bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Surgery on Circulating Malignant Tumour Cells in Oral Squamous Cell Carcinoma
Authors: Curtin Justin , Thomson Peter , Wong Gordon , Lam Alfred , Choi Siu-Wai
Published: January 2023

Importance: The extent to which surgical management of oral squamous cell carcinoma (OSCC) disseminates cancer is currently unknown. Objective: To determine changes in numbers of malignant cells released into systemic circulation immediately following tumour removal and over the first seven post-operative days. Design: An observational study from March 2019 to February 2021. Setting: This study was undertaken at Queen Mary University Hospital, Hong Kong. Participants: Patients with biopsy-proven oral SCC were considered for eligibility. Patients under 18 years of age, pregnant or lactating women and those unable to understand the study details or unable to sign the consent form were excluded. Twenty-two patients were enrolled (12 male and 10 female) with mean age of 65.5 years. Intervention: Primary tumour management was performed in accord with multi-disciplinary team agreement. Anaesthesia and post-operative care were unaltered and provided in accord with accepted clinical practice. Main Outcomes and Measures: Three types of malignant cells detected in peripheral blood samples were enumerated and sub-typed based on the presence of chromosomal aneuploidy and immunohistochemical characteristics. To test the hypothesis that malignant cells are released by surgery, the numbers of single circulating tumour cells (CTCs), circulating tumour microemboli (CTM) and circulating endothelial cells (CTECs) were recorded pre-operatively, upon tumour removal and the second and seventh post-operative days. Results: Of a potential 88 data collection points, specimens were not obtainable in 12 instances. Tumour removal resulted in a statistically significant increase in CTCs and a non-statistically significant rise in CTMs. CTCs, CTMs and CTECs were detected in the majority of patients up to the seventh post-operative day. Individual patients demonstrated striking increases in post-operative CTCs and CTECs numbers. Conclusions/Relevance: Surgical management of OSCC has a significant impact on the systemic distribution of cancer cells. Malignant cells persisted post-operatively in a manner independent of recognised staging methods suggesting differences in tumour biology between individuals. Further investigation is warranted to determine whether circulating malignant cell enumeration can be used to refine risk stratification for patients with OSCC.
Efficacy of Organ Preservation Strategy by Adjuvant Chemoradiotherapy after Non-Curative Endoscopic Resection for Superficial SCC: A Multicenter Western Study
Authors: Berger Arthur , Perrod Guillaume , Pioche Mathieu , Barret Maximilien , Cesbron-Métivier Elodie , Lépilliez Vincent , Hupé Marianne , Perez-Cuadrado-Robles Enrique , Cholet Franck , Daubigny Augustin , Texier Charles , Ali Einas Abou , Chabrun Edouard , Jacques Jérémie , Wallenhorst Timothee , Chevaux Jean Baptiste , Schaefer Marion , Cellier Christophe , Rahmi Gabriel
Published: January 2023

Background. In case of high risk of lymph node invasion after endoscopic resection (ER) of superficial esophageal squamous cell carcinoma (SCC), adjuvant chemoradiotherapy (CRT) can be an alternative to surgery. We assessed long-term clinical outcomes of adjuvant therapy by CRT after non-curative ER for superficial SCC. Methods. We performed a retrospective multicenter study. From April 1999 to April 2018, all consecutive patients who underwent ER for SCC with tumor infiltration beyond the muscularis mucosae were included. Results. A total of 137 ER were analyzed. The overall nodal or metastatic recurrence-free survival rate at 5 years was 88% and specific recurrence-free survival rates at 5 years with and without adjuvant therapy were, respectively, 97.9% and 79.1% (p = 0.011). Independent factors for nodal and/or distal metastatic recurrence were age (HR = 1.075, p = 0.031), Sm infiltration depth > 200 µm (HR = 4.129, p = 0.040), and the absence of adjuvant CRT or surgery (HR = 11.322, p = 0.029). Conclusion. In this study, adjuvant therapy is associated with a higher recurrence-free survival rate at 5 years after non-curative ER. This result suggests this approach may be considered as an alternative to surgery in selected patients.
Preclinical Models of Low-Grade Gliomas
Authors: Dasgupta Pushan , Balasubramanyian Veerakumar , de Groot John F. , Majd Nazanin K.
Published: January 2023

Diffuse infiltrating low-grade glioma (LGG) is classified as WHO grade 2 astrocytoma with isocitrate dehydrogenase (IDH) mutation and oligodendroglioma with IDH1 mutation and 1p/19q codeletion. Despite their better prognosis compared with glioblastoma, LGGs invariably recur, leading to disability and premature death. There is an unmet need to discover new therapeutics for LGG, which necessitates preclinical models that closely resemble the human disease. Basic scientific efforts in the field of neuro-oncology are mostly focused on high-grade glioma, due to the ease of maintaining rapidly growing cell cultures and highly reproducible murine tumors. Development of preclinical models of LGG, on the other hand, has been difficult due to the slow-growing nature of these tumors as well as challenges involved in recapitulating the widespread genomic and epigenomic effects of IDH mutation. The most recent WHO classification of CNS tumors emphasizes the importance of the role of IDH mutation in the classification of gliomas, yet there are relatively few IDH-mutant preclinical models available. Here, we review the in vitro and in vivo preclinical models of LGG and discuss the mechanistic challenges involved in generating such models and potential strategies to overcome these hurdles.
The Same–Up–Down Staging System for Recurrent Early Glottic Cancer
Authors: Licci Giuseppe , Locatello Luca Giovanni , Maggiore Giandomenico , Cozzolino Flavia , Caini Saverio , Gallo Oreste
Published: January 2023

