bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Ib trial of durvalumab plus tremelimumab in combination with particle therapy in patients with advanced hepatocellular carcinoma with macrovascular invasion: DEPARTURE trial.
Authors: Koroki Keisuke , Ogasawara Sadahisa , Makishima Hirokazu , Wakatsuki Masaru , Takahashi Asahi , Kanzaki Hiroaki , Kobayashi Kazufumi , Inoue Masanori , Kiyono Soichiro , Nakamura Masato , Kanogawa Naoya , Kondo Takayuki , Nakamoto Shingo , Shiko Yuki , Ozawa Yoshihito , Inaba Yosuke , Kurokawa Tomoya , Hanaoka Hideki , Yamada Shigeru , Kato Naoya
Published: August 2024

34

Background: The HIMALAYA trial established the combination of durvalumab and tremelimumab (STRIDE) as first-line treatment for advanced hepatocellular carcinoma (HCC). Carbon ion radiotherapy (C-ion RT) allows precise tumor targeting while sparing nearby normal tissue. Our strategy used C-ion RT to target a key tumor with macrovascular invasion (MVI) for disease management and potential MVI control, complemented by STRIDE. Recognising that C-ion RT stimulates immune responses, we posited that merging C-ion RT with STRIDE might enhance therapeutic effects. We present updated data of additional follow-up. Methods: This is a Phase Ib, multicenter study evaluating durvalumab with particle beam radiotherapy in HCC patients with MVI (Cohort A) and STRIDE (Cohort B). Both cohorts began with patients resistant to standard treatments. After safety confirmation, the study expanded to include therapy-naïve patients, totaling 15. C-ion RT begins after day 8 of the first cycle, following the initial drug dose. The relative biological effectiveness weighted dose is set at 60 Gy in four fractions over one week, targeting one representative intrahepatic nodule with MVI. The primary endpoint is adverse event rates, including dose limiting toxicity (DLT), with secondary endpoints on progression free survival (PFS) and overall survival (OS) (jRCT2031210046). This analysis of OS was conducted from the additional follow-up data from the primary analysis. Results: From July 2021 to January 2023, 15 advanced HCC patients were enrolled in our study (Cohort A: 3, Cohort B: 12). Four in Cohort B were systemic therapy-naïve. All cases confirmed MVI radiologically; with tumor invasion observed in the main portal vein for 4 patients and in the inferior vena cava for one. DLT evaluations in 3 from each cohort showed no incidents. While Cohort A had no adverse events, 4 patients in Cohort B (26.7%) experienced serious treatment-related adverse events. The median PFS was a significant 4.67 months (95%CI, 1.35–6.64). At the clinical cut-off date of March 31, 2024, 10 OS events were observed. The median OS was 10.4 months (95% CI, 5.6–15.2), and the 6- and 12-month OS rates were 66.7% and 46.7%, respectively. Conclusions: The safety of STRIDE in combination with particle therapy has been confirmed in advanced HCC with MVI. This combination, especially the irradiation of tumors with MVI using C-ion RT, holds promise in managing prognostic determinant tumors and potentially enhancing OS. Clinical trial information: jRCT2031210046 .
Association between the occurrence of immune-related adverse events and survival outcomes in patients with cancer treated with perioperative immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Komatsu Taiga , Chida Kohei , Horita Nobuyuki , Cortellini Alessio , Naqash Abdul Rafeh , Fujiwara Yu
Published: August 2024

39

Background: Although multiple studies have revealed that the occurrence of immune-related adverse events (irAEs) is associated with better survival in patients with advanced cancer, the association in patients with early-stage disease in the perioperative setting remains unclear. We performed a systematic review and meta-analysis to evaluate this association in the neoadjuvant and adjuvant settings. Methods: We performed a database search in PubMed/MEDLINE and Embase to identify eligible articles up to March 2024. We included studies evaluating the association between the occurrence of irAEs and survival outcomes in patients with solid tumors receiving at least one ICI in the perioperative setting. Cancer type, ICI agent, the number of patients, and survival outcomes (hazard ratio [HR] with 95% confidence interval [CI]) were summarized. We performed a random-effect model meta-analysis of survival outcomes that contained HR and 95% CI information from more than two studies. Results: After screening 884 articles, we found 15 eligible articles of which four studies reporting only treatment-related adverse events without irAE information were excluded. Finally, 11 studies (Clinical trials: n=3, Cohort studies: n=8) analyzing the association between the incidence of irAEs and survival were identified. Melanoma, triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and urothelial carcinoma were evaluated in seven, two, one, and one study, respectively. While ten studies defined the irAE group as any-type and any-grade irAEs, one study defined the irAE group as any-type and grade 2-5 irAEs. OS was evaluated in five studies (four studies for melanoma), of which two studies suggested that the occurrence of irAEs was associated with longer OS. A meta-analysis of three studies showed a tendency of the association between the occurrence of any-type and any-grade irAEs and longer OS (Pooled HR=0.69, 95% CI 0.47-1.00, p = 0.05). RFS was evaluated in eight studies (seven for melanoma), of which seven studies indicated the association between the incidence of any-type irAEs (any-grade: 6 studies, grade 2-5: 1 study) and longer RFS. A meta-analysis of five studies revealed a significant association between the occurrence of any-type irAEs (any-grade: 4 studies, grade 2-5: 1 study) and longer RFS (Pooled HR=0.52, 95% CI 0.41 - 0.67, p < 0.0001]); however, Funnel plot indicated a presence of publication bias. Conclusions: This study suggests an association between irAEs and longer survival from perioperative ICI therapy, particularly in patients with melanoma. The result should be cautiously interpreted given a possible presence of publication and immortal bias. Further prospective studies and individual patient data meta-analysis are needed to validate this result.
Predictive analysis of breast cancer metastasis and identification of genetic markers using machine learning.
Authors: Umadevi Kovuri , Sundeep Dola
Published: August 2024

