bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating extracellular vesicles expressing PD1 and PD-L1 predict response and mediate resistance to checkpoint inhibitors immunotherapy in metastatic melanoma
Authors: Serratì Simona , Guida Michele , Di Fonte Roberta , De Summa Simona , Strippoli Sabino , Iacobazzi Rosa Maria , Quarta Alessandra , De Risi Ivana , Guida Gabriella , Paradiso Angelo , Porcelli Letizia , Azzariti Amalia 
Published: January 2022

Abstract
Background
The immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1+ EV mediate resistance to anti-PD1, instead the role of PD1+ EV is not fully understood.

Methods
We isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1+ EVs and PD1+ EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1+ EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.

Results
The level of PD-L1+ EVs released from melanoma and CD8+ T cells and that of PD1+ EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1+ EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1+ EVs, from T cells and B cells, and high level of PD-L1+ EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1+ EVs from melanoma and PD1+ EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.

Conclusion
Our study identified circulating PD1+ EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.
CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3
Authors: Yang Lei , Chen Yi , Liu Ning , Lu Yanwen , Ma Wenliang , Yang Zhenhao , Gan Weidong , Li Dongmei 
Published: January 2022

Abstract
Background
Functions of CircMET (hsa_circ_0082002) which is a circular RNA and derived from MET gene remain understood incompletely. In the present study, Xp11.2 translocation/NONO-TFE3 fusion renal cell carcinoma (NONO-TFE3 tRCC) with up-regulated CircMET was employed to investigate its mechanism in cancer progression and post-transcriptional regulation.

Methods
FISH and real-time PCR were performed to explore the expression and localization circMET in NONO-TFE3 tRCC tissues and cells. The functions of circMET in tRCC were investigated by proliferation analysis, EdU staining, colony and sphere formation assay. The regulatory mechanisms among circMET, CDKN2A and SMAD3 were investigated by luciferase assay, RNA immunoprecipitation, RNA pulldown and targeted RNA demethylation system.

Results
The expression of circMET was upregulated by NONO-TFE3 fusion in NONO-TFE3 tRCC tissues and cells, and overexpression of circMET significantly promoted the growth of NONO-TFE3 tRCC. Mechanistic studies revealed that circMET was delivered to cytosol by YTHDC1 in N6-methyladenosine (m6A)-depend manner. CircMET enhances mRNA decay of CDKN2A by direct interaction and recruitment of YTHDF2. Meanwhile, circMET competitively absorbed miR-1197 and prevented those from SMAD3 mRNA.

Conclusions
CircMET promotes the development of NONO-TFE3 tRCC, and the regulation to both CDKN2A and SMAD3 of circMET was revealed. CircMET has the potential to serve as a novel target for the molecular therapy of NONO-TFE3 tRCC as well as the other cancer with high-expressing circMET.
A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study
Authors: Li Kai , Lin Yusheng , Luo Yichen , Xiong Xiao , Wang Lu , Durante Kameron , Li Junkuo , Zhou Fuyou , Guo Yi , Chen Shaobin , Chen Yuping , Zhang Dianzheng , Yeung Sai-Ching Jim , Zhang Hao 
Published: January 2022

Abstract
Background
The tRNA-derived small RNAs (tsRNAs) are produced in a nuclease-dependent manner in responses to variety of stresses that are common in cancers. We focus on a cancer-enriched tsRNA signature to develop a salivary exosome-based non-invasive biomarker for human esophageal squamous cell carcinoma (ESCC).

Methods
Cancer-enriched small RNAs were identified by RNA sequencing of salivary exosomes obtained from ESCC patients (n = 3) and healthy controls (n = 3) in a pilot study and further validated in discovery cohort (n = 66). A multicenter prospective observational study was conducted in two ESCC high-incidence regions (n = 320 and 200, respectively) using the newly developed biomarker signature.

Results
The tsRNA (tRNA-GlyGCC-5) and a previously undocumented small RNA were specifically enriched in salivary exosomes of ESCC patients, ESCC tissues and ESCC cells. The bi-signature composed of these small RNAs was able to discriminate ESCC patients from the controls with high sensitivity (90.50%) and specificity (94.20%). Based on the bi-signature Risk Score for Prognosis (RSP), patients with high-RSP have both shorter overall survival (OS) (HR 4.95, 95%CI 2.90–8.46) and progression-free survival (PFS) (HR 3.69, 95%CI 2.24–6.10) than those with low-RSP. In addition, adjuvant therapy improved OS (HR 0.47, 95%CI 0.29–0.77) and PFS (HR 0.36, 95%CI 0.21–0.62) only for patients with high but not low RSP. These findings are consistent in both training and validation cohort.