(1) Background: The treatment of recurrent early glottic cancer (rEGC) remains challenging. We wanted to investigate how the oncological outcomes are affected by the initial and recurrent stages, in order to propose our newly developed Same–Up–Down (SUD) staging system. (2) Methods: In our cohort of 258 rEGC patients, we retrospectively assessed the prognostic performances of the rTNM (the TNM staging system for recurrence), CLRSS, CLRSS-2, and SUD staging systems by univariate and multivariate Cox analysis, comparing their predictive capability using Harrell’s C-index. (3) Results: The SUD classification satisfactorily predicted both overall survival (p = 0.022) and second-recurrence-free survival (p = 0.024, as same + down vs. upstage) in our cohort. It also outperformed the other three systems in terms of prediction of survival, with an improvement of 1.52%, 1.18%, and 3.96% in the predictive capacity of overall survival, disease-specific survival, and second-recurrence-free survival, respectively. (4) Conclusions: The SUD staging system can efficiently predict survival in rEGC patients, whose prognosis heavily depends on both the initial and recurrent locoregional extension.
Immune Microenvironment and Immunotherapies for Diffuse Intrinsic Pontine Glioma
Authors: Chen Yujia , Zhao Chao , Li Shenglun , Wang Jun , Zhang Hongwei
Published: January 2023

Diffuse intrinsic pontine glioma (DIPG) is a primary glial glioma that occurs in all age groups but predominates in children and is the main cause of solid tumor-related childhood mortality. Due to its rapid progression, the inability to operate and insensitivity to most chemotherapies, there is a lack of effective treatment methods in clinical practice for DIPG patients. The prognosis of DIPG patients is extremely poor, with a median survival time of no more than 12 months. In recent years, there have been continuous breakthroughs for immunotherapies in various hematological tumors and malignant solid tumors with extremely poor prognoses, which provides new insights into tumors without effective treatment strategies. Meanwhile, with the gradual development of stereotactic biopsy techniques, it is gradually becoming easier and safer to obtain live DIPG tissue, and the understanding of the immune properties of DIPG has also increased. On this basis, a series of immunotherapy studies of DIPG are under way, some of which have shown encouraging results. Herein, we review the current understanding of the immune characteristics of DIPG and critically reveal the limitations of current immune research, as well as the opportunities and challenges for immunological therapies in DIPG, hoping to clarify the development of novel immunotherapies for DIPG treatment.
Barriers to Breast Cancer-Screening Adherence in Vulnerable Populations
Authors: Ponce-Chazarri Laura , Ponce-Blandón Jose Antonio , Immordino Palmira , Giordano Antonio , Morales Fátima
Published: January 2023

Breast cancer screening through periodic mammography has been effective in decreasing mortality and reducing the impact of this disease. However, adherence to screening does not meet the desired expectations from all populations. The main objective of this review is to explore the barriers that affect adherence to breast cancer–screening programs in vulnerable populations according to race and/or ethnicity in order to propose measures to reduce the lack of adherence. We conducted a search of publications in the PubMed Central and Scopus databases. The eligible criteria for the articles were as follows: original quantitative studies appearing in SJR- and/or JCR-indexed journals from 2016 to 2021 in English or Spanish. Most of them present common barriers, such as race/ethnicity (47%), low socioeconomic (35.3%) and educational levels (29.4%), no family history of cancer and being single (29.4%), medical mistrust and a health information gap (23.5%), lack of private health insurance (17.6%) and not having annual health checks (17.6%). The target populations with the lowest adherence were Black, Asian, Hispanic and foreign women. Implementing awareness campaigns focused on these populations should be promoted, as well as working on diversity, cultural acceptance and respect with healthcare workers, in order to improve breast cancer–screening adherence worldwide.
Plasma Extracellular Vesicle Characteristics as Biomarkers of Resectability and Radicality of Surgical Resection in Pancreatic Cancer—A Prospective Cohort Study
Authors: Badovinac David , Goričar Katja , Lavrin Teja , Zavrtanik Hana , Dolžan Vita , Lenassi Metka , Tomažič Aleš
Published: January 2023

Due to possible diagnostic misjudgment of tumor resectability, patients with pancreatic ductal adenocarcinoma (PDAC) might be exposed to non-radical resection or unnecessary laparotomy. With small extracellular vesicles (sEV) obtained by liquid biopsy, we aimed to evaluate their potential as biomarkers of tumor resectability, radicality of resection and overall survival (OS). Our prospective study included 83 PDAC patients undergoing surgery with curative intent followed-up longitudinally. sEV were isolated from plasma, and their concentration and size were determined. Fifty patients underwent PDAC resection, and thirty-three had no resection. Preoperatively, patients undergoing resection had higher sEV concentrations than those without resection (p = 0.023). Resection was predicted at the cutoff value of 1.88 × 109/mL for preoperative sEV concentration (p = 0.023) and the cutoff value of 194.8 nm for preoperative mean diameter (p = 0.057). Furthermore, patients with R0 resection demonstrated higher preoperative plasma sEV concentrations than patients with R1/R2 resection (p = 0.014). If sEV concentration was above 1.88 × 109/mL or if the mean diameter was below 194.8 nm, patients had significantly longer OS (p = 0.018 and p = 0.030, respectively). Our proof-of-principle study identified preoperative sEV characteristics as putative biomarkers of feasibility and radicality of PDAC resection that also enable discrimination of patients with worse OS. Liquid biopsy with sEV could aid in PDAC patient stratification and treatment optimization in the future.
Poor Mobilizers in Lymphoma but Not Myeloma Patients Had Significantly Poorer Progression-Free Survival after Autologous Stem Cell Transplantation: Results of a Large Retrospective, Single-Center Observational Study
Authors: Steiner Normann , Göbel Georg , Mauser Leonie , Mühlnikel Lena , Fischinger Marie , Künz Tina , Willenbacher Wolfgang , Hetzenauer Gabriele , Rudzki Jakob , Nussbaumer Walter , Mayer Wolfgang , Gunsilius Eberhard , Kircher Brigitte , Wolf Dominik , Nachbaur David
Published: January 2023