4

Background: The study devises a framework integrating machine learning (ML) paradigms with explainable artificial intelligence (XAI) to prognosticate the metastatic trajectory of breast cancer (BC) and delineate critical genomic indicators pertinent to metastasis. Methods: An examination was conducted on 98 initial BC specimens, which included 34 instances evolving into distant metastasis within a quintennial monitoring phase and 44 instances evincing no recurrence for a minimum pentad post-diagnosis. Genomic datasets underwent rigorous biostatistical scrutiny, followed by the implementation of an elastic net algorithm for feature discernment, thereby constraining the scope to a salient subset of genomic markers implicated in BC metastasis. An ensemble of advanced predictive models encompassing Light Gradient Boosting Machine (LightGBM), Categorical Boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Gradient Boosting Trees (GBT), and Adaptive Boosting (AdaBoost) was deployed. Model efficacy was gauged through metrics such as accuracy, F1 score, precision, recall, the Area Under the Receiver Operating Characteristic Curve (AUC), and the Brier score. To elucidate the reasoning behind the ML predictions and to navigate the opacity inherent in such models, a SHapley Additive exPlanations (SHAP) approach was invoked. Results: The predictive acumen of the LightGBM model was superior, evidenced by a striking accuracy of 96% and an AUC of 99.3%. Parallel to biostatistical assessments, SHAP analysis leveraging XAI illuminated that augmented expression levels of specific genes, namely TSPYL5, ATP5E, CA9, NUP210, SLC37A1, ARIH1, PSMD7, UBQLN1, PRAME, and UBE2T (with statistical significance p ≤ 0.05), correlated with an escalated risk of BC metastasis. Conversely, diminished expression of CACTIN, TGFB3, SCUBE2, ARL4D, OR1F1, ALDH4A1, PHF1, and CROCC (p ≤ 0.05) was similarly associated with heightened metastatic susceptibility in BC. Conclusions: The insights garnered from this investigation may catalyze preventative strategies against BC progression and metastatic dissemination, thereby enhancing therapeutic efficacy through personalized intervention modalities for BC patients.
Use of a novel proteomimetic nanoplatform for simultaneous delivery of antigens with adjuvants to impact tumor growth in multiple tumor models.
Authors: Wang Max Mu
Published: August 2024

40

Background: Patient-specific cancer vaccines derived from tumor antigen have been explored as a promising therapeutic strategy, however, challenges delivering vaccine components in a coordinated fashion to elicit antitumor responses remain. To overcome these, we utilize a novel nanoplatform called the Protein-Like Polymer (PLP), which allows for sustained and targeted delivery of tumor antigens in conjunction with adjuvants. Methods: PLPs containing peptide antigens were synthesized via ROMP and characterized. A library of compounds with different sidechain linkage chemistries, degrees of polymerization (DP), and inclusion/exclusion of Oligo-ethylene glycol (OEG) were made to determine design rules for immune activation. Cell uptake and functional assays using payload-specific T Cells were conducted. Immunization in three independent tumor models was done to show generalizability. Ability of PLPs to co-deliver adjuvants was tested by electrostatically coupling small molecule STING agonist, 2’3’ cGAMP. Results: Conjugating antigens to the polymer via a cleavable disulfide linkage, which reduces intracellularly in APCs, resulted in increased endosomal localization, higher levels of induced T cell proliferation, cytokine production, and expression of activation markers in CTLs and APCs. Incorporating a diluent amount of OEG side chains reduced enzymatic degradation while increasing immunogenicity and uptake. Additionally, increasing the DP, and therefore the density of antigen side chains, further improved vaccine efficacy and resistance to proteolysis. Antigen-PLP conjugates enhanced dendritic cell activation and T-cell response only when paired with cells from their cognate system, with no activity in immune cells not expressing receptors for the payload demonstrating antigen-specificity. Mice bearing established B16F10, MC38, or TC-1 tumors treated with PLPs containing gp100, adpgk, or E7 respectively all showed increased survival times, reduced tumor burden with corresponding changes in immune cell profiles, and immunological memory upon rechallenge. Impressively, mice treated with STING-PLP complexes had significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p < 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which traditionally requires intratumoral injection. Studies on the effects of vaccinating with pools of neoantigens multiplexed onto one PLP are ongoing. Conclusions: This work validates the ability of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling, highlighting its potential to revolutionize cancer vaccinology.
Effect of oncolytic Newcastle disease virus harboring PTEN gene on pancreatic adenocarcinoma growth through inhibition of PI3K/mTOR signaling and promotion of apoptosis.
Authors: Jang Hyun
Published: August 2024

