bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Clinical Outcome and Prognostic Factors of Children and Adolescents with Localized Rhabdomyosarcoma Treated on the CWS-2002P Protocol
Authors: Koscielniak Ewa , Blank Bernd , Vokuhl Christian , Kazanowska Bernarda , Ladenstein Ruth , Niggli Felix , Ljungman Gustaf , Handgretinger Rupert , Seitz Guido , Fuchs Jörg , Fröhlich Birgit , Scheer Monika , Wessalowski Rüdiger , Schmid Irene , Sparber-Sauer Monika , Klingebiel Thomas
Published: February 2022

We report here the results of the prospective, non-randomized, historically controlled CWS-2002P study in patients ≤ 21 years with localized RMS developed with the aim to improve the long-term outcome by adapting the burden of therapy to risk profile and to investigate the feasibility and relation to the outcome of maintenance therapy (MT) in the high-risk groups. Patients were allocated into low-risk (LR), standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. Chemotherapy consisted of vincristine (VCR) and dactinomycin (ACTO-D) for all patients with the addition of ifosfamide (IFO) in the SR, HR, and VHR and doxorubicin (DOX) in the HR and VHR groups. Low-dose cyclophosphamide and vinblastine maintenance therapy (MT) over 6 months was recommended in the HR and VHR groups. A total of 444 patients have been included in this analysis. With a median follow-up of 9·6 years (IQR 7·6–10·9) for patients alive, the 5-year EFS and OS for the whole group was 73% (95% CI 69–77) and 80% (95% CI 76–84), respectively. The 5-year EFS by risk group was 100% in the LR, 79% (95% CI 72–84) in the SR, 69% (95% CI 63–75) in the HR, and 42% (95% CI 23–61) in the VHR (log-rank p = 0.000). The 5-year EFS was 77% (95% CI 70–84) for 155 patients in the HR group who received MT as compared to 63% (95% CI 50–76) for 49 patients who did not (log-rank p = 0.015). Neither the reduction in the IFO dose in the SR nor the increased dose intensity of DOX in HR groups influenced the outcome when compared to the previous CWS and other European studies. MT was feasible, seemed to have an impact on prognosis, and should be studied in a well-controlled prospective trial in this patient population. The weighting of risk factors used for therapy stratification needs to be reevaluated.
Multifunctional Silver(I) Complexes with Metronidazole Drug Reveal Antimicrobial Properties and Antitumor Activity against Human Hepatoma and Colorectal Adenocarcinoma Cells
Authors: Żyro Dominik , Radko Lidia , Śliwińska Agnieszka , Chęcińska Lilianna , Kusz Joachim , Korona-Głowniak Izabela , Przekora Agata , Wójcik Michał , Posyniak Andrzej , Ochocki Justyn
Published: February 2022

Silver salts and azole derivatives are well known for their antimicrobial properties. Recent evidence has demonstrated also their cytotoxic and genotoxic potential toward both normal and cancer cells. Still, little is known about the action of complexes of azoles with silver(I) salts. Thus, the goal of the study was to compare the chemical, cytotoxic and antimicrobial properties of metronidazole complexes with silver(I) nitrate and silver(I) sulfate to metronidazole and pure silver(I) salts. We synthetized a novel complex, [Ag(MTZ)2]2SO4, and confirmed its chemical structure and properties using 1H and 13C NMR spectroscopy and X-Ray, IR and elemental analysis. To establish the stability of complexes [Ag(MTZ)2NO3] and [Ag(MTZ)2]2SO4, they were exposed to daylight and UV-A rays and were visually assessed. Their cytotoxicity toward human cancer cells (HepG2, Caco-2) and mice normal fibroblasts (Balb/c 3T3 clone A31) was determined by MTT, NRU, TPC and LDH assays. The micro-dilution broth method was used to evaluate their antimicrobial properties against Gram-positive and Gram-negative bacteria. A biofilm eradication study was also performed using the crystal violet method and confocal laser scanning microscopy. The photo-stability of the complexes was higher than silver(I) salts. In human cancer cells, [Ag(MTZ)2]2SO4 was more cytotoxic than Ag2SO4 and, in turn, AgNO3 was more cytotoxic than [Ag(MTZ)2NO3]. For Balb/c 3T3 cells, Ag2SO4 was more cytotoxic than [Ag(MTZ)2]2SO4, while the cytotoxicity of AgNO3 and [Ag(MTZ)2NO3] was similar. Metronidazole in the tested concentration range was non-cytotoxic for both normal and cancer cells. The complexes showed increased bioactivity against aerobic and facultative anaerobic bacteria when compared to metronidazole. For the majority of the tested bacterial strains, the silver(I) salts and complexes showed a higher antibacterial activity than MTZ; however, some bacterial strains presented the reverse effect. Our results showed that silver(I) complexes present higher photo-stability, cytotoxicity and antimicrobial activity in comparison to MTZ and, to a certain extent, to silver(I) salts.
Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy
Authors: Van Trimpont Maaike , Peeters Evelien , De Visser Yanti , Schalk Amanda M. , Mondelaers Veerle , De Moerloose Barbara , Lavie Arnon , Lammens Tim , Goossens Steven , Van Vlierberghe Pieter
Published: February 2022