In our single-center study, 357 myeloma and lymphoma patients between 2009 and 2019 were mobilized with granulocyte colony-stimulating factor (G-CSF 7.5 µg/kg bid for four days) plus a fixed dose of 24 mg Plerixafor when indicated (Plerixafor Group, n = 187) or G-CSF alone (G-CSF Group, n = 170). The target CD34 cell yields were ≥2.0 × 106 CD34+ cells/kg in lymphoma and ≥4.0 × 106 CD34+ cells/kg in myeloma patients to enable putative second transplants in the latter. There were no significant differences in engraftment kinetics or transfusion requirements between the Plerixafor Group and the control group in the myeloma cohort, with lymphoma patients not requiring Plerixafor showing significantly faster neutrophil recovery, a trend to faster platelet recovery, and a significantly lower need for platelet transfusions, probably due to the significantly lower number of CD34-positive cells re-transfused. While in myeloma patients the outcome (overall survival, progression-free survival) following autologous stem cell transplantation (ASCT) was similar between the Plerixafor Group and the control group, hard to mobilize lymphoma patients had significantly poorer progression-free survival (47% vs. 74% at 36 months after ASCT, p = 0.003) with a trend also to poorer overall survival (71% vs. 84%). In conclusion, while there seem to be no differences in stemness capacity and long-term engraftment efficiency between the Plerixafor and the G-CSF Group in lymphoma as well as myeloma patients, poor mobilizing lymphoma patients per se constitute a high-risk population with a poorer outcome after ASCT. Whether disease characteristics and/or a more intense or stem cell-toxic pre-mobilization chemo-/radiotherapy burden in this cohort are responsible for this observation remains to be shown in future studies.
Priming of Colorectal Tumor-Associated Fibroblasts with Zoledronic Acid Conjugated to the Anti-Epidermal Growth Factor Receptor Antibody Cetuximab Elicits Anti-Tumor Vδ2 T Lymphocytes
Authors: Fernandez Jordi Leonardo Castrillo , Benelli Roberto , Costa Delfina , Campioli Alessio , Tavella Sara , Zocchi Maria Raffaella , Poggi Alessandro
Published: January 2023

Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of Vδ2 T cells. CRC-TAF, obtained from patients, express the epidermal growth factor receptor (EGFR) and the butyrophilin family members BTN3A1/BTN2A1. These butyrophilins mediate the presentation of the phosphoantigens, accumulated in the cells due to ZA effect, to Vδ2 T cells. CRC-TAF exposed to soluble ZA acquired the ability to trigger the proliferation of Vδ2 T cells, in part represented by effector memory cells lacking CD45RA and CD27. In turn, expanded Vδ2 T cells exerted relevant cytotoxic activity towards CRC cells and CRC-TAF when primed with soluble ZA. Of note, also the ADC made of the anti-EGFR cetuximab (Cet) and ZA (Cet-ZA), that we recently described, induced the proliferation of anti-tumor Vδ2 T lymphocytes and their activation against CRC-TAF. These findings indicate that ZA can educate TAF to stimulate effector memory Vδ2 T cells; the Cet-ZA ADC formulation can lead to the precise delivery of ZA to EGFR+ cells, with a double targeting of TAF and tumor cells.
Upfront Surgery versus Neoadjuvant Perioperative Chemotherapy for Resectable Colorectal Liver Metastases: A Machine-Learning Decision Tree to Identify the Best Potential Candidates under a Parenchyma-Sparing Policy
Authors: Famularo Simone , Milana Flavio , Cimino Matteo , Franchi Eloisa , Giuffrida Mario , Costa Guido , Procopio Fabio , Donadon Matteo , Torzilli Guido
Published: January 2023