49

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and intractable cancer, warranting the need for more effective therapies. Cell proliferation, progression, and severity in PDAC are highly activated owing to KRAS mutations and low PTEN expression. Methods: A recombinant Newcastle disease virus (rNDV) harboring PTEN (rNDV-PTEN) was constructed to infect PDAC cells to artificially induce PTEN expression. The cancer killing effect of the rNDV-PTEN virus was observed in an in vitro assay, and 107.0 pfu/dose(0.1 ml) of the rNDV-PTEN virus was inoculated through intravenous injection into a PANC-1 cell transplanted mouse to prove the tumor growth inhibition effect. Apoptotic signaling-related proteins were analyzed with Western blotting and qPCR assays based on the mRNA. During the treatment, biomarkers were also analyzed. Results: Factitious PTEN expression in KRAS-mutated PDAC cells following rNDV-PTEN infection lowered PI3K/AKT/mTOR signaling, induced PDAC cell death, and suppressed tumor growth. PTEN overexpression promoted apoptotic and autophagic signaling pathways in PANC-1 cells and orthotopic xenograft mice. rNDV-PTEN has substantial cancer cell-killing effects and inhibits tumor growth. rNDV-PTEN injection into animals did not elicit an immune response against rNDV and improved blood parameters, such as glucose, triglyceride, and total cholesterol levels. Conclusions: rNDV-PTEN showed a strong tumor-suppressive effect on PDAC, which was caused by an abnormally activated PI3K/AKT/mTOR signaling pathway due to KRAS mutations and PTEN loss. We also showed that rNDV-PTEN is relatively safe for use in cancer therapy. Further studies using patient-derived PDAC cells with the same genetic background, as well as more extensive animal safety tests, are required to demonstrate rNDV-PTEN as a PDAC therapeutic. However, PTEN gene-containing rNDV may be a very promising therapeutic candidate for pancreatic cancer treatment.
Quantitative evaluation of oncogenic KRAS signaling and therapeutic effects of molecular-targeted drugs in living cells by single-molecule imaging.
Authors: Yokoi Ryoma , Tajima Jesse Yu , Kiyama Shigeru , Tanaka Yoshihiro , Murase Katsutoshi , Futamura Manabu , Suzuki Kenichi , Matsuhashi Nobuhisa
Published: August 2024

76

Background: Oncogenic KRAS mutations pose challenges due to their constitutive activation and resistance to drugs in colorectal cancer. However, several aspects remain unresolved. Single-molecule imaging has revealed distinct behaviors of KRAS. Inactive KRAS wild-type (WT) molecules exhibit continuous lateral diffusion on the plasma membrane, while activated or oncogenic KRAS molecules display slower diffusion and transient trapping due to interactions with signaling molecules. These observations suggest that the overall signal intensity of KRAS within a cell is finely regulated by integrating short-term pulse signals during transient trapping. Methods: We conducted single-molecule observations of KRAS (WT, G13D, and G12D/C/V) in living colon cancer cells, both with and without molecular-targeted drugs, before and after EGF stimulation. We quantitatively analyzed their diffusional behavior to evaluate KRAS signaling and the therapeutic effects of molecular-targeted drugs. Results: The temporal fraction of trapped KRAS WT was highest at 2 minutes (6.4%) and decreased to pre-activation level (3.0%) at 5 minutes after EGF stimulation. Although the temporal fractions of trapped KRAS mutants were higher than those of KRAS WT both before stimulation (5%) and after stimulation (10%), their diffusional behaviors were mutation-specific. The temporal fraction of trapped KRAS G13D increased sharply, and those of KRAS G12D and G12C increased at a moderate rate, while that of KRAS G12V did not elevate after EGF stimulation. Cetuximab treatment significantly reduced the temporal fraction of trapped KRAS WT after stimulation, but only moderately decreased those of KRAS mutants. Notably, transient trappings of KRAS G12D and G12C were abrogated by KRAS inhibitors, and the combined therapy of KRAS inhibitors and cetuximab demonstrated additive effects. Conclusions: Our findings indicate that the mutation-specific diffusional behavior of oncogenic KRAS can be quantitatively assessed by single-molecule imaging. This method serves as a powerful tool to uncover the mechanisms underlying oncogenic KRAS signaling and evaluate the therapeutic efficacy of molecular-targeted drugs in living cells.
Racial differences of secondary metastasis in patients with colon cancer: A United States population-based cohort study.
Authors: Suenghataiphorn Thanathip , Kulthamrongsri Narathorn , Tribuddharat Narisara , Danpanichkul Pojsakorn , Lohawatcharagul Tuntanut , Saowapa Sakditad , Thongpiya Jerapas , Chaisidhivej Natapat , Osataphan Soravis Alm
Published: August 2024

80

Background: Disparities in health outcomes exist among racial and ethnic groups in the United States, notably in patients with colon cancer. Metastasis is the primary cause of cancer morbidity and mortality. However, data on the metastasis risks and clinical outcomes on hospitalized individuals with colon cancer is still limited. Therefore, we aim to assess the association between metastatic colon cancer and racial differences. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to explore patients who have colon cancer as the primary diagnosis. Additionally, we identified evidence of metastasis, as recorded by ICD-10-CM. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was racial differences in organ metastasis and secondary outcomes included mortality and length of stay. Statistical significance was established at p-value of 0.05. Results: We identified 80,130 patients with primary diagnosis of colon cancer at discharge. The mean age was 67.4 years; 49.7% were female. Caucasians accounted for 69.3%, with African Americans at 13.3% and Hispanics at 8.2%. 15% of the patients had liver metastasis, whereas 22% had lung metastasis. In a multivariate analysis adjusting for patient, COVID-19, chemotherapy usage and hospital factors, African Americans had higher risk of lung metastasis (aOR 1.22; 95%CI (1.07, 1.40), p = 0.003), higher risk of liver metastasis (aOR 1.51; 95%CI (1.31, 1.74), p = 0.021) and longer length of stay (b = 0.95; 95%CI (0.56, 1.33), p = 0.001). Hispanics also had higher risk of lung (aOR 1.22, p < 0.05) and liver metastasis (aOR 1.24, p = 0.021). We observed an increase in risk of metastasis and mortality but non-statistically significant in some parameters and races, as shown in table provided. Conclusions: In conclusion, our study revealed that racial difference is associated with higher risk of metastasis, as well as other outcomes. To establish a causal relationship between races, metastasis, and mortality in patients with colon cancer, further longitudinal research is necessary. [Table: see text]
Trends in megestrol acetate prescription among Korean patients with biliary-pancreatic cancer and their impact.
Authors: Kim Ju Won , Oh Hoon Ji
Published: August 2024

85

Background: Chemotherapy-induced anorexia poses a significant challenge for cancer patients, particularly in biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC), known for their poor response to treatment. Megestrol acetate (MA), a commonly prescribed appetite stimulant, is associated with concerns regarding thrombosis and polypharmacy. Understanding the trends in MA prescription and its cascade effects is essential for optimizing cancer care. Methods: We conducted a retrospective cohort study using data from the Health Insurance and Review Assessment Service (HIRA) database in South Korea. The study included patients diagnosed with BTC and PDAC between 2008 and 2017. Prescription trends for MA, thrombosis events, anticoagulant prescriptions, and total parenteral nutrition (TPN) were analyzed. Statistical analysis included Chi-square tests and Kaplan-Meier estimates. Results: In our analysis of 41,670 patients with BTC and PDAC between 2008 and 2017, MA prescriptions increased notably, with PDAC patients rising from 7.85% to 51.84%. TPN prescriptions remained consistently high, especially among patients prescribed MA. For instance, in 2008, 94.71% of BTC patients prescribed MA received TPN, compared to 70.34% without MA. Similarly, in 2017, 87.56% of those prescribed MA received TPN, compared to 61.63% without MA. Among BTC patients with long-term MA prescriptions, 16.34% received anticoagulants, compared to 4.92% without MA (p<0.001). Among PDAC patients, 18.3% with long-term MA prescriptions received anticoagulants, compared to 7.12% without MA (p<0.001). Conclusions: The study highlights the escalating trend in MA prescriptions among BTC and PDAC patients, along with increased thrombosis diagnoses and anticoagulant prescriptions. These findings underscore the importance of understanding and managing the cascade effects of MA use and associated polypharmacy in optimizing cancer care and improving patient outcomes.
Exploratory phase I study of HF1K16 for the treatment of patients with refractory/recurrent advanced glioma.
Authors: Huang Ruofan , Zheng Anjie , Xu Yuhong , Zhang Xiaochen , Wu Jinsong
Published: August 2024

TPS32

Background: Glioblastoma (GBM) is the most common primary and aggressive malignant brain tumor in adults. Almost all patients with glioblastoma eventually have disease relapse and the median overall survival (OS) remains at only 30 weeks for those recurrent GBM patients. However, very few therapies had been approved over the past two decades, emphasizing the need for novel treatments. It is now wildly acknowledged that the immune microenvironment in brain offers adequate opportunities to implement immunotherapy for the treatment. Since most recurrent tumors had previously been exposed to the genotoxic stress of irradiation and/or chemotherapy, it is predicted to resulted in a higher mutational load and more immunogenic. However, The limited success of T cell immunomodulatory approach for advanced glioma has prompted a deeper understanding of the brain tumor and the immune microenvironment. GBM tumors are well-appreciated to be a immunosuppressive and a hallmark of GBM immunosuppression is the appearance of circulating myeloid-derived suppressor cells (MDSCs) at higher levels. Our preliminary data suggests that HF1K16, a liposome ATRA (all trans retinoic acid) suspension, is capable of relieving immune suppression induced by MDSCs. Further, we recently completed a phase I dose escalation study which showed that HF1K16 is safe, well-tolerated with preliminary efficacy in brain tumor. Thus, we hypothesized that HF1K16 may reverse GBM-associated immune suppression and leading to an increase in TILs and improved survival. Methods: This is an advanced glioma-specific expansion arm for adult patients with prior confirmed brain tumor and failed standard treatment. We plan to enroll 20~30 evaluable patients. Key eligibility criteria include candidates age ≥ 18 years, Karnofsky performance status ≥ 60 with and at least one measurable lesion. The primary endpoint is determination of overall response rate (ORR), duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) according to RANO criteria. Secondary endpoints include longitudinal assessment of the peripheral immune response by changes in MDSC and T cell subsets and numbers. HF1K16 infusions were administered in 21-day cycles (q.o.d days 1-14). Prior to and during treatment, peripheral blood mononuclear cells were collected and analyzed with flow cytometry to monitor the changes in myeloid cell phenotype and T cell composition. The recruitment of patients is anticipated completed in 2024. Clinical trial information: NCT05388487 .
Predictors of Hydrocephalus Risk After Stereotactic Radiosurgery for Vestibular Schwannomas: Utility of the Evans Index
Authors: Santhumayor Brandon A. , Mashiach Elad , Meng Ying , Rotman Lauren , Golub Danielle , Bernstein Kenneth , Vasconcellos Fernando De Nigris , Silverman Joshua S. , Harter David H. , Golfinos John G. , Kondziolka Douglas
Published: August 2024

BACKGROUND AND OBJECTIVES:

Hydrocephalus after Gamma Knife® stereotactic radiosurgery (SRS) for vestibular schwannomas is a rare but manageable occurrence. Most series report post-SRS communicating hydrocephalus in about 1% of patients, thought to be related to a release of proteinaceous substances into the cerebrospinal fluid. While larger tumor size and older patient age have been associated with post-SRS hydrocephalus, the influence of baseline ventricular anatomy on hydrocephalus risk remains poorly defined.

METHODS:

A single-institution retrospective cohort study examining patients who developed symptomatic communicating hydrocephalus after undergoing Gamma Knife® SRS for unilateral vestibular schwannomas from 2011 to 2021 was performed. Patients with prior hydrocephalus and cerebrospinal fluid diversion or prior surgical resection were excluded. Baseline tumor volume, third ventricle width, and Evans Index (EI)—maximum width of the frontal horns of the lateral ventricles/maximum internal diameter of the skull—were measured on axial postcontrast T1-weighted magnetic resonance imaging.