L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.
Combination of Tipifarnib and Sunitinib Overcomes Renal Cell Carcinoma Resistance to Tyrosine Kinase Inhibitors via Tumor-Derived Exosome and T Cell Modulation
Authors: Greenberg Jacob W. , Kim Hogyoung , Ahn Miae , Moustafa Ahmed A. , Zhou He , Barata Pedro C. , Boulares A. Hamid , Abdel-Mageed Asim B. , Krane Louis S.
Published: February 2022

Background: Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance. Methods: 786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Exosomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis. Results: SR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated with increased expression of PD-L1 on SR exosomes when compared to sunitinib-sensitive (SS) exosomes. Additionally, Tipi treatment downregulated PD-L1 expression on exosomes derived from SR cell lines. Tipi’s ability to downregulate PD-L1 in exosomes has a significant application within patients. Exosomes collected from patients with RCC showed increased PD-L1 expression over subjects without RCC. Next, exosome concentrations were then compared after Tipi treatment, with all SS cell lines displaying an even greater reduction. On immunoblot assay, 293T cells showed a dose-dependent increase in Alix with no change in either nSMase or Rab27a. Conversely, all the SS and SR cell lines displayed a decrease in all three markers. After a cell proliferation employed a 48-h treatment on all SS and SR cell lines, the drug combination displayed synergistic ability to decrease tumor growth. Conclusions: Tipifarnib attenuates both the exosome endosomal sorting complex required for endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways, thereby blocking exosome biogenesis and secretion as well as downregulating PD-L1 on SS and SR cells.
Characterisation of the Stromal Microenvironment in Lobular Breast Cancer
Authors: Gómez-Cuadrado Laura , Bullock Esme , Mabruk Zeanap , Zhao Hong , Souleimanova Margarita , Noer Pernille , Turnbull Arran , Oxvig Claus , Bertos Nicholas , Byron Adam , Dixon J. , Park Morag , Haider Syed , Natrajan Rachael , Sims Andrew , Brunton Valerie
Published: February 2022

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, and it exhibits a number of clinico-pathological characteristics distinct from the more common invasive ductal carcinoma (IDC). We set out to identify alterations in the tumor microenvironment (TME) of ILC. We used laser-capture microdissection to separate tumor epithelium from stroma in 23 ER+ ILC primary tumors. Gene expression analysis identified 45 genes involved in regulation of the extracellular matrix (ECM) that were enriched in the non-immune stroma of ILC, but not in non-immune stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets, with PAPPA and TIMP2 being associated with better survival in ILC but not IDC. PAPPA, a gene involved in IGF-1 signaling, was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. Analysis of PAPPA- and IGF1-associated genes identified a paracrine signaling pathway, and active PAPP-A was shown to be secreted from primary CAFs. This is the first study to demonstrate molecular differences in the TME between ILC and IDC identifying differences in matrix organization and growth factor signaling pathways.
Cost-Effectiveness of Molecularly Guided Treatment in Diffuse Large B-Cell Lymphoma (DLBCL) in Patients under 60
Authors: Regier Dean A. , Chan Brandon , Costa Sarah , Scott David W. , Steidl Christian , Connors Joseph M. , Karsan Aly , Marra Marco A. , Kridel Robert , Cromwell Ian , Pollard Samantha
Published: February 2022

Background: Classifying diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subtypes could allow for personalized cancer control. Evidence suggests that subtype-guided treatment may be beneficial in the activated B-cell (ABC) subtype of DLBCL, among patients under the age of 60. Methods: We estimated the cost-effectiveness of age- and subtype-specific treatment guided by gene expression profiling (GEP). A probabilistic Markov model examined costs and quality-adjusted life-years gained (QALY) accrued to patients under GEP-classified COO treatment over a 10-year time horizon. The model was calibrated to evaluate the adoption of ibrutinib as a first line treatment among patients under 60 years with ABC subtype DLBCL. The primary data source for efficacy was derived from published estimates of the PHOENIX trial. These inputs were supplemented with patient-level, real-world data from BC Cancer, which provides comprehensive cancer services to the population of British Columbia. Results: We found the cost-effectiveness of GEP-guided treatment vs. standard care was $77,806 per QALY (24.3% probability of cost-effectiveness at a willingness-to-pay (WTP) of $50,000/QALY; 53.7% probability at a WTP of $100,000/QALY) for first-line treatment. Cost-effectiveness was dependent on assumptions around decision-makers’ WTP and the cost of the assay. Conclusions: We encourage further clinical trials to reduce uncertainty around the implementation of GEP-classified COO personalized treatment in this patient population.
Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study
Authors: Poveda Andres , Lopez-Reig Raquel , Oaknin Ana , Redondo Andres , Rubio Maria Jesus , Guerra Eva , Fariñas-Madrid Lorena , Gallego Alejandro , Rodriguez-Freixinos Victor , Fernandez-Serra Antonio , Juan Oscar , Romero Ignacio , Lopez-Guerrero Jose A.
Published: February 2022

We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1–5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0–5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3–4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses.
Cancer Worry Distribution and Willingness to Undergo Colonoscopy at Three Levels of Hypothetical Cancer Risk—A Population-Based Survey in Sweden
Authors: Hawranek Carolina , Maxon Johan , Andersson Andreas , Van Guelpen Bethany , Hajdarevic Senada , Numan Hellquist Barbro , Rosén Anna
Published: February 2022

Purpose: We describe levels of cancer worry in the general population as measured with the Cancer Worry Scale (CWS) and investigate the association with colonoscopy screening intentions in three colorectal cancer risk scenarios. Methods: The data were sourced through a population-based survey. Respondents (n = 943) completed an eight-item CWS and questions on colonoscopy screening interest at three hypothetical risk levels. Results: Respondents without a personal cancer history (n = 853) scored 9.46 on the six-item CWS (mean, SD 2.72). Mean scores were significantly higher in women (9.91, SD 2.89) as compared to men (9.06, SD 2.49, p < 0.001). Linear regression showed higher cancer worry in women and those with children when controlling for education, age group, and country of birth. High cancer worry (six-item CWS mean >12) was identified in 25% of women and in 17% of men. Among those, 71% would attend a colonoscopy screening compared to 52% of those with low cancer worry (p < 0.001, 5% CRC-risk). Conclusions: The distribution of cancer worry in a general population sample showed higher mean scores in women, and levels overlapped with earlier findings in cancer-affected samples. Respondents with high cancer worry were more inclined to undergo a colonoscopy screening, and intention increased with higher levels of hypothetical risk.
The Transcription Factor IRF9 Promotes Colorectal Cancer via Modulating the IL-6/STAT3 Signaling Axis
Authors: Sharma Bhesh Raj , Karki Rajendra , Sundaram Balamurugan , Wang Yaqiu , Vogel Peter , Kanneganti Thirumala-Devi
Published: February 2022

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and innate immune responses and inflammation are known to affect the course of disease. Interferon (IFN) signaling in particular is critical for modulating inflammation-associated diseases including CRC. While the effects of IFN signaling in CRC have been studied, results have been conflicting. Furthermore, individual molecules in the IFN pathway that could be therapeutically targeted have distinct functions, with many of their diverse roles in CRC remaining unclear. Here, we found that IRF9 had an oncogenic effect in CRC; loss of IRF9 reduced tumorigenesis in both azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced and spontaneous CRC models. IRF9 also reduced DSS-induced colitis and inflammation in the colon, but it had no effect on the NF-κB and MAPK signaling activation. Instead, IRF9 enhanced the transcription and production of the inflammatory cytokine IL-6. By promoting IL-6 release, IRF9 drove the activation of pro-oncogenic STAT3 signaling in the colon. Overall, our study found that IRF9 promoted the development of CRC via modulation of the IL-6/STAT3 signaling axis, identifying multiple potential targets and suggesting new therapeutic strategies for the treatment of CRC.
New Insights into Hormonal Therapies in Uterine Sarcomas
Authors: Maccaroni Elena , Lunerti Valentina , Agostinelli Veronica , Giampieri Riccardo , Zepponi Laura , Pagliacci Alessandra , Berardi Rossana
Published: February 2022

Uterine sarcoma (US) is a rare mesenchymal malignant cancer type, accounting for 3–7% of uterine malignancies. US prognosis is still poor due to high local and distant recurrence rates. As for molecular features, US may present variable oestrogen receptor (ER) and progesterone receptor (PR) expressions, mostly depending on histotype and grading. Surgery represents the mainstay of treatment for early-stage disease, while the role of adjuvant chemotherapy or local radiotherapy is still debated and defined on the basis of histotype, tumour grading and stage. In metastatic setting, uterine sarcomas’ treatment includes palliative surgery, a metastases resection, chemotherapy, hormonal therapy and targeted therapy. As for the chemotherapy regimen used, drugs that are considered most effective are doxorubicin (combined with ifosfamide or alone), gemcitabine combined with docetaxel and, more recently, trabectedin or pazopanib. Hormonal therapies, including aromatase inhibitors (AIs), progestins and gonadotropin-releasing hormone analogues (GnRH-a) may also represent an effective option, in particular for low-grade endometrial stromal sarcoma (LGESS), due to their favourable toxicity profile and patients’ compliance, while their role is still under investigation in uterine leiomyosarcoma (uLMS), high-grade endometrial stromal sarcoma (HGESS), undifferentiated uterine sarcoma (USS) and other rarer US. The present review aims to analyse the existing evidence and future perspectives on hormonal therapies in US, in order to clarify their potential role in daily clinical practice.
Computational Analyses of YY1 and Its Target RKIP Reveal Their Diagnostic and Prognostic Roles in Lung Cancer
Authors: Vivarelli Silvia , Falzone Luca , Grillo Caterina Maria , Bonavida Benjamin , Crimi Claudia , La Mantia Ignazio , Libra Massimo
Published: February 2022

Lung cancer (LC) represents a global threat, being the tumor with the highest mortality rate. Despite the introduction of novel therapies (e.g., targeted inhibitors, immune-checkpoint inhibitors), relapses are still very frequent. Accordingly, there is an urgent need for reliable predictive biomarkers and therapeutically druggable targets. Yin-Yang 1 (YY1) is a transcription factor that may work either as an oncogene or a tumor suppressor, depending on the genotype and the phenotype of the tumor. The Raf Kinase Inhibitory Protein (RKIP), is a tumor suppressor and immune enhancer often found downregulated in the majority of the examined cancers. In the present report, the role of both YY1 and RKIP in LC is thoroughly explored through the analysis of several deposited RNA and protein expression datasets. The computational analyses revealed that YY1 negatively regulates RKIP expression in LC, as corroborated by the deposited YY1-ChIP-Seq experiments and validated by their robust negative correlation. Additionally, YY1 expression is significantly higher in LC samples compared to normal matching ones, whereas RKIP expression is lower in LC and high in normal matching tissues. These observed differences, unlike many current biomarkers, bear a diagnostic significance, as proven by the ROC analyses. Finally, the survival data support the notion that both YY1 and RKIP might represent strong prognostic biomarkers. Overall, the reported findings indicate that YY1 and RKIP expression levels may play a role in LC as potential biomarkers and therapeutic targets. However, further studies will be necessary to validate the in silico results.
Constitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphoma
Authors: Quinet Grégoire , Xolalpa Wendy , Reyes-Garau Diana , Profitós-Pelejà Núria , Azkargorta Mikel , Ceccato Laurie , Gonzalez-Santamarta Maria , Marsal Maria , Andilla Jordi , Aillet Fabienne , Bosch Francesc , Elortza Felix , Loza-Alvarez Pablo , Sola Brigitte , Coux Olivier , Matthiesen Rune , Roué Gaël , Rodriguez Manuel S.
Published: February 2022

Protein ubiquitylation coordinates crucial cellular events in physiological and pathological conditions. A comparative analysis of the ubiquitin proteome from bortezomib (BTZ)-sensitive and BTZ-resistant mantle cell lymphoma (MCL) revealed an enrichment of the autophagy–lysosome system (ALS) in BTZ-resistant cells. Pharmacological inhibition of autophagy at the level of lysosome-fusion revealed a constitutive activation of proteaphagy and accumulation of proteasome subunits within autophagosomes in different MCL cell lines with acquired or natural resistance to BTZ. Inhibition of the autophagy receptor p62/SQSTM1 upon verteporfin (VTP) treatment disrupted proteaphagosome assembly, reduced co-localization of proteasome subunits with autophagy markers and negatively impacted proteasome activity. Finally, the silencing or pharmacological inhibition of p62 restored the apoptosis threshold at physiological levels in BTZ-resistant cells both in vitro and in vivo. In total, these results demonstrate for the first time a proteolytic switch from the ubiquitin–proteasome system (UPS) to ALS in B-cell lymphoma refractory to proteasome inhibition, pointing out a crucial role for proteaphagy in this phenomenon and paving the way for the design of alternative therapeutic venues in treatment-resistant tumors.
Sentinel Lymph Node Biopsy in Endometrial Cancer: Dual Injection, Dual Tracer—A Multidisciplinary Exhaustive Approach to Nodal Staging
Authors: Torrent Anna , Amengual Joana , Sampol Catalina Maria , Ruiz Mario , Rioja Jorge , Matheu Gabriel , Roca Pilar , Cordoba Octavi
Published: February 2022

Introduction: Sentinel lymph node (SLN) has recently been introduced as a standard staging technique in endometrial cancer (EC). There are some issues regarding team experience and para-aortic detection. Objective: to report the accuracy of SLN detection in EC with a dual tracer (ICG and Tc99) and dual injection site (cervix and fundus) during the learning curve. Methods: A prospective, observational single-center trial including 48 patients diagnosed with early-stage EC. Dual intracervical tracer (Tc99 and ICG) was injected at different times. High-risk patients had a second fundus injection with both tracers. Results: the detection rates were as follows: 100% (48/48) overall for SLNs; 98% (47/48) overall for pelvic SLNs; 89.5% (43/48) for bilateral SLNs; and 2% (1/48) for isolated para-aortic SLNs. In high-risk patients, the para-aortic overall DR was 66.7% (22/33); 60.7% (17/28) with ICG and 51.5% (17/33) with Tc99 (p = 0.048)). Overall rate of lymph node involvement was 14.6% (7/48). Macroscopic pelvic metastasis was found in four patients (8.3%) and microscopic in one case (2%). No metastasis was found in any para-aortic SLNs. Half of the patients with positive pelvic SLNs had positive para-aortic nodes. In high-risk patients, when para-aortic SLNs mapped failed, 36.4% (4/11) had positive nodes in para-aortic lymphadenectomy. The sensitivity and negative predictive value (NPV) of SLN pelvic detection was 100%. Conclusions: Multidisciplinary exhaustive approach gives a suitable accuracy of SLN during learning curve. Dual injection (cervical and fundal) with dual tracer (ICG and Tc99) offers good overall detection rates and increases para-aortic SLN detection.
Global Genomic and Proteomic Analysis Identified Critical Pathways Modulated by Proto-Oncogene PELP1 in TNBC
Authors: Liu Zexuan , Altwegg Kristin A. , Liu Junhao , Weintraub Susan T. , Chen Yidong , Lai Zhao , Sareddy Gangadhara R. , Viswanadhapalli Suryavathi , Vadlamudi Ratna K.
Published: February 2022