Addressing patients to neoadjuvant systemic chemotherapy followed by surgery rather than surgical resection upfront is controversial in the case of resectable colorectal –liver metastases (CLM). The aim of this study was to develop a machine-learning model to identify the best potential candidates for upfront surgery (UPS) versus neoadjuvant perioperative chemotherapy followed by surgery (NEOS). Patients at first liver resection for CLM were consecutively enrolled and collected into two groups, regardless of whether they had UPS or NEOS. An inverse –probability weighting (IPW) was performed to weight baseline differences; survival analyses; and risk predictions were estimated. A mortality risk model was built by Random-Forest (RF) to assess the best –potential treatment (BPT) for each patient. The characteristics of BPT-upfront and BPT-neoadjuvant candidates were automatically identified after developing a classification –and –regression tree (CART). A total of 448 patients were enrolled between 2008 and 2020: 95 UPS and 353 NEOS. After IPW, two balanced pseudo-populations were obtained: UPS = 432 and NEOS = 440. Neoadjuvant therapy did not significantly affect the risk of mortality (HR 1.44, 95% CI: 0.95–2.17, p = 0.07). A mortality prediction model was fitted by RF. The BPT was NEOS for 364 patients and UPS for 84. At CART, planning R1vasc surgery was the main factor determining the best candidates for NEOS and UPS, followed by primitive tumor localization, number of metastases, sex, and pre-operative CEA. Based on these results, a decision three was developed. The proposed treatment algorithm allows for better allocation according to the patient’s tailored risk of mortality.
Salvage Perioperative Interstitial High-Dose-Rate Interventional Radiotherapy (Brachytherapy) for Local Recurrences of the Chest Wall Following Mastectomy and Previous External Irradiation
Authors: Soror Tamer , Banys-Paluchowski Maggie , Melchert Corinna , Rades Dirk , Rody Achim , Muras Kerstin , Xie Meiting , Kovács György
Published: January 2023

(1) Background: To investigate the technical feasibility, safety, and efficacy of interstitial perioperative high-dose-rate interventional radiotherapy (HDR-IRT, brachytherapy) as a local salvage treatment combined with surgery for local chest wall recurrences following mastectomy and subsequent external beam radiation treatment (EBRT). (2) Methods: A retrospective analysis of 56 patients treated with interstitial HDR-IRT in combination with local surgery of a chest wall recurrence of breast cancer after previous treatment with mastectomy and EBRT from 2008 to 2020. (3) Results: Local recurrence following HDR-IRT was encountered in seven (12.5%) patients. The 1-year local recurrence-free survival (RFS), 3-year RFS, and 5-year RFS were 91%, 82%, and 82%, respectively. The 1-year overall survival (OS), 3-year OS, and 5-year OS was 85.5%, 58%, and 30%, respectively. Acute grade 1–2 radiation dermatitis was observed in 22 (39.3%) patients. Late ≥grade 3 toxicities were encountered in five (8.9%) patients. (4) Conclusions: Salvage perioperative interstitial high-dose-rate interventional radiotherapy (brachytherapy) combined with surgery seems to be an effective interdisciplinary management with acceptable treatment-related toxicity for local recurrences of the chest wall following mastectomy and previous external irradiation.
Associated Factors of Spontaneous Hemorrhage in Brain Metastases in Patients with Lung Adenocarcinoma
Authors: Kim Song Soo , Lee Seoyoung , Park Mina , Joo Bio , Suh Sang Hyun , Ahn Sung Jun
Published: January 2023

Background: Hemorrhage in brain metastases (BMs) from lung cancer is common and associated with a poor prognosis. Research on associated factors of spontaneous hemorrhage in patients with BMs is limited. This study aimed to investigate the predictive risk factors for BM hemorrhage and assess whether hemorrhage affects patient survival. Methods: We retrospectively evaluated 159 BMs from 80 patients with lung adenocarcinoma from January 2017 to May 2022. Patients were classified into hemorrhagic and non-hemorrhagic groups. Patient demographics, lung cancer molecular subtype, treatment type, and tumor–node–metastasis stage were compared between the groups. Multivariate generalized estimating equation (GEE) analysis and gradient boosting were performed. To determine whether BM hemorrhage can stratify overall survival after BM (OSBM), univariate survival analysis was performed. Results: In the univariate analysis, hemorrhagic BMs were significantly larger and had a history of receiving combination therapy with tyrosine kinase inhibitor (TKI) and intracranial radiation (p < 0.05). Multivariate GEE showed that tumor size and combination therapy were independent risk factors for BM hemorrhage (p < 0.05). Gradient boosting demonstrated that the strongest predictor of BM hemorrhage was tumor size (variable importance: 49.83), followed by age (16.65) and TKI combined with intracranial radiation (13.81). There was no significant difference in OSBM between the two groups (p = 0.33). Conclusions: Hemorrhage in BMs from lung adenocarcinomas may be associated with BM tumor size and a combination of TKI and intracranial radiotherapy. BM hemorrhage did not affect OSBM.
Cancer-Associated B Cells in Sarcoma
Authors: Kendal Joseph K. , Shehata Michael S. , Lofftus Serena Y. , Crompton Joseph G.
Published: January 2023

Despite being one of the first types of cancers studied that hinted at a major role of the immune system in pro- and anti-tumor biology, little is known about the immune microenvironment in sarcoma. Few types of sarcoma have shown major responses to immunotherapy, and its rarity and heterogeneity makes it challenging to study. With limited systemic treatment options, further understanding of the underlying mechanisms in sarcoma immunity may prove crucial in advancing sarcoma care. While great strides have been made in the field of immunotherapy over the last few decades, most of these efforts have focused on harnessing the T cell response, with little attention on the role B cells may play in the tumor microenvironment. A growing body of evidence suggests that B cells have both pro- and anti-tumoral effects in a large variety of cancers, and in the age of bioinformatics and multi-omic analysis, the complexity of the humoral response is just being appreciated. This review explores what is currently known about the role of B cells in sarcoma, including understanding the various B cell populations associated with sarcoma, the organization of intra-tumoral B cells in tertiary lymphoid structures, recent trials in immunotherapy in sarcoma, intra-tumoral immunoglobulin, the pro-tumor effects of B cells, and exciting future areas for research.
c-MYC-Driven Polyamine Metabolism in Ovarian Cancer: From Pathogenesis to Early Detection and Therapy
Authors: Chen Yihui , León-Letelier Ricardo A. , Abdel Sater Ali Hussein , Vykoukal Jody , Dennison Jennifer B. , Hanash Samir , Fahrmann Johannes F.
Published: January 2023

c-MYC and its paralogues MYCN and MYCL are among the most frequently amplified and/or overexpressed oncoproteins in ovarian cancer. c-MYC plays a key role in promoting ovarian cancer initiation and progression. The polyamine pathway is a bona fide target of c-MYC signaling, and polyamine metabolism is strongly intertwined with ovarian malignancy. Targeting of the polyamine pathway via small molecule inhibitors has garnered considerable attention as a therapeutic strategy for ovarian cancer. Herein, we discuss the involvement of c-MYC signaling and that of its paralogues in promoting ovarian cancer tumorigenesis. We highlight the potential of targeting c-MYC-driven polyamine metabolism for the treatment of ovarian cancers and the utility of polyamine signatures in biofluids for early detection applications.
Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC)
Authors: Gregori Alessandro , Bergonzini Cecilia , Capula Mjriam , Mantini Giulia , Khojasteh-Leylakoohi Fatemeh , Comandatore Annalisa , Khalili-Tanha Ghazaleh , Khooei Alireza , Morelli Luca , Avan Amir , Danen Erik H. , Schmidt Thomas , Giovannetti Elisa
Published: January 2023

Introduction: PDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological approaches to evaluate the role of the cell-adhesion molecule ITGA2, a key regulator of ECM, in PDAC resistance to gemcitabine. Methods: The prognostic value of ITGA2 was analysed in publicly available databases and tissue-microarrays of two cohorts of radically resected and metastatic patients treated with gemcitabine. PANC-1 and its gemcitabine-resistant clone (PANC-1R) were analysed by RNA-sequencing and label-free proteomics. The role of ITGA2 in migration, proliferation, and apoptosis was investigated using hydrogel-coated wells, siRNA-mediated knockdown and overexpression, while collagen-embedded spheroids assessed invasion and ECM remodeling. Results: High ITGA2 expression correlated with shorter progression-free and overall survival, supporting its impact on prognosis and the lack of efficacy of gemcitabine treatment. These findings were corroborated by transcriptomic and proteomic analyses showing that ITGA2 was upregulated in the PANC-1R clone. The aggressive behavior of these cells was significantly reduced by ITGA2 silencing both in vitro and in vivo, while PANC-1 cells growing under conditions resembling PDAC stiffness acquired resistance to gemcitabine, associated to increased ITGA2 expression. Collagen-embedded spheroids of PANC-1R showed a significant matrix remodeling and spreading potential via increased expression of CXCR4 and MMP2. Additionally, overexpression of ITGA2 in MiaPaCa-2 cells triggered gemcitabine resistance and increased proliferation, both in vitro and in vivo, associated to upregulation of phospho-AKT. Conclusions: ITGA2 emerged as a new prognostic factor, highlighting the relevance of stroma mechanical properties as potential therapeutic targets to counteract gemcitabine resistance in PDAC.
Treatment Strategies for Non-Small Cell Lung Cancer with Common EGFR Mutations: A Review of the History of EGFR TKIs Approval and Emerging Data
Authors: Marin-Acevedo Julian A. , Pellini Bruna , Kimbrough ErinMarie O. , Hicks J. Kevin , Chiappori Alberto
Published: January 2023

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations.
Inflammation and Prostate Cancer: Pathological Analysis from Pros-IT CNR 2
Authors: Sessa Francesco , Nicoletti Rossella , De Nunzio Cosimo , Porreca Angelo , Magrini Stefano Maria , Mirone Vincenzo , Tubaro Andrea , Serni Sergio , Gontero Paolo , Noale Marianna , Maggi Stefania , Gacci Mauro ,   on behalf of the Pros-IT2 Study Group
Published: January 2023

Background: Extensive research effort has been devoted to investigating the link between inflammation and PCa. However, this relationship remains unclear and controversial. The aim of our multi-center study was to investigate this association by histologically evaluating the distribution of PI and PCA in prostate biopsy cores from patients of eight referral centers in Italy. Results: We evaluated 2220 cores from 197 patients; all the frustules were re-evaluated by dedicated pathologists retrospectively. Pathologists assigned IRANI scores and determined the positions of PIs; pathologists also re-evaluated the presence of PCa and relative ISUP grade. PCa was recorded in 749/2220 (33.7%). We divided this sample into a PCa PI group (634/749 cores [84.7%]) and a non-PCa + PI group (1157/1471 cores [78.7%]). We observed a statistically significant difference in the presence of inflammation among cores with cancer (p < 0.01). Moreover, periglandular inflammation was higher in the cores with neoplasia, while stromal inflammation was higher in cores without neoplasia (38.5% vs. 31.1% and 55.4% vs. 63.5% p < 0.01). Conclusions: In our experience, there is evidence of an association between PI and PCa at a tissue level. Further studies are needed to confirm our findings and to identify patients who might benefit from target therapies to prevent PCa occurrence and/or progression.
SARS-CoV-2 Establishes a Productive Infection in Hepatoma and Glioblastoma Multiforme Cell Lines
Authors: Smirnova Olga A. , Ivanova Olga N. , Fedyakina Irina T. , Yusubalieva Gaukhar M. , Baklaushev Vladimir P. , Yanvarev Dmitry V. , Kechko Olga I. , Mitkevich Vladimir A. , Vorobyev Pavel O. , Fedorov Vyacheslav S. , Bartosch Birke , Valuev-Elliston Vladimir T. , Lipatova Anastasiya L. , Ivanov Alexander V.
Published: January 2023

Severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and rapidly caused a pandemic that led to the death of >6 million people due to hypercoagulation and cytokine storm. In addition, SARS-CoV-2 triggers a wide array of pathologies, including liver dysfunction and neurological disorders. It remains unclear if these events are due to direct infection of the respective tissues or result from systemic inflammation. Here, we explored the possible infection of hepatic and CNS cell lines by SARS-CoV-2. We show that even moderate expression levels of the angiotensin-converting enzyme 2 (ACE2) are sufficient for productive infection. SARS-CoV-2 infects hepatoma Huh7.5 and HepG2 cells but not non-transformed liver progenitor or hepatocyte/cholangiocyte-like HepaRG cells. However, exposure to the virus causes partial dedifferentiation of HepaRG cells. SARS-CoV-2 can also establish efficient replication in some low-passage, high-grade glioblastoma cell lines. In contrast, embryonal primary astrocytes or neuroblastoma cells did not support replication of the virus. Glioblastoma cell permissiveness is associated with defects in interferon production. Overall, these results suggest that liver dysfunction during COVID-19 is not due to infection of these tissues by SARS-CoV-2. Furthermore, tumors may potentially serve as reservoirs for the virus during infection.
The Use of a Non-Invasive Biomarker for Colorectal Cancer Screening: A Comparative Cost-Effectiveness Modeling Study
Authors: Wong Martin C. S. , Huang Junjie , Wong Yuet-Yan , Ko Samantha , Chan Victor C. W. , Ng Siew C. , Chan Francis K. L.
Published: January 2023

This study aimed to examine the cost-effectiveness of fecal biomarker M3 panel compared to fecal immunochemical test (FIT) and colonoscopy in an Asian population. In a hypothetical population of 100,000 persons aged 50 years who received FIT yearly, M3 biomarker yearly, or colonoscopy every 10 years until the age of 75 years. Participants with positive FOBT or a result of “high risk” identified using the M3 biomarker are offered colonoscopy. We assumed surveillance colonoscopy is repeated every 3 years, and examined the treatment cost. A comparison of various outcome measures was conducted using Markov modelling. The incremental cost-effectiveness ratio (ICER) of FIT, M3 biomarker, and colonoscopy was USD108,176, USD133,485 and USD159,596, respectively. Comparing with FIT, the use of M3 biomarker could lead to significantly smaller total loss of cancer-related life-years (2783 vs. 5279); a higher number of CRC cases prevented (1622 vs. 146), a higher proportion of CRC cases prevented (50.2% vs. 4.5%), more life-years saved (2852 vs. 339), and cheaper total costs per life-year saved (USD212,553 vs. 773,894). The total costs per life-year saved is more affordable than that achieved by colonoscopy as a primary screening tool (USD212,553 vs. USD236,909). The findings show that M3 biomarkers may be more cost-effective than colonoscopy.
Phenyl Formate as a CO Surrogate for the Reductive Cyclization of Organic Nitro Compounds to Yield Different N-Heterocycles: No Need for Autoclaves and Pressurized Carbon Monoxide
Authors: Ragaini Fabio , Ferretti Francesco , Fouad Manar Ahmed
Published: January 2023

The reductive cyclization of different organic nitro compounds by carbon monoxide, catalyzed by transition metal complexes, is a very efficient and clean strategy for the synthesis of many N-heterocycles. However, its use requires the use of autoclaves and pressurized CO lines. In this perspective, the authors will present the results obtained in their laboratories on the use of phenyl formate as a convenient CO surrogate, able to liberate carbon monoxide under the reaction conditions and allowing the use of a cheap glass pressure tube as a reaction vessel. In most cases, yields were better than those previously reported by the use of pressurized CO, proving that the use of CO surrogates can be a viable alternative to the gaseous reagent.
Polymer-Supported Dioxidovanadium(V) Complex-Based Heterogeneous Catalyst for Multicomponent Biginelli Reaction Producing Biologically Active 3,4-Dihydropyrimidin-2-(1H)-ones
Authors: Maurya Mannar R. , Patter Akhil , Singh Devesh , Ghosh Kaushik
Published: January 2023

Dioxidovanadium(V) complex [VVO2(sal-aebmz)] (1) (where Hsal-aebmz = Schiff base derived from the condensation of salicylaldehyde and 2-aminoethylbenzimidazole) has been immobilized on chloromethylated polystyrene (PS-Cl) cross-linked with divinylbenzene to obtain [VVO2(sal-aebmz)]@PS (2), a heterogeneous complex. Both complexes, after characterization, have been used as catalysts to explore a single pot multicomponent (benzaldehyde or its derivatives, urea and ethyl acetoacetate) Biginelli reaction producing biologically active 3,4-dihydropyrimidin-2-(1H)-one (DHPM)-based biomolecules under solvent-free conditions in the presence of H2O2 as a green oxidant. Various reaction conditions such as amounts of catalyst and oxidant, temperature, time, and solvent have been optimized to obtain the maximum yield of DHPMs. The polymer-immobilized complex has been found to show excellent catalytic activity, giving ca. 95% yield of DHPMs under the optimized reaction conditions selectively. Oxidant plays an important role in enhancing the yield of DHPMs.
A Simple Strategy Stabilizing for a CuFe/SiO2 Catalyst and Boosting Higher Alcohols’ Synthesis from Syngas
Authors: Gong Nana , Wu Yingquan , Ma Qingxiang , Tan Yisheng
Published: January 2023