RESULTS:

A total of 378 patients met the inclusion criteria; 14 patients (3.7%) developed symptomatic communicating hydrocephalus and 10 patients (2.6%) underwent shunt placement and 4 patients (1.1%) were observed with milder symptoms. The median age of patients who developed hydrocephalus was 69 years (IQR, 67-72) and for patients younger than age 65 years, the risk was 1%. For tumor volumes <1 cm3, the risk of requiring shunting was 1.2%. The odds of developing symptomatic hydrocephalus were 5.0 and 7.7 times higher in association with a baseline EI > 0.28 (P = .024) and tumor volume >3 cm3 (P = .007), respectively, in multivariate analysis. Fourth ventricle distortion on pre-SRS imaging was significantly associated with hydrocephalus incidence (P < .001).

CONCLUSION:

Patients with vestibular schwannoma with higher baseline EI, larger tumor volumes, and fourth ventricle deformation are at increased odds of developing post-SRS hydrocephalus. These patients should be counseled regarding risk of hydrocephalus and carefully monitored after SRS.
Microsurgical Resection of Trigeminal Schwannoma Through Transorbital Approach: 2-Dimensional Operative Video
Authors: Motiwala Mustafa , Konda Parvesh , Sajjad Jahangir , Baqai Muhammad Waqas Saeed , Ford Rebecca , Cernei Cristina , Abhinav Kumar
Published: August 2024

We present the case of an asymptomatic 34-year-old woman who was found to have an incidental left trigeminal schwannoma.
1,2
Owing to the rapid increase in size on imaging, an atypical finding for this type of lesion,
3
as well as the risk of cranial nerve involvement and need for tissue diagnosis, the patient underwent a microsurgical left transorbital approach with lateral orbitotomy to resect the lesion.
4,5
Piecemeal resection was performed, and the internal contents of the cavernous sinus were preserved. Ultimately, gross total resection was achieved with no residual disease identified on postoperative imaging. No new neurologic deficits were noted after surgery. The technical considerations for the transorbital approach and the literature review on the outcomes for middle fossa lesions accessed by a lateral orbitotomy are reviewed.
6-10
The patient consented to the procedure and to the publication of her images. Institutional Review Board approval was deemed unnecessary due to the retrospective, case-report nature of this work.
Gata6 functions in zebrafish endoderm to regulate late differentiating arterial pole cardiogenesis
Authors: Sam Jessica , Torregroza Ingrid , Evans Todd
Published: August 2024

Mutations in GATA6 are associated with congenital heart disease, most notably conotruncal structural defects. However, how GATA6 regulates cardiac morphology during embryogenesis is undefined. We used knockout and conditional mutant zebrafish alleles to investigate the spatiotemporal role of gata6 during cardiogenesis. Loss of gata6 specifically impacts atrioventricular valve formation and recruitment of epicardium, with a prominent loss of arterial pole cardiac cells, including those of the ventricle and outflow tract. However, there are no obvious defects in cardiac progenitor cell specification, proliferation or death. Conditional loss of gata6 starting at 24 h is sufficient to disrupt the addition of late differentiating cardiomyocytes at the arterial pole, with decreased expression levels of anterior secondary heart field (SHF) markers spry4 and mef2cb. Conditional loss of gata6 in the endoderm is sufficient to phenocopy the straight knockout, resulting in a significant loss of ventricular and outflow tract tissue. Exposure to a Dusp6 inhibitor largely rescues the loss of ventricular cells in gata6−/− larvae. Thus, gata6 functions in endoderm are mediated by FGF signaling to regulate the addition of anterior SHF progenitor derivatives during heart formation.
Regulation of ROP GTPase cycling between active and inactive states is essential for vegetative organogenesis in Marchantia polymorpha
Authors: Sakai Yuuki , Ueno Aki , Yonetsuka Hiroki , Goh Tatsuaki , Kato Hirotaka , Kondo Yuki , Fukaki Hidehiro , Ishizaki Kimitsune
Published: August 2024

Rho/Rac of plant (ROP) GTPases are plant-specific proteins that function as molecular switches, activated by guanine nucleotide exchange factors (GEFs) and inactivated by GTPase-activating proteins (GAPs). The bryophyte Marchantia polymorpha contains single copies of ROP (MpROP), GEFs [ROPGEF and SPIKE (SPK)] and GAPs [ROPGAP and ROP ENHANCER (REN)]. MpROP regulates the development of various tissues and organs, such as rhizoids, gemmae and air chambers. The ROPGEF KARAPPO (MpKAR) is essential for gemma initiation, but the functions of other ROP regulatory factors are less understood. This study focused on two GAPs: MpROPGAP and MpREN. Mpren single mutants showed defects in thallus growth, rhizoid tip growth, gemma development, and air-chamber formation, whereas Mpropgap mutants showed no visible abnormalities. However, Mpropgap Mpren double mutants had more severe phenotypes than the Mpren single mutants, suggesting backup roles of MpROPGAP in processes involving MpREN. Overexpression of MpROPGAP and MpREN resulted in similar gametophyte defects, highlighting the importance of MpROP activation/inactivation cycling (or balancing). Thus, MpREN predominantly, and MpROPGAP as a backup, regulate gametophyte development, likely by controlling MpROP activation in M. polymorpha.
Geographic variation of Pinus heldreichii Christ from the Western Balkans based on cone and seed morphology
Authors: Hodžić Mirzeta Memišević , Hajrudinović-Bogunić Alma , Bogunić Faruk , Marku Vasil , Ballian Dalibor
Published: August 2024

Pinus heldreichii (Bosnian pine) is a Balkan-Apennine endemic and relict pine species that inhabits high mountains in the Mediterranean and sub-Mediterranean regions. Nineteen populations of P. heldreichii from the Western Balkans encompassing 187 individual trees were examined to evaluate morphological variation, a rarely studied aspect of the species. Univariate and multivariate statistics were applied in order to assess the variation of morphological traits of cones and seeds, evaluate the relationships among the sampled populations and verify geographic differentiation in the Dinaric Alps versus Scardo-Pindic mountains. The observations of P. heldreichii covering the populations from the western margins and the centre of the species distribution range indicated a morphological variation among populations and their geographic structure. In general, the southern populations (Scardo-Pindic group) had lower values for the most of morphological traits than the northern ones (Dinaric group). The observed geographic differences between these populations exhibit a north-western to south-eastern gradient, with a few inconsistencies. The southernmost sampled population, Tomorr in Albania, showed remarkable morphological divergence from the other studied populations and appeared to be a distinct morphological group. The pattern of morphological variation in Bosnian pine most likely resulted from multiple effects of long-term isolation and fragmentation in high mountain systems, adaptation to extreme environments and human disturbances.
"Is the Ground Ready?" Exploring the use of feminist pedagogy in refugee language education in Greece through a feminist, intersectional approach
Authors: Μυτάκου Τερέζα
Published: August 2024

Η παρούσα διατριβή διερευνά τη χρήση της φεμινιστικής παιδαγωγικής σε ένα πλαίσιο εκπαίδευσης προσφύγων στην Ελλάδα. Κύριος στόχος της είναι να εξετάσει το κατά πόσο μια τέτοια παιδαγωγική προσέγγιση μπορεί να είναι εφικτή στο συγκεκριμένο πλαίσιο, μέσα από τα ακόλουθα τρία υπο-ερωτήματα: «Ποια είναι τα εμπόδια στην εφαρμογή της φεμινιστικής παιδαγωγικής σε ένα πλαίσιο εκπαίδευσης προσφύγων στην Ελλάδα;», «Ποιες είναι οι ευκαιρίες;», «Πώς αντιλαμβάνονται μια τέτοια προσέγγιση εκπαιδευτικοί και μαθητές/-τριες;». Η έρευνα υιοθετεί μια φεμινιστική και διαθεματική επιστημολογία και μεθοδολογία έρευνας, με έμφαση στην αναστοχαστικότητα και τη μεγαλύτερη συνειδητοποίηση της θέσης (positionality) μου ως ερευνήτριας και εκπαιδευτικού στο πεδίο. Η συλλογή των δεδομένων έγινε σε ένα σχολείο για παιδιά με προσφυγικό υπόβαθρο στο νησί της Λέρου, όπου και εργάστηκα ως δασκάλα της αγγλικής γλώσσας για οκτώ μήνες. Κατά τη συλλογή δεδομένων χρησιμοποιήθηκαν τα ακόλουθα εργαλεία: α) ημι-δομημένες συνεντεύξεις με οκτώ εκπαιδευτικούς, έναν συντονιστή και μία συντονίστρια, β) συζητήσεις στην τάξη με μία μαθήτρια και έναν μαθητή εφηβικής ηλικίας, γ) χρήση ενός ημερολογίου έρευνας (researcher diary). Η ανάλυση των δεδομένων έγινε με βάση το μοντέλο της αναστοχαστικής θεματικής ανάλυσης (reflexive thematic analysis) των Braun και Clarke (2021). Τα θέματα που παράχθηκαν ήταν τα εξής: «Το Φύλο ως Σύνθετη Κατασκευή», «Το Τραύμα ως Παρόν, αλλά όχι Καθοριστικό», «Η Κουλτούρα και η Γλώσσα ως Εμπόδια». Η διατριβή εξετάζει αφενός τα εμπόδια στην εφαρμογή μιας φεμινιστικής παιδαγωγικής προσέγγισης, και αφετέρου τις ευκαιρίες για την εφαρμογή της που προέκυψαν μέσω της έρευνας. Τα ευρήματα υποδεικνύουν την μείζονα σημασία της φεμινιστικής παιδαγωγικής στην εκπαίδευση των προσφύγων, κυρίως λόγω του στόχου της να αναπτύξουν οι μαθητές και οι μαθήτριες κριτική συνείδηση γύρω από ζητήματα φύλου και καταπίεσης, καθώς και της δυνατότητάς της να βοηθήσει στην αντιμετώπιση του τραύματος και στην ενίσχυση της ανθεκτικότητας, χαρακτηριστικά τα οποία είναι αλληλένδετα με τους στόχους της εκπαίδευσης των προσφύγων.
Including van der Waals interactions in first-principles electronic structure calculations
Authors: Ανδρινόπουλος Λάμπρος
Published: August 2024

Οι αλληλεπιδράσεις διασποράς (van der Waals ή vdW) είναι μακράς εμβέλειας, μη τοπικού χαρακτήρα και είναι σημαντικές για την κατανόηση και την πρόβλεψη της δομής και της ενέργειας σε πολλά συστήματα. Παραδείγματα τέτοιων συστημάτων περιλαμβάνουν ασθενώς συνδεδεμένα διμερή, μόρια σε επιφάνειες και μοριακούς κρυστάλλους. Λόγω της εγγενούς μη τοπικότητας αυτών των αλληλεπιδράσεων, δεν υπολογίζονται από τα παραδοσιακά τοπικά και ημι-τοπικά συναρτησοειδή ανταλλαγής και συσχέτισης στη θεωρία συναρτησοειδούς πυκνότητας (DFT). Σε αυτή τη διατριβή, διερευνήθηκαν και εφαρμόστηκαν δύο διαφορετικές προσεγγίσεις για τη συμπερίληψη αλληλεπιδράσεων διασποράς στη θεωρία συναρτησοειδούς πυκνότητας. Η πρώτη προσέγγιση βασίζεται σε μια πρόσφατα αναπτυγμένη μέθοδο που χαρτογραφεί την πυκνότητα ηλεκτρονίων θεμελιώδους κατάστασης DFT σε ένα σύνολο από μέγιστα εντοπισμένες συναρτήσεις Wannier (MLWF). Αυτές οι MLWF λειτουργούν ως θραύσματα της πυκνότητας ηλεκτρονίων που χρησιμοποιούνται σε ένα άθροισμα κατά ζεύγη της συμβολής vdW στη συνολική ενέργεια. Αυτή η συνεισφορά προστίθεται στη συνολική ενέργεια θεμελιώδους κατάστασης DFT με τρόπο μετα-επεξεργασίας. Η μέθοδος, όπως προτάθηκε αρχικά, έχει μια σειρά από ελλείψεις που περιορίζουν την προγνωστική της δύναμη. Για να ξεπεράσουμε αυτά τα προβλήματα, αναπτύξαμε και εφαρμόσαμε ορισμένες βελτιώσεις σε αυτό και δείξαμε ότι αυτές οι τροποποιήσεις παράγουν υπολογισμένες ενέργειες δέσμευσης και γεωμετρίες ισορροπίας που συμφωνούν στενότερα με τα αποτελέσματα των υπολογισμών κβαντοχημικών συζευγμένων συστάδων. Η δεύτερη προσέγγιση, γνωστή ως μέθοδος συναρτησοειδούς πυκνότητας vdW (vdW-DF), ενσωματώνει έναν μη τοπικό όρο vdW απευθείας στο συναρτησοειδές ανταλλαγής και συσχέτισης. Μετά από μια πρόσφατη αποτελεσματική εφαρμογή κωδικοποιήσαμε αυτήν την προσέγγιση και μια σειρά λειτουργιών vdW (vdW-DF, vdW-DF2, optB88, optPBE) στο πακέτο DFT γραμμικής κλιμάκωσης ONETEP, επιτρέποντας την επεξεργασία πολύ μεγάλων συστημάτων που προηγουμένως ήταν πολύ απαιτητικά υπολογιστικά. Εφαρμόσαμε τη μέθοδο vdW-DF σε ένα σύστημα ενδιαφέροντος για εφαρμογές σε φωτοβολταϊκά, συγκεκριμένα σε μοριακούς κρυστάλλους φουλερενίου (C60) και ερευνήσαμε την επίδραση της συμπερίληψης αλληλεπιδράσεων vdW στη σχετική σταθερότητα διαφορετικών κρυσταλλικών δομών.
RBP-Tar – a searchable database for experimental RBP binding sites
Authors: Gresova Katarina , Racek Tomas , Martinek Vlastimil , Cechak David , Svobodova Radka , Alexiou Panagiotis
Published: August 2024

Background: RNA-binding proteins (RBPs) play a critical role in regulating gene expression by binding to specific sites on RNA molecules. Identifying these binding sites is crucial for understanding the many functions of RBPs in cellular function, development and disease. Current experimental methods for identifying RBP binding sites, such as ultra-violet (UV) crosslinking and immunoprecipitation (CLIP), and especially the enhanced CLIP (eCLIP) protocol, were developed to identify authentic RBP binding sites experimentally. Methods: To make this data more accessible to the scientific community, we have developed RBP-Tar (https://ncbr.muni.cz/RBP-Tar), a web server and database that utilises eCLIP data for 167 RBPs mapped on the human genome. The web server allows researchers to easily search and retrieve binding site information by genomic location and RBP name. Use case: Researchers can produce lists of all known RBP binding sites on a gene of interest, or produce lists of binding sites for one RBP on different genomic loci. Conclusions: Our future goal is to continue to populate the web server with additional experimental datasets from CLIP experiments as they become available and processed, making it an increasingly valuable resource for the scientific community.
Outcomes associated with isoniazid preventive therapy for tuberculosis prevention among human immunodeficiency virus positive patients attending antiretroviral therapy clinics in Mangalore
Authors: Coelho Steffi , Satish Vaishnavi , Dsouza Adail Lorainne , Achappa Basavaprabhu , Dsouza Nikhil Victor , Holla Ramesh , Kotian Himani , M R Pavan
Published: August 2024

Background The World Health Organization recommends that Isoniazid Preventive Therapy (IPT) should be administered to all People living with Human immunodeficiency virus (PLHIV) not currently suffering from tuberculosis (TB) to reduce the incidence of the same. The objectives of this study were to determine the incidence of PLHIV who contracted TB after receiving 6 months of IPT (followed up for ≥ 2 years), the incidence of PLHIV who developed tuberculosis when not on IPT, and the occurrence of adverse drug reactions due to IPT. Methods A Retrospective Cohort study was conducted in two ART centers in Mangalore, which included PLHIV who had completed 6 months of IPT from January 2017 to May 2018 and were followed up until May 2020; patients in the comparison group consisted of those attending ART centers during the same period who did not receive IPT. These data were retrieved from the case files of these patients from June to November 2020, entered into MS Excel, and analyzed using statistical package for social science (SPSS) version 25. Results The study included 1014 patients: 525 (51.8%) received IPT and 489 (48.2%) did not. Eight (1.5%) patients developed TB after IPT completion compared to 32 (6.5%) patients who developed TB from the non-IPT group. There was a 77% reduction in the incidence of developing TB in those patients who received IPT as compared to those who haven’t receive IPT (RR of 0.23, p value <0.0001). The reason for stopping IPT were due to side effects of IPT, experienced by 77 (14.6%) patients. Conclusions This study indicated that the completion of IPT significantly reduced the TB burden, showing significant protection against TB for a minimum duration of 2 years. Thus, implementation of IPT should be strengthened, and strict compliance should be ensured to reduce TB infection among PLHIV.
Examining the effects of anxiety and education level on mental health: The role of spiritual intelligence as an intervening variable in post COVID-19 patients in Indonesia
Authors: Ansyori Anis , Yunus Ahmad , Imam Sentot , Peristiowati Yuly
Published: August 2024

Background The COVID-19 pandemic has profoundly affected global health systems and daily life, exacerbating vulnerabilities, particularly in Indonesia. This study investigates the impact of anxiety and education level on mental health, with spiritual intelligence as an intervening variable among post-COVID-19 patients in Indonesia. Methods A cross-sectional design was employed, analyzing data from 390 post-COVID-19 patients in Indonesia. Structured questionnaires were used to assess anxiety, education level, spiritual intelligence, and mental health. Results The findings indicate that anxiety significantly affects both spiritual intelligence and mental health, with spiritual intelligence acting as a mediating factor. Additionally, higher educational attainment is positively associated with enhanced spiritual intelligence and improved mental health outcomes. Conclusions The study underscores the importance of incorporating spiritual development practices into mental health interventions and educational programs to boost resilience and overall well-being in the post-pandemic era. These practices can help mitigate the adverse effects of anxiety and educational disparities on mental health.
Glucose metabolism disorders and changes in cardiovascular risk among adult Peruvian population
Authors: Sedano-Espinoza Jhohann , Perez-Ochoa Kevin , Yalico-Quispe Erick , Bernabe-Ortiz Antonio
Published: August 2024

Background Rates of cardiovascular diseases are increasing annually, and glucose metabolism disorders play an important role in cardiovascular risk. This study aimed to assess changes in cardiovascular risk over time according to the levels of blood glucose, especially prediabetes and type 2 diabetes. Methods Prospective cohort study conducted in the northern Peru. Two were the outcomes of interest, evaluated at the cohort’s baseline and six years after: cardiovascular risk (in percentage), defined using the laboratory-free risk score (HEARTS from the World Health Organization), and the mean arterial pressure (in mmHg); whereas the exposure was glucose metabolism disorder, especially prediabetes and type 2 diabetes, compared to normoglycaemia. Associations were evaluated using mixed linear regression models, and coefficients (β) and 95% confidence intervals (95% CI) were reported. Results A total of 1607 subjects were recruited, with a mean age of 48.0 (standard deviation [SD]: 10.5) years, and 50.3% women. Baseline prevalence of prediabetes and type 2 diabetes was 16.9% (95%CI: 15.1%-18.9%) and 11.0% (95%CI: 9.5%-12.6%), respectively; whereas the average of the cardiovascular risk and mean arterial pressure was 3.0% (SD: 2.5%) and 93.1 (SD: 11.9) mmHg, respectively. At baseline, those with prediabetes and type 2 diabetes had a higher cardiovascular risk (0.31% and 0.33%, respectively) and a higher mean arterial pressure (3.3 and 4.2 mmHg, respectively) than those with normal glycaemia. No significant change was found in cardiovascular risk between baseline and follow-up; however, there was a reduction in mean arterial pressure levels, greater among those with normoglycaemia than in cases of prediabetes and type 2 diabetes. Conclusions Glucose metabolism disorders were associated with an increased cardiovascular risk and mean arterial pressure at baseline, but only with higher levels of mean arterial pressure at follow-up. These findings suggest the need for cardiovascular risk assessment in patients with prediabetes and type 2 diabetes.
The genome sequence of a lichen-forming fungus, Cladonia squamosa Hoffm.
Authors: Yahr Rebecca ,   Royal Botanic Garden Edinburgh Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: August 2024

We present a genome assembly from a specimen of lichen-forming fungus, Cladonia squamosa (Ascomycota; Lecanoromycetes; Lecanorales; Cladoniaceae). The genome sequence is 38.0 megabases in span. Most of the assembly is scaffolded into 26 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 50.9 kilobases in length.
The genome sequence of a robberfly, Dysmachus trigonus (Meigen, 1804)
Authors: Sivell Olga , Raper Chris , Mitchell Ryan , Sivell Duncan ,   Natural History Museum Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: August 2024

We present a genome assembly from an individual male robberfly, Dysmachus trigonus (Arthropoda; Insecta; Diptera; Asilidae). The genome sequence has a length of 450.3 megabases. Most of the assembly is scaffolded into 7 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 16.93 kilobases in length.
The genome sequence of the Hawthorn Fruit Fly, Anomoia purmunda (Harris, 1780)
Authors: Crowley Liam M. , McCulloch James , Medd Nathan ,   University of Oxford and Wytham Woods Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: August 2024

We present a genome assembly from a female Hawthorn Fruit Fly, Anomoia purmunda (Arthropoda; Insecta; Diptera; Tephritidae). The genome sequence has a length of 798.30 megabases. Most of the assembly is scaffolded into 6 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 16.48 kilobases in length.
The genome sequence of an ichneumonid wasp, Ophion obscuratus Fabricius, 1798
Authors: Sivell Duncan , Sivell Olga , Broad Gavin R. ,   Natural History Museum Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: August 2024

We present a genome assembly from a male Ophion obscuratus (Arthropoda; Insecta; Hymenoptera; Ichneumonidae). The genome sequence has a total length of 742.60 megabases. Most of the assembly is scaffolded into 13 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 32.5 kilobases in length.