The PELP1 oncogene is commonly overexpressed in many cancers, including triple negative breast cancer (TNBC). However, the mechanisms by which PELP1 contributes to TNBC progression are not well understood. To elucidate these mechanisms, we generated CRISPR-Cas9 mediated PELP1 knockout TNBC cell lines, and alterations in the proteome were examined using global data-independent acquisition mass spectrometry (DIA-MS). Further mechanistic studies utilized shRNA knockdown, Western blotting, and RNA-seq approaches. TCGA data sets were utilized for determining the status of PELP1 in TNBC patient tumors and for examining its correlation with ribosomal proteins. Global DIA-MS studies revealed that 127 proteins are upregulated while 220 proteins are downregulated upon PELP1-KO. Bioinformatic analyses suggested that the oncogenic activities of PELP1 involve regulation of expression of ribosomal proteins and ribosomal complexes. RNA-seq studies further suggested PELP1 modulates the functions of transcription factor c-Myc in TNBC. TCGA data confirmed PELP1 has high expression in TNBC patient tumors, and this high expression pattern correlates with c-Myc, a regulator of ribosomal proteins. Collectively, our global approach studies suggest that PELP1 contributes to TNBC progression by modulation of cell cycle, apoptosis, and ribosome biogenesis pathways.
Escalated Maximum Dose in the Planning Target Volume Improves Local Control in Stereotactic Body Radiation Therapy for T1-2 Lung Cancer
Authors: Inagaki Takaya , Doi Hiroshi , Ishida Naoko , Ri Aritoshi , Tatsuno Saori , Wada Yutaro , Uehara Takuya , Inada Masahiro , Nakamatsu Kiyoshi , Hosono Makoto , Nishimura Yasumasa
Published: February 2022

Stereotactic body radiotherapy (SBRT) is a treatment option for early-stage lung cancer. The purpose of this study was to investigate the optimal dose distribution and prognostic factors for local control (LC) after SBRT for lung cancer. A total of 104 lung tumors from 100 patients who underwent SBRT using various treatment regimens were analyzed. Dose distributions were corrected to the biologically effective dose (BED). Clinical and dosimetric factors were tested for association with LC after SBRT. The median follow-up time was 23.8 months (range, 3.4–109.8 months) after SBRT. The 1- and 3-year LC rates were 95.7% and 87.7%, respectively. In univariate and multivariate analyses, pathologically confirmed squamous cell carcinoma (SQ), T2 tumor stage, and a Dmax < 125 Gy (BED10) were associated with worse LC. The LC rate was significantly lower in SQ than in non-SQ among tumors that received a Dmax < 125 Gy (BED10) (p = 0.016). However, there were no significant differences in LC rate between SQ and non-SQ among tumors receiving a Dmax ≥ 125 Gy (BED10) (p = 0.198). To conclude, SQ, T2 stage, and a Dmax < 125 Gy (BED10) were associated with poorer LC. LC may be improved by a higher Dmax of the planning target volume.
Classification of Breast Cancer Nottingham Prognostic Index Using High-Dimensional Embedding and Residual Neural Network
Authors: Zhou Li , Rueda Maria , Alkhateeb Abedalrhman
Published: February 2022

The Nottingham Prognostics Index (NPI) is a prognostics measure that predicts operable primary breast cancer survival. The NPI value is calculated based on the size of the tumor, the number of lymph nodes, and the tumor grade. Next-generation sequencing advancements have led to measuring different biological indicators called multi-omics data. The availability of multi-omics data triggered the challenge of integrating and analyzing these various biological measures to understand the progression of the diseases. High-dimensional embedding techniques are incorporated to present the features in the lower dimension, i.e., in a 2-dimensional map. The dataset consists of three -omics: gene expression, copy number alteration (CNA), and mRNA from 1885 female patients. The model creates a gene similarity network (GSN) map for each omic using t-distributed stochastic neighbor embedding (t-SNE) before being merged into the residual neural network (ResNet) classification model. The aim of this work was to (i) extract multi-omics biomarkers that are associated with the prognosis and prediction of breast cancer survival; and (ii) build a prediction model for multi-class breast cancer NPI classes. We evaluated this model and compared it to different high-dimensional embedding techniques and neural network combinations. The proposed model outperformed the other methods with an accuracy of 98.48%, and the area under the curve (AUC) equals 0.9999. The findings in the literature confirm associations between some of the extracted omics and breast cancer prognosis and survival including CDCA5, IL17RB, MUC2, NOD2 and NXPH4 from the gene expression dataset; MED30, RAD21, EIF3H and EIF3E from the CNA dataset; and CENPA, MACF1, UGT2B7 and SEMA3B from the mRNA dataset.
Organ-on-a-Chip Platforms for Drug Screening and Delivery in Tumor Cells: A Systematic Review
Authors: Gonçalves Inês M. , Carvalho Violeta , Rodrigues Raquel O. , Pinho Diana , Teixeira Senhorinha F. C. F. , Moita Ana , Hori Takeshi , Kaji Hirokazu , Lima Rui , Minas Graça
Published: February 2022

The development of cancer models that rectify the simplicity of monolayer or static cell cultures physiologic microenvironment and, at the same time, replicate the human system more accurately than animal models has been a challenge in biomedical research. Organ-on-a-chip (OoC) devices are a solution that has been explored over the last decade. The combination of microfluidics and cell culture allows the design of a dynamic microenvironment suitable for the evaluation of treatments’ efficacy and effects, closer to the response observed in patients. This systematic review sums the studies from the last decade, where OoC with cancer cell cultures were used for drug screening assays. The studies were selected from three databases and analyzed following the research guidelines for systematic reviews proposed by PRISMA. In the selected studies, several types of cancer cells were evaluated, and the majority of treatments tested were standard chemotherapeutic drugs. Some studies reported higher drug resistance of the cultures on the OoC devices than on 2D cultures, which indicates the better resemblance to in vivo conditions of the former. Several studies also included the replication of the microvasculature or the combination of different cell cultures. The presence of vasculature can influence positively or negatively the drug efficacy since it contributes to a greater diffusion of the drug and also oxygen and nutrients. Co-cultures with liver cells contributed to the evaluation of the systemic toxicity of some drugs metabolites. Nevertheless, few studies used patient cells for the drug screening assays.
Mitochondrial Neurodegeneration
Authors: Zeviani Massimo , Viscomi Carlo
Published: February 2022

Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA found in mitochondria themselves, and are termed mitochondrial DNA (mtDNA). Mutations striking either genome can lead to mitochondrial impairment, determining infantile, childhood or adult neurodegeneration. Mitochondrial disorders are complex neurological syndromes, and are often part of a multisystem disorder. In this paper, we divide the diseases into those caused by mtDNA defects and those that are due to mutations involving nuclear genes; from a clinical point of view, we discuss pediatric disorders in comparison to juvenile or adult-onset conditions. The complementary genetic contributions controlling organellar function and the complexity of the biochemical pathways present in the mitochondria justify the extreme genetic and phenotypic heterogeneity of this new area of inborn errors of metabolism known as ‘mitochondrial medicine’.
RNAi Screening Uncovers a Synthetic Sick Interaction between CtIP and the BARD1 Tumor Suppressor
Authors: Bolck Hella A. , Przetocka Sara , Meier Roger , von Aesch Christine , Zurfluh Christina , Hänggi Kay , Spegg Vincent , Altmeyer Matthias , Stebler Michael , Nørrelykke Simon F. , Horvath Peter , Sartori Alessandro A. , Porro Antonio
Published: February 2022

Human CtIP is best known for its role in DNA end resection to initiate DNA double-strand break repair by homologous recombination. Recently, CtIP has also been shown to protect reversed replication forks from nucleolytic degradation upon DNA replication stress. However, still little is known about the DNA damage response (DDR) networks that preserve genome integrity and sustain cell survival in the context of CtIP insufficiency. Here, to reveal such potential buffering relationships, we screened a DDR siRNA library in CtIP-deficient cells to identify candidate genes that induce synthetic sickness/lethality (SSL). Our analyses unveil a negative genetic interaction between CtIP and BARD1, the heterodimeric binding partner of BRCA1. We found that simultaneous disruption of CtIP and BARD1 triggers enhanced apoptosis due to persistent replication stress-induced DNA lesions giving rise to chromosomal abnormalities. Moreover, we observed that the genetic interaction between CtIP and BARD1 occurs independently of the BRCA1-BARD1 complex formation and might be, therefore, therapeutical relevant for the treatment of BRCA-defective tumors.
Epithelial Mesenchymal Transition (EMT) and Associated Invasive Adhesions in Solid and Haematological Tumours
Authors: Greaves David , Calle Yolanda
Published: February 2022

In solid tumours, cancer cells that undergo epithelial mesenchymal transition (EMT) express characteristic gene expression signatures that promote invasive migration as well as the development of stemness, immunosuppression and drug/radiotherapy resistance, contributing to the formation of currently untreatable metastatic tumours. The cancer traits associated with EMT can be controlled by the signalling nodes at characteristic adhesion sites (focal contacts, invadopodia and microtentacles) where the regulation of cell migration, cell cycle progression and pro-survival signalling converge. In haematological tumours, ample evidence accumulated during the last decade indicates that the development of an EMT-like phenotype is indicative of poor disease prognosis. However, this EMT phenotype has not been directly linked to the assembly of specific forms of adhesions. In the current review we discuss the role of EMT in haematological malignancies and examine its possible link with the progression towards more invasive and aggressive forms of these tumours. We also review the known types of adhesions formed by haematological malignancies and speculate on their possible connection with the EMT phenotype. We postulate that understanding the architecture and regulation of EMT-related adhesions will lead to the discovery of new therapeutic interventions to overcome disease progression and resistance to therapies.
Optimization of Effective Doping Concentration of Emitter for Ideal c-Si Solar Cell Device with PC1D Simulation
Authors: Subramanian Maruthamuthu , Nagarajan Balaji , Ravichandran Aishwarya , Subhash Betageri Varsha , Thirunavukkarasu Gokul Sidarth , Jamei Elmira , Seyedmahmoudian Mehdi , Stojcevski Alex , Mekhilef Saad , Minnam Reddy Vasudeva Reddy
Published: February 2022

Increasing silicon solar cell efficiency plays a vital role in improving the dominant market share of photo-voltaic systems in the renewable energy sector. The performance of the solar cells can be evaluated by making a profound analysis on various effective parameters, such as the sheet resistance, doping concentration, thickness of the solar cell, arbitrary dopant profile, etc., using software simulation tools, such as PC1D. In this paper, we present the observations obtained from the evaluation carried out on the impact of sheet resistance on the solar cell’s parameters using PC1D software. After which, the EDNA2 simulation tool was used to analyse the emitter saturation current density for the chosen arbitrary dopant profile. Results indicated that the diffusion profile with low surface concentration and shallow junction depth can improve the blue response at the frontal side of the solar cell. The emitter saturation current density decreases from 66.52 to 36.82 fA/cm2 for the subsequent increase in sheet resistance. The blue response also increased from 89.6% to 97.5% with rise in sheet resistance. In addition, the short circuit density and open circuit voltage was also observed to be improved by 0.6 mA/cm2 and 3 mV for the sheet resistance value of 130 Ω/sq, which resulted in achieving the highest efficiency of 20.6%.
Solvothermal Synthesis of Calcium-Deficient Hydroxyapatite via Hydrolysis of α-Tricalcium Phosphate in Different Aqueous-Organic Media
Authors: Karalkeviciene Rasa , Raudonyte-Svirbutaviciene Eva , Gaidukevic Justina , Zarkov Aleksej , Kareiva Aivaras
Published: February 2022

In the present work, the effects of various organic solvents (solvent nature and fraction within the solution) and solvothermal conditions on the formation of calcium-deficient hydroxyapatite (CDHA) via hydrolysis of α-tricalcium phosphate (α-TCP) are investigated. The wet precipitation method is applied for α-TCP synthesis, and the hydrolysis reaction is performed in solutions with different water-to-organic solvent ratios under solvothermal conditions at 120 °C for 3 h and at 200 °C for 5 h. Ethyl alcohol, isopropyl alcohol, and butyl alcohol did not inhibit the hydrolysis of α-TCP, while methyl alcohol and ethylene glycol have a more prominent inhibitory effect on the hydrolysis, hence the formation of single-phased CDHA. From all the solvents analysed, ethylene glycol has the highest impact on the sample morphology. Under certain water to ethylene glycol ratios and solvothermal conditions, samples containing a significant fraction of rods are obtained. However, samples prepared with ethylene glycol are characterised by a particularly low BET surface area.
Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network
Authors: Law Jeanna Wallenta , Mitra Debanjali , Kaplan Henry G. , Alfred Tamuno , Brufsky Adam M. , Emir Birol , McCracken Haley , Liu Xianchen , Broome Ronda G. , Zhang Chenan , DiCristo Caroline , Chen Connie
Published: February 2022

This retrospective single-arm study assessed real-world treatment patterns and clinical outcomes in patients with hormone receptor—positive/human epidermal growth factor receptor 2—negative (HR+/HER2−) advanced/metastatic breast cancer (A/MBC) who received palbociclib plus an aromatase inhibitor as first-line therapy in US community health systems. Using electronic health records from the Syapse Learning Health Network, 242 patients were identified as having received first-line palbociclib plus an aromatase inhibitor between 3 February 2015, and 31 July 2019 (data cutoff 1 February 2020) resulting in a minimum potential 6-month follow-up period. In total, 56.6% of patients had de novo A/MBC at initial breast cancer diagnosis, 50.8% had bone-only disease, and 32.2% had visceral disease. Median follow-up was 22.4 months. Disease progression (26.4%) and intolerance/toxicity (14.9%) were the main reasons for treatment discontinuation. The median (95% CI) real-world progression-free survival was 31.7 (27.9—not estimable (NE)) months and 2-year estimated overall survival (OS) rate was 78.0%. In total, 25.6% of patients died; however, OS data are limited by the small population size and insufficient follow-up time. These real-world effectiveness outcomes complement findings from other real-world studies and randomized controlled trials and support palbociclib plus an aromatase inhibitor as first-line therapy for HR+/HER2− A/MBC.
Psychosocial Implications of COVID-19 on Head and Neck Cancer
Authors: Dermody Sarah M. , Shuman Andrew G.
Published: February 2022

The COVID-19 pandemic has fundamentally changed healthcare access, delivery, and treatment paradigms throughout oncology. Patients with head and neck cancer comprise an especially vulnerable population due to the nature of their disease and the transmission mechanism of the SARS-CoV-2 virus. The consequences of triage decisions and delays in care have serious psychosocial implications for patients. The development of structured psychosocial support programs, coupled with clear and consistent communication from treating physicians, can help mitigate perceptions of abandonment and distress that may accompany delays in care. As the unpredictability of the pandemic’s course continues to burden both providers and patients, we must be proactive in addressing the psychosocial implications of these delays in care.
Diversity of Wood-Decaying Fungi in Wuliangshan Area, Yunnan Province, P.R. China
Authors: He Xiao , Zhao Chang-Lin
Published: February 2022

Five surveys were carried out in the Wuliangshan area, Yunnan Province, P.R. China, based on a combination of morphological features and molecular evidence. Around 2454 specimens of wood-decaying fungi were collected. The paper summarizes the obtained results on the wood-decaying fungi of this area, consisting in 95 species distributed in 59 genera, 23 families and 9 orders. Their hosts and substrates were also identified. A checklist of wood-decaying fungi is given. Sequences of the ITS nrRNA gene region of the studied specimens were generated and phylogenetic analysis was performed with maximum likelihood, maximum parsimony and Bayesian inference methods. The present list of wood-decaying fungi enriches the knowledge of fungal diversity worldwide and supplies the basic data for future applications.
Mesocarnivore Distribution along Gradients of Anthropogenic Disturbance in Mediterranean Landscapes
Authors: Torre Ignasi , Pulido Tomàs , Vilella Marc , Díaz Mario
Published: February 2022

Wildfires are important sources of landscape change in Mediterranean environments, creating large patches of low-growth natural habitats (i.e., scrublands) inside protected areas, whereas woodland patches remain mostly near well protected human settlements. Landscape patterns resulting from these gradients influence habitat suitability for mesocarnivores regarding food and shelter. In winter and summer 2019, we sampled 16 independent line-transects with four camera traps each (64 cameras overall), covering the main habitats of the study area (woodlands, scrublands, and crops). Cameras were baited to compensate for the low detectability of target species, and mesocarnivore contacts were analysed by means of GLMMs and occupancy models. Our results showed a positive and stronger association of wild species with woodland habitats, despite the low proportion of habitat available, higher presence of competitors (other mesocarnivores), and potential predators (human pets, i.e., dogs), and low natural prey availability than in scrubland (i.e., small mammals). However, mesocarnivores will find protection against predators and resting sites in forests as well as other food opportunities in crops and urban areas, despite the possible interference with humans and their pets. Potential cascading effects linked to ecological roles of Mediterranean mesocarnivores on the succession of Mediterranean landscapes would imply longer-term effects of human disturbance on landscape trends.
Impact of SARS-CoV-2 Infection in Patients with Neurological Pathology
Authors: Axelerad Any Docu , Muja Lavinia Florenta , Stroe Alina Zorina , Zlotea Lavinia Alexandra , Sirbu Carmen Adella , Docu Axelerad Silviu , Jianu Dragos Catalin , Frecus Corina Elena , Mihai Cristina Maria
Published: February 2022

The COVID-19 disease, caused by infection with SARS-CoV-2, rapidly transformed into a pandemic following its emergence, and it continues to affect the population at a global level. This disease is associated with high mortality rates and mainly affects the pulmonary spectrum, with signs of interstitial pneumonia or other pathological modifications. Signs indicative of SARS-CoV-2 infection can be observed using pulmonary radiography or computed tomography scans and are closely linked to acute respiratory distress; however, there is accumulating evidence that the virus affects the central nervous system. Several symptoms, such as headaches, cough, fatigue, myalgia, ageusia, and anosmia, have also been reported along with neurological syndromes such as stroke, encephalopathy, Guillain–Barre syndrome, convulsions, and coma; the most frequent associated complication is ischemic stroke. Diagnosis of infection with SARS-CoV-2 virus is based on a positive RT-PCR test. Imaging investigations, such as thoracic computed tomography scans, are not used to diagnose COVID-19, monitor for pulmonary disease, or follow dynamic disease evolution, but they may be used in the case of a negative RT-PCR test. This paper presents the research performed on a group of 150 cases of patients affected by neurological disorders and that were subsequently confirmed to be infected with SARS-CoV-2, which was carried out over a period of 10 months within the Neurology Department and Laboratory of Magnetic Resonance Imaging of “Sf. Andrei” Emergency Hospital in Constanta. The collected data are observational and provide perspectives on the neurological pathology associated with the SARS-CoV-2 virus, and on the frequently associated risk factors, associated comorbidities, and the ages of patients who were affected by the virus, as well as the clinical and paraclinical manifestations of the patients admitted to the hospital’s neurology department.