Stable F-T-based catalyst development in direct CO hydrogenation to higher alcohols is still a challenge at present. In this study, CuFe/SiO2 catalysts with a SiO2 support treated with a piranha solution were prepared and evaluated in a long-term reaction. The treated catalyst showed higher total alcohols’ selectivity and great stability during a reaction of more than 90 h. It was found that the treatment with the piranha solution enriched the surface hydroxyl groups on SiO2, so that the Cu–Fe active components could be firmly anchored and highly dispersed on the support, resulting in stable catalytic performance. Furthermore, the in situ DRIFTS revealed that the adsorption strength of CO on Cu+ on the treated catalyst surface was weakened, which made the C-O bond less likely to be cleaved and thus significantly inhibited the formation of hydrocarbon products. Meanwhile, the non-dissociated CO species were obviously enriched on the Cu0 surface, promoting the formation of alcohol products, and thus the selectivity of total alcohols was increased. This strategy will shed light on the design of supported catalysts with stabilized structures for a wide range of catalytic reactions.
Cellular and Subcellular Characteristics of Neuromuscular Junctions in Muscles with Disparate Duty Cycles and Myofiber Profiles
Authors: Deschenes Michael R. , Mifsud Mia K. , Patek Leah G. , Flannery Rachel E.
Published: January 2023

The neuromuscular system accounts for a large portion (~40%) of whole body mass while enabling body movement, including physical work and exercise. At the core of this system is the neuromuscular junction (NMJ) which is the vital synapse transducing electrical impulses from the motor neurons to their post-synaptic myofibers. Recent findings suggest that subcellular features (active zones) of the NMJ are distinctly sensitive to changes in activity relative to cellular features (nerve terminal branches, vesicles, receptors) of the NMJ. In the present investigation, muscles with different recruitment patterns, functions, and myofiber type profiles (soleus, plantaris, extensor digitorum longus [EDL]) were studied to quantify both cellular and subcellular NMJ characteristics along with myofiber type profiles. Results indicated that, in general, dimensions of subcellular components of NMJs mirrored cellular NMJ features when examining inter-muscle NMJ architecture. Typically, it was noted that the NMJs of the soleus, with its most pronounced recruitment pattern, were larger (p < 0.05) than NMJs of less recruited muscles. Moreover, it was revealed that myofiber size did not dictate NMJ size as soleus muscles displayed the smallest fibers (p < 0.05) while the plantaris muscles exhibited the largest fibers. In total, these data show that activity determines the size of NMJs and that generally, size dimensions of cellular and subcellular components of the NMJ are matched, and that the size of NMJs and their underlying myofibers are uncoupled.
Midgut Volvulus Adds a Murine, Neutrophil-Driven Model of Septic Condition to the Experimental Toolbox
Authors: Elrod Julia , Kiwit Antonia , Lenz Moritz , Rohde Holger , Börnigen Daniela , Alawi Malik , Mohr Christoph , Pagerols Raluy Laia , Trochimiuk Magdalena , Knopf Jasmin , Reinshagen Konrad , Herrmann Martin , Boettcher Michael
Published: January 2023

Background: Severe infections that culminate in sepsis are associated with high morbidity and mortality. Despite continuous efforts in basis science and clinical research, evidence based-therapy is mostly limited to basic causal and supportive measures. Adjuvant therapies often remain without clear evidence. The objective of this study was to evaluate the septic volvulus ischemia-reperfusion model in comparison to two already established models and the role of neutrophil extacellular traps (NETs) in this model. Methods: The technique of the murine model of midgut volvulus was optimized and was compared to two established models of murine sepsis, namely cecal ligation and puncture (CLP) and intra-peritoneal (i.p.) injection of lipopolysaccharide (LPS). Results: Midgut volvulus for 15 min caused a comparable mortality (38%) as CLP (55%) and peritoneal LPS injection (25%) at 48 h. While oxidative stress was comparable, levels of circulating free DNA (cfDNA), and splenic/hepatic and pulmonary translocation of bacteria were decreased and increased, respectively at 48 h. DNases were increased compared to the established models. Proteomic analysis revealed an upregulation of systemic Epo, IL-1b, Prdx5, Parp1, Ccl2 and IL-6 at 48 h in comparison to the healthy controls. Discussion and Conclusion: Midgut volvulus is a stable and physiological model for sepsis. Depending on the duration and subsequent tissue damage, it represents a combination of ischemia-reperfusion injury and hyperinflammation.
Any Role for Microbiota in Cholangiocarcinoma? A Comprehensive Review
Authors: Elvevi Alessandra , Laffusa Alice , Gallo Camilla , Invernizzi Pietro , Massironi Sara
Published: January 2023