Conclusions
The tsRNA-based signature not only has the potential for diagnosis and prognosis but also may serve as a pre-operative biomarker to select patients who would benefit from adjuvant therapy.

Trial registration
A prospective study of diagnosis biomarkers of esophageal squamous cell carcinoma, ChiCTR2000031507. Registered 3 April 2016 - Retrospectively registered.
KRAB zinc finger protein ZNF676 controls the transcriptional influence of LTR12-related endogenous retrovirus sequences
Authors: Iouranova Alexandra , Grun Delphine , Rossy Tamara , Duc Julien , Coudray Alexandre , Imbeault Michael , de Tribolet-Hardy Jonas , Turelli Priscilla , Persat Alexandre , Trono Didier 
Published: January 2022

AbstractBackgroundTransposable element-embedded regulatory sequences (TEeRS) and their KRAB-containing zinc finger protein (KZFP) controllers are increasingly recognized as modulators of gene expression. We aim to characterize the contribution of this system to gene regulation in early human development and germ cells.ResultsHere, after studying genes driven by the long terminal repeat (LTR) of endogenous retroviruses, we identify the ape-restricted ZNF676 as the sequence-specific repressor of a subset of contemporary LTR12 integrants responsible for a large fraction of transpochimeric gene transcripts (TcGTs) generated during human early embryogenesis. We go on to reveal that the binding of this KZFP correlates with the epigenetic marking of these TEeRS in the germline, and is crucial to the control of genes involved in ciliogenesis/flagellogenesis, a biological process that dates back to the last common ancestor of eukaryotes.ConclusionThese results illustrate how KZFPs and their TE targets contribute to the evolutionary turnover of transcription networks and participate in the transgenerational inheritance of epigenetic traits.
Activation of TCA cycle restrains virus-metabolic hijacking and viral replication in mouse hepatitis virus-infected cells
Authors: Lee Sang R. , Roh Jeong Yeon , Ryu Jihoon , Shin Hyun-Jin , Hong Eui-Ju 
Published: January 2022

Abstract
Background
One of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused coronavirus disease 2019 (COVID-19) pandemic and threatened worldwide. However, therapy for COVID-19 has rarely been proven to possess specific efficacy. As the virus relies on host metabolism for its survival, several studies have reported metabolic intervention by SARS-CoV-2.

Results
We investigated the coronavirus-metabolic hijacking using mouse hepatitis virus (MHV) as a surrogate for SARS-CoV-2. Based on the altered host metabolism by MHV infection, an increase of glycolysis with low mitochondrial metabolism, we tried to investigate possible therapeutic molecules which increase the TCA cycle. Endogenous metabolites and metabolic regulators were introduced to restrain viral replication by metabolic intervention. We observed that cells deprived of cellular energy nutrition with low glycolysis strongly suppress viral replication. Furthermore, viral replication was also significantly suppressed by electron transport chain inhibitors which exhaust cellular energy. Apart from glycolysis and ETC, pyruvate supplement suppressed viral replication by the TCA cycle induction. As the non-glucose metabolite, fatty acids supplement decreased viral replication via the TCA cycle. Additionally, as a highly possible therapeutic metabolite, nicotinamide riboside (NR) supplement, which activates the TCA cycle by supplying NAD+, substantially suppressed viral replication.

Conclusions
This study suggests that metabolite-mediated TCA cycle activation suppresses replication of coronavirus and suggests that NR might play a role as a novel therapeutic metabolite for coronavirus.
Adapting systematic scoping study methods to identify cancer-specific physical activity opportunities in Ontario, Canada
Authors: Fong Angela J. , Sabiston Catherine M. , Kauffeldt Kaitlyn D. , Tomasone Jennifer R. 
Published: January 2022

Abstract
Background
Identifying cancer-specific physical activity programs and post-secondary courses targeting students in academic settings (i.e., “real world” opportunities) may promote physical activity behaviors among cancer survivors. Using knowledge synthesis methods such as systematic scoping study methods may facilitate knowledge tool development and guide evidence-based practice to improve knowledge transfer. However, identifying these opportunities poses a challenge as systematic scoping study methods have yet to be applied and adapted to this context. Thus, to extend systematic scoping study methods, the purpose of the current investigation is to describe the adaptation of systematic scoping study methods in the context of cancer-specific “real world” opportunities in Ontario, Canada.

Methods
Systematic scoping study methods were adapted to develop a knowledge tool, which was a credible resource website for researchers, clinicians, and survivors. Three search strategies including Advanced Google Search, targeted website search, and consultations with experts were used to identify eligible (e.g., appropriate for cancer survivors, offered in the community) cancer-specific physical activity programs. Only the targeted website search was used to search post-secondary institutions because they are centralized onto one government website.

Results
Fifty-eight programs and 10 post-secondary courses met the eligibility criteria. Relevant data from these opportunities were extracted, charted, synthesized, and uploaded onto the resource website. The most successful search strategy for cancer-specific physical activity programs was the targeted website search followed by Google Advanced Search and consultations with content experts.

Conclusions
Challenges were experienced due to lack of standard reporting among opportunities, bias of potentially relevant records, and changing nature of resulting records. The current investigation demonstrated that systematic scoping study methods can be applied to cancer-specific physical activity programs and post-secondary courses in the context of cancer survivorship in Ontario yielding robust results. The method can be further adapted and updated in future knowledge syntheses in health-related contexts.

Systematic review registration
The systematic scoping review method protocol has not been registered.
Development of dispersive solid-phase microextraction coupled with high-pressure liquid chromatography for the preconcentration and determination of the selected neonicotinoid insecticides
Authors: Waleng Ngwako Joseas , Selahle Shirley Kholofelo , Mpupa Anele , Nomngongo Philiswa Nosizo 
Published: January 2022

AbstractNeonicotinoid insecticides have raised a lot of societal concerns due to their environmental ubiquity and unique mode of action. Therefore, it is of great research interest to monitor their occurrence in the environmental waters. However, these compounds exist at low concentrations that is below instrument detection limits. This study reports the applicability of magnetic poly (3 aminobenzoic acid)-based activated carbon (Fe3O4@PABA/AC) composite as an adsorbent in dispersive magnetic solid-phase microextraction (d-MSPME) of neonicotinoid insecticides from wastewater and river water samples. The as-synthesized adsorbent was characterized and confirmed by Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, Brunauer–Emmett–Teller and X-ray diffraction spectroscopy. The analytes of interest were detected and quantified by high-performance liquid chromatography coupled with diode array detector (HPLC–DAD). The parameters affecting the extraction and preconcentration processes, such as pH, extraction time, mass of adsorbent, desorption time and eluent volume, were optimized using fractional factorial design and central composite design. Under optimum conditions, the limits of detection and quantification were in the ranges of 0.41–0.82 µg L−1 and 1.4–2.7 µg L−1, respectively. The linearity ranged from 1.4–700 µg L−1 with correlation of determination (R2) values varied between 0.9933 and 0.9987. The intra-day and inter-day precisions were 0.35–0.75% and 1.7–5.5%, respectively. The spike recovery experiments were conducted to evaluate the accuracy of the d-MSPME analytical method in real samples, and the percentage recoveries ranged from 86.7 to 99.2%. Therefore, this method shows great potential applicability in preconcentrating the pollutants from the environment.
Analysis of urgent follow up visits and complications after intravitreal injections: a retrospective cohort study
Authors: Miller Alexander , Wilneff Matthew A. , Yazji Andrew , Petrinec Emily , Carbone Michael , Miller Chase , McCrossin Christina , Donkor Richard , Miller David G. 
Published: January 2022

Abstract
Background
Intravitreal injections (IVIs), a common treatment in ophthalmology, result in acute complications and urgent follow-up visits causing significant burden to both patient and physician. We evaluated the incidence of acute complications following IVIs which occurred within seven days of injection.

Methods
A retrospective cohort study conducted at a private retinal practice, in Cleveland, Ohio. Using the practice management software database, we examined 73,286 injections of patients with unscheduled or urgent visits within 7 days of an injection from August 1st,2018 to August 1st,2020. Data collected included: age, gender, eye, medication injected, diagnosis, reason for urgent follow-up, time between injection and urgent follow-up, and type of anesthesia administered. Data was analyzed using SPSS v.28 (SPSS Inc., Chicago IL).

Results
Study included 73,286 injections, with 441 injections (n = 441) resulting in urgent follow-up visits (0.60%). Mean patient age was 72.1 (± 30.4) years, with 187 male (42.4%) and 254 female (57.6%) patients. IVI medications included: aflibercept (60.3%), ranibizumab (22.4%), bevacizumab (13.4%), dexamethasone intravitreal implant (2%), triamcinolone acetonide (1.6%) brolucizumab (1.59%), fluocinolone acetonide intravitreal implant 0.19 mg (0.2%), and fluocinolone acetonide intravitreal implant 0.18 mg (0.03%) (Table 1). Medications associated with urgent visits included: aflibercept (42.9%), bevacizumab (37.4%), ranibizumab (7.9%), dexamethasone intravitreal implant (6.8%), brolucizumab (2.7%), and triamcinolone acetonide (2.3%) (Table 2). Days between injection and urgent follow-up was on average 3.96 ± 2.14 days. Urgent follow-ups included blurred vision in 164 patients (37.2% of urgent visits), flashes, floaters or posterior vitreous detachment (PVD) in 55 (12.5%), pain in 42 (9.5%), 43 (9.8%) corneal abrasions, 33 (7.5%) subconjunctival hemorrhages, corneal dryness or foreign body sensation in 30 (6.6%), endophthalmitis in 20 (4.5%), 18 (4.1%)vitreous hemorrhages, iritis or uveitis in 11 (2.5%), miscellaneous complications in 9 (2.0%), 7 (1.6%) elevated intraocular pressures, choroidal neovascular membrane in 4 (0.9%), 4 (0.9%) retinal detachments or tears, and 2 (0.45%) traumatic cataracts (Table 3).

Conclusion
IVIs resulted in 0.60% urgent/unscheduled follow-up visits within 7 days of injection. Most common causes were blurred vision and symptoms of PVD.
Factors that influence psychiatric trainees’ choice of higher training specialty: mixed-methods study
Authors: Wolstenholme Nicholas , McKinnon Iain , Lloyd Adrian J. 
Published: January 2022

Aims and methodFactors influencing trainees’ decisions about choosing and remaining in higher training subspecialties have not been widely researched. We administered telephone questionnaires to higher specialist trainees in the north-east of England to ascertain what influences these decisions. Thematic analysis was employed to develop overall constructs.ResultsTwenty-seven trainees were interviewed, resulting in six overall constructs. These were: supervisory experiences; perceived work–life balance; career prospects; training and working environments; interest in the chosen subspecialty; and previous experience within the chosen subspecialty. Most trainees interviewed felt they had made the right specialty choice.Clinical implicationsThis study demonstrates the particular importance of exposure to a specialty and perceptions of the supervisory experience in determining trainees’ choices of, and decisions to remain in, a particular psychiatric specialty. Factors highlighted in this study must inform training, recruitment and workforce planning in order to bolster the recruitment and retention of trainees into higher specialty training.
Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update
Authors: Eisen Andrea , Somerfield Mark R. , Accordino Melissa K. , Blanchette Phillip S. , Clemons Mark J. , Dhesy-Thind Sukhbinder , Dillmon Melissa S. , D'Oronzo Stella , Fletcher Glenn G. , Frank Elizabeth S. , Hallmeyer Sigrun , Makhoul Issam , Moy Beverly , Thawer Alia , Wu Joy Y. , Van Poznak Catherine H. 
Published: January 2022

PURPOSE To update recommendations of the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) adjuvant bone-modifying agents in breast cancer guideline. METHODS An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. RESULTS Four articles met eligibility criteria and form the evidentiary basis for revision of the previous recommendations. RECOMMENDATIONS Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool provides estimates of the benefit of adjuvant bisphosphonate therapy and may aid in decision making. Factors influencing the decision to recommend adjuvant bisphosphonate use should include patients' risk of recurrence, risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy. When an adjuvant bisphosphonate is used to prevent breast cancer recurrence, the therapeutic options recommended by the Panel include oral clodronate, oral ibandronate, and intravenous zoledronic acid. The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline; this is a consensus recommendation. The Panel does not recommend adjuvant denosumab to prevent breast cancer recurrence, because studies did not show a consistent reduction of breast cancer recurrence in any subset of those with early-stage breast cancer. Additional information can be found at www.asco.org/breast-cancer-guideline .
A Case of Infantile Alagille Syndrome With Severe Dyslipidemia: New Insight into Lipid Metabolism and Therapeutics
Authors: Nakajima Hisakazu , Tsuma Yusuke , Fukuhara Shota , Kodo Kazuki 
Published: January 2022

Abstract
Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by congenital heart disease, hepatic cholestasis, dyslipidemia, and characteristic facies since infancy. Cholestