and 21/7 regimens—over other application forms. Patient education and proper therapy management, supported by additional tools, contribute to the specific management of side effects and high adherence. This allows quality of life to be maintained during long-term therapy with CDK4/6 inhibitors in patients with metastatic breast cancer.
Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance
Authors: Berckmans Yani , Ene Hila M. , Ben-Meir Kerem , Martinez-Conde Antonia , Wouters Roxanne , Van den Ende Bieke , Van Mechelen Sara , Monin Roni , Frechtel-Gerzi Roni , Gabay Hila , Dor-On Eyal , Haber Adi , Weinberg Uri , Vergote Ignace , Giladi Moshe , Coosemans An , Palti Yoram
Published: June 2024

Background

Ovarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models.

Methods

A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed.

Results

The nature of TTFields-drug interaction was dependent on the drug’s underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control.

Conclusion

By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.
Assessment of different head tilt angles in volumetric modulated arc therapy for hippocampus-avoidance whole-brain radiotherapy
Authors: Yuan Cuiyun , Xu Sisi , Li Yang , Quan Enzhuo , Chen Dongjie , Liang Jun , Liu Chenbin
Published: June 2024

Purpose

In the field of radiation therapy for brain metastases, whole-brain hippocampus-avoidance treatment is commonly employed. this study aims to examine the impact of different head tilt angles on the dose distribution in the whole-brain target area and organs at risk. It also aims to determine the head tilt angle to achieve optimal radiation therapy outcomes.

Methods

CT images were collected from 8 brain metastases patients at 5 different groups of head tilt angle. The treatment plans were designed using the volumetric modulated arc therapy (VMAT) technique. The 5 groups of tilt angle were as follows: [0°,10°), [10°,20°), [20°,30°), [30°,40°), and [40°,45°]. The analysis involved assessing parameters such as the uniformity index, conformity index, average dose delivered to the target, dose coverage of the target, hot spots within the target area, maximum dose, and average dose received by organs at risk. Additionally, the study evaluated the correlation between hippocampal dose and other factors, and established linear regression models.

Results

Significant differences in dosimetric results were observed between the [40°,45°] and [0°,10°) head tilt angles. The [40°,45°] angle showed significant differences compared to the [0°,10°) angle in the average dose in the target area (31.49 ± 0.29 Gy vs. 31.99 ± 0.29 Gy, p=0.016), dose uniformity (1.20 ± 0.03 vs. 1.24 ± 0.03, p=0.016), hotspots in the target area (33.64 ± 0.35 Gy vs. 34.42 ± 0.49 Gy, p=0.016), maximum hippocampal dose (10.73 ± 0.36 Gy vs. 11.66 ± 0.59 Gy, p=0.008), maximum dose in the lens (2.82 ± 1.10 Gy vs. 4.99 ± 0.16 Gy, p=0.016), and average dose in the lens (1.93 ± 0.29 Gy vs. 4.22 ± 0.26 Gy, p=0.008). There is a moderate correlation between the maximum dose in the hippocampi and the PTV length (r=0.49, p=0.001). Likewise, the mean dose in the hippocampi is significantly correlated with the hippocampi length (r=0.34, p=0.04).

Conclusion

The VMAT plan with a head tilt angle of [40°,45°] met all dose constraints and demonstrated improved uniformity of the target area while reducing the dose to organs at risk. Furthermore, the linear regression models suggest that increasing the head tilt angle within the current range of [0°,45°] is likely to lead to a decrease in the average hippocampal dose.
Exploring potential predictive biomarkers through historical perspectives on the evolution of systemic therapies into the emergence of neoadjuvant therapy for the treatment of hepatocellular carcinoma
Authors: Wang Chuanlei , Wei Feng , Sun Xiaodong , Qiu Wei , Yu Ying , Sun Dawei , Zhi Yao , Li Jing , Fan Zhongqi , Lv Guoyue , Wang Guangyi
Published: June 2024

Hepatocellular carcinoma (HCC), a type of liver cancer, ranks as the sixth most prevalent cancer globally and represents the third leading cause of cancer-related deaths. Approximately half of HCC patients miss the opportunity for curative treatment and are then limited to undergoing systemic therapies. Currently, systemic therapy has entered the era of immunotherapy, particularly with the advent of immune-checkpoint inhibitors (ICIs), which have significantly enhanced outcomes for patients with advanced HCC. Neoadjuvant treatment for HCC has become a possibility—findings from the IMbrave 050 trial indicated that ICIs offer the benefit of recurrence-free survival for high-risk HCC patients post-resection or local ablation. However, only a small fraction of individuals benefit from systemic therapy. Consequently, there is an urgent need to identify predictive biomarkers for treatment response and outcome assessment. This study reviewed the historical progression of systemic therapy for HCC, highlighting notable therapeutic advancements. This study examined the development of systemic therapies involving conventional drugs and clinical trials utilized in HCC treatment, as well as potential predictive biomarkers for advanced and/or locally advanced HCC. Various studies have revealed potential biomarkers in the context of HCC treatment. These include the association of dendritic cells (DCs) with a favorable response to neoadjuvant therapy, the presence of enriched T effector cells and tertiary lymphoid structures, the identification of CD138+ plasma cells, and distinct spatial arrangements of B cells in close proximity to T cells among responders with locally advanced HCC receiving neoadjuvant cabozantinib and nivolumab treatment. Furthermore, pathological response has been associated with intratumoral cellular triads consisting of progenitor CD8+ T cells and CXCL13+ CD4+ T helper cells surrounding mature DCs in patients receiving neoadjuvant cemiplimab for resectable HCC. Despite no widely recognized predictive biomarkers for HCC individualized treatment, we believe neoadjuvant trials hold the most promise in identifying and validating them. This is because they can collect multiple samples from resectable HCC patients across stages, especially with multi-omics, bridging preclinical and clinical gaps.
Nuttalliella namaqua Bedford, 1931, a sole extant species of the genus Nuttalliella – a scoping review
Authors: Ledwaba Maphuti Betty , Malatji Dikeledi Petunia
Published: June 2024

Nuttalliella namaqua Bedford, 1931 is the sole extant tick species that belongs to the genus and family Nuttalliella and Nuttalliellidae respectively. With the characteristics that are respectively distinctive to hard and soft ticks, it is regarded as the species closest to the ancestral lineage of ticks as well as the missing link between the Argasidae and Ixodidae families. In this review, literature search of the articles reporting on N. namaqua was done in Google Scholar and PubMed databases. After relevance and eligibility screening, 12 articles were deemed eligible and appraised. The results showed that N. namaqua was respectively distinct to limited regions of Africa such as Botswana, Namibia, Mozambique, South Africa and Tanzania. The review also indicated that N. namaqua was collected from murid rodents, African Savanna hare, scrub hare, elephant shrews, rock hyraxes, black backed jackal, lizards and off-host in locations that include under a stone, rock crevices, on a rock wall and respectively in the nests of an eagle and a lesser striped swallow. Irrespective of all the reports, natural hosts of the nymphs are still not clearly defined. Numerous phylogeny studies have reported Nuttalliellidae as the sister-lineage to Argasidae and Ixodidae tick families. Moreover, a recent report indicated that the similarities between Nuttalliellidae and the fossil families Deinocrotonidae and Legionaris award them to be merged into one family, preferably Nuttalliellidae Thus, further research on this family, will perhaps provide more knowledge about its unclear distribution, life cycle as well as the evolution of ticks in general.
Family resilience mediates exposure to adverse childhood experiences on insufficient sleep among children: findings from a population-based study
Authors: Baiden Philip , Vazquez Christian E. , LaBrenz Catherine A. , Brown Fawn A.
Published: June 2024

Background

Sleep plays a vital role in the well-being of children and adolescents. Researchers have identified adverse childhood experiences (ACEs) as an important factor associated with poor sleep among adolescents. The objective of this study was to examine the mediating role of family resilience on the association between ACEs and insufficient sleep among adolescents in the United States.

Methods

Data for this study came from the 2018–2019 National Survey of Children's Health (N = 28,097). The outcome variable in this study was insufficient sleep, and the main explanatory variable was exposure to ACEs. The mediating variable was family resilience. Data were analyzed using binary logistic regression.

Results

Based on parent reports, one in five (22.4%) adolescents did not meet the recommended sleep hours on an average night. About half of the adolescents had no ACEs, 24.2% had one ACE, and 14.6% had three or more ACEs. Controlling for the effect of other factors and family resilience, the odds of having insufficient sleep were 1.63 times higher for children exposed to three or more ACEs (AOR = 1.63, 95% CI = 1.30–2.05). Family resilience partially mediates the association between exposure to ACEs and insufficient sleep. Each additional increase in family resilience decreased the odds of having insufficient sleep by a factor of 12% (AOR = 0.88, 95% CI = 0.86–0.91).

Conclusions

Family resilience partially mediated exposure to ACEs on insufficient sleep. There are modifiable factors that may improve sleep outcomes among adolescents who have been exposed to adversity. Future research can help elucidate findings and establish the directionality of this association.
The impact of combined administration of ropivacaine and dexamethasone on postoperative analgesia in perianal surgery with pudendal nerve block under ultrasound guidance: a prospective randomized controlled study
Authors: Yang Tao-Ran , Pu Dan , Cheng Yan , Fan Cheng-Xi , Hu Ya-Jun , Wang Ru-Rong , Li Xue-Han
Published: June 2024

Background

In recent years, severe pain after perianal surgery has seriously affected the prognosis of hospitalized patients. How to maximize the improvement of postoperative pain and perioperative comfort becomes particularly important.

Methods

This study was a double-blind randomized controlled trial (Registration No.: ChiCTR2100048760, Registration Date: 16 July 2021, Link: www.chictr.org.cn/showproj.html?proj=130226), and patients were randomly divided into two groups: one group underwent postoperative 20 mL bilateral pudendal nerve block with 0.5% ropivacaine (P group), and the other group underwent postoperative 20 mL bilateral pudendal nerve block with 0.5% ropivacaine + 8 mg dexamethasone (PD group). The primary outcome was the incidence of moderate to severe pain at the first postoperative dressing change. Secondary outcomes included Quality of recovery-15 (QoR-15) score at 3 days after surgery, sleep quality, pain score at 3 days after surgery, and incidence of adverse events.

Results

In the main outcome indicators, the incidence was 41.7% in the P group and 24.2% in the PD group (p = 0.01). The QoR-15 score and sleep quality in PD group were better than those in P group 2 days before surgery. The incidence of postoperative urinary retention was significantly decreased in PD group (p = 0.01).

Conclusion

Local anesthesia with dexamethasone combined with pudendal nerve block after perianal surgery can reduce the incidence of moderate to severe pain during the first dressing change. This may be one of the approaches to multimodal analgesia after perianal surgery.

Clinical Trial Registration

https://www.chictr.org.cn/, identifier ChiCTR2100048760.
Case report: dose-dependent interaction between dexamethasone and voriconazole in severely ill patients with non-Hodgkin’s lymphoma being treated for invasive pulmonary aspergillosis
Authors: Huang Jingjing , Chen Yang , Zhong Ming , Tan Ruoming
Published: June 2024

Background

Voriconazole is primarily metabolized by CYP2C19 and CYP3A4. Drug interactions that affect this pathway can alter its plasma exposures, resulting in untargeted voriconazole concentrations.

Case summary

In this case report, we describe the case of a 64-year-old man who was treated for non-Hodgkin’s lymphoma with continuous glucocorticoids co-administrated with voriconazole against invasive pulmonary aspergillosis. A decrease in trough concentration (Cmin) of voriconazole was observed and related with co-administration of dexamethasone in the patient carrying the CYP2C19 *1*2 genotype: voriconazole Cmin/dose ratios of 0.018 (0.1 mg L−1/5.7 mg kg−1 day−1), 0.18 (1 mg L−1/5.7 mg kg−1 day−1), and 0.23 (2 mg L−1/8.6 mg kg−1 day−1) at dexamethasone doses of 20, 12.5, and 2.5 mg, respectively. Sub-therapeutic voriconazole Cmin was associated with high- and moderate-dose dexamethasone (20 and 12.5 mg), leading to failure of antifungal treatment.

Conclusion

The extent of voriconazole–dexamethasone interaction was determined by the dose of dexamethasone and associated with the CYP2C19 *1*2 genotype. Therapeutic drug monitoring of voriconazole is necessary to avoid clinically relevant interactions for optimal antifungal therapy.
Enhancing water stress tolerance of bread wheat during seed germination and seedling emergence: caffeine-induced modulation of antioxidative defense mechanisms
Authors: Ali Qasim , Perveen Rashida , Saeed Farah , Manzoor Hunaina , Ali Shafaqat , Hussain Muhammad Iftikhar , Ahmad Ajaz
Published: June 2024

Better crop stand establishment, a function of rapid and uniform seedling emergence, depends on the activities of germination-related enzymes, which is problematic when there is insufficient soil moisture. Different ways are in practice for counteracting this problem, including seed priming with different chemicals, which are considered helpful in obtaining better crop stand establishment to some extent through improved seed germination and seedling emergence. In this growth room experiment, caffeine was used as a seed priming agent to improve germination under moisture scarcity. Polyethylene glycol-8000 (18%) was added to Hoagland’s nutrient solution to create drought stress (−0.65 MPa). The experiment was arranged in a completely randomized design (CRD), having four replications of each treatment. A newly developed wheat genotype SB-1 was used for the experimentation. Different doses of caffeine, i.e., 4 ppm, 8 ppm, 12 ppm, and 16 ppm, including no soaking and water soaking, were used as seed priming treatments. Water deficit caused oxidative stress and adversely affected the seed germination, seedling vigor, activities of germination enzymes, photosynthetic pigments, and antioxidative defense mechanism in roots and shoots of seedlings. Caffeine seed priming ameliorated the negative effects of water deficit on seed germination and seedling vigor, which was attributed to the reduction in lipid peroxidation and improvement in the activities of germination-related enzymes like glucosidase, amylase, and protease. Conclusively, seed priming with 12 ppm caffeine outperformed the other treatments and hence is recommended for better crop stand establishment under conditions of soil moisture deficit.
An insight into the roles of ubiquitin-specific proteases in plants: development and growth, morphogenesis, and stress response
Authors: Wang Xiuwen , Liu Xuan , Song Kaixuan , Du Liang
Published: June 2024

Ubiquitination is a highly conserved and dynamic post-translational modification in which protein substrates are modified by ubiquitin to influence their activity, localization, or stability. Deubiquitination enzymes (DUBs) counter ubiquitin signaling by removing ubiquitin from the substrates. Ubiquitin-specific proteases (UBPs), the largest subfamily of DUBs, are conserved in plants, serving diverse functions across various cellular processes, although members within the same group often exhibit functional redundancy. Here, we briefly review recent advances in understanding the biological roles of UBPs, particularly the molecular mechanism by which UBPs regulate plant development and growth, morphogenesis, and stress response, which sheds light on the mechanistic roles of deubiquitination in plants.
Unusual vitamin E profile in the oil of a wild African oil palm tree (Elaeis guineensis Jacq.) enhances oxidative stability of provitamin A
Authors: Gutbrod Philipp , Pottier Delphine , Shirvani Safoora , Gutbrod Katharina , Djien-Nyami Félicité , Emade Ngoudjede Raïssa , Ngando-Ebongue Georges , Dörmann Peter
Published: June 2024

Introduction

The African oil palm (Elaeis guineensis Jacq.) is the predominant oil crop in the world. In addition to triacylglycerols, crude palm oil (CPO) extracted from the mesocarp of the fruits, contains high amounts of provitamin A (carotenes) and vitamin E (tocochromanols). Because of their unsaturated nature, the carotenes are prone to oxidation and therefore are in part limiting for the shelf life of CPO.

Methods

A tree with unusual toochromanol composition was identified by HPLC screening of the mesocarp of wild trees. Polymorphisms in a candidate gene were identified by DNA sequencing. The candidate protein was heterologously expressed in Escherichia coli coli and Arabidopsis thaliana to test for enzyme activity. Oxidative stability of the CPO was studied by following carotene degradation over time.

Results

In the present study, a wild Oil Palm tree (C59) from Cameroon was identified that lacks α-tocopherol and α-tocotrienol and instead accumulates the respective γ forms, suggesting that the activity of γ-tocopherol methyltransferase (VTE4) was affected. Sequencing of the VTE4 locus in the genome of plant C59 identified a G/C polymorphism that causes the exchange of a highly conserved tryptophan at position 290 with serine. The W290S exchange renders the VTE4 enzyme inactive, as shown after expression in Escherichia coli and Arabidopsis thaliana. The oxidative stability of carotenes in the mesocarp of the wild palm C59 was enhanced compared with control accessions. Furthermore, supplementation of commercial palm oil with different tocochromanols showed that γ-tocotrienol exerts a stronger effect during the protection of carotenes against oxidation than α-tocotrienol.

Discussion

Therefore, the introduction of the high γ-tocotrienol trait into elite breeding lines represents a potent strategy to protect carotenes against oxidation and extend the shelf life of CPO, hence allowing the development of a value added high-carotene CPO to be used to fight against vitamin A deficiency.