Alterations in the human microbiota have been linked to carcinogenesis in several cancers. To date, few studies have addressed the role of the microbiota in cholangiocarcinoma (CCA). Our work aims to update the knowledge about the role of the microbiota in the CCA microenvironment, and to highlight possible novel insights for the development of new diagnostic, prognostic, or even therapeutic strategies. We thus conducted a review of the literature. In recent years, great progress has been made in understanding the pathogenesis, the clinical and histological behavior, and the molecular profile of CCA. Much evidence suggests that the bile microbiota plays an essential role in biliary diseases, including CCA. Some studies have demonstrated that alterations in the qualitative and quantitative composition of the intestinal commensal bacteria lead to overall cancer susceptibility through various pathways. Other studies suggest that the gut microbiota plays a role in the pathogenesis and/or progression of CCA. The clinical implications are far-reaching, and the role of the microbiota in the CCA microenvironment may lead to considering the exciting implications of implementing therapeutic strategies that target the microbiota-immune system axis.
Acknowledgment to the Reviewers of Cells in 2022
Authors:   Cells Editorial Office
Published: January 2023

High-quality academic publishing is built on rigorous peer review [...]
Pediatric Glaucoma—From Screening, Early Detection to Management
Authors: Shen Ruyue , Li Venice S. W. , Wong Mandy O. M. , Chan Poemen P. M.
Published: January 2023

Pediatric glaucoma (PG) covers a rare and heterogeneous group of diseases with variable causes and presentations. Delayed diagnosis of PG could lead to blindness, bringing emotional and psychological burdens to patients’ caregivers. Recent genetic studies identified novel causative genes, which may provide new insight into the etiology of PG. More effective screening strategies could be beneficial for timely diagnosis and treatment. New findings on clinical characteristics and the latest examination instruments have provided additional evidence for diagnosing PG. In addition to IOP-lowering therapy, managing concomitant amblyopia and other associated ocular pathologies is essential to achieve a better visual outcome. Surgical treatment is usually required although medication is often used before surgery. These include angle surgeries, filtering surgeries, minimally invasive glaucoma surgeries, cyclophotocoagulation, and deep sclerectomy. Several advanced surgical therapies have been developed to increase success rates and decrease postoperative complications. Here, we review the classification and diagnosis, etiology, screening, clinical characteristics, examinations, and management of PG.
A Prospective Evaluation of the Effects of the COVID-19 Pandemic on Youth with Primary Headache Disorders
Authors: Connelly Mark , Dilts Jennifer , Boorigie Madeline , Gerson Trevor
Published: January 2023

Alterations in certain academic and social/family routines during the COVID-19 pandemic have been speculated to be either a risk factor or buffer for poor health outcomes for youth with stress-sensitive health conditions such as primary headache disorders. The current study evaluated patterns and moderators of pandemic impacts on youth with primary headache disorders, with an aim of extending our understanding of the relationship between stress, resilience, and outcomes in this population. Children recruited from a headache clinic in the midwestern United States reported on their headaches, schooling, routines, psychological stress, and coping at four timepoints ranging from within a few months of the pandemic onset to a long-term follow-up 2 years later. Changes in headache characteristics over time were analyzed for association with demographics, school status, altered routines, and stress, and coping. At baseline, 41% and 58% of participants reported no change in headache frequency or intensity, respectively, relative to pre-pandemic levels, with the remainder almost equally divided between reporting an improvement or worsening. The results of multilevel growth model analyses indicated that headache intensity remained more elevated over time since the start of the pandemic for respondents whose stress scores were relatively higher (b = 0.18, t = −2.70, p = 0.01), and headache-related disability remained more elevated over time for older respondents (b = 0.01, t = −2.12, p = 0.03). The study results suggest, overall, that the outcomes of primary headache disorders in youth were not systematically altered by the COVID-19 pandemic.
Carica Papaya Reduces High Fat Diet and Streptozotocin-Induced Development of Inflammation in Adipocyte via IL-1β/IL-6/TNF-α Mediated Signaling Mechanisms in Type-2 Diabetic Rats
Authors: Rebecca Roy Jeane , Janaki Coimbatore Sadagopan , Jayaraman Selvaraj , Periyasamy Vijayalakshmi , Balaji Thotakura , Vijayamalathi Madhavan , Veeraraghavan Vishnu Priya , Krishnamoorthy Kalaiselvi , Prasad Monisha
Published: January 2023

The prevalence of obesity in contemporary society has brought attention to how serious it is all around the world. Obesity, a proinflammatory condition defined by hypertrophied adipocytes and immune cells that reside in adipose tissue, is characterized by elevated circulating levels of proinflammatory cytokines. The pro-inflammatory mediators trigger a number of inflammatory pathways and affect the phosphorylation of a number of insulin-signaling pathways in peripheral tissues. In this work, we pointed the outcome of the leaves of Carica papaya (C. papaya) on the inflammatory molecules by in vivo and in silico analysis in order to prove its mechanisms of action. Adipocytokines, antioxidant enzymes, gene and protein expression of pro-inflammatory signaling molecules (mTOR, TNF-α, IL-1β, IL-6 and IKKβ) by q-RT-PCR and immunohistochemistry, as well as histopathological analysis, in adipose tissues were carried out. C. papaya reinstated the levels of adipocytokines, antioxidant enzymes and mRNA levels of mTOR, TNF-α, IL-1β, IL-6 and IKKβ in the adipose tissues of type 2 diabetic rats. Molecular docking and dynamics simulation studies revealed that caffeic acid, transferulic acid and quercetin had the top hit rates against IKKβ, TNF-α, IL-6, IL-1β, and mTOR. This study concludes that C. papaya put back the altered effects in fatty tissue of type 2 diabetic rats by restoring the adipocytokines and the gene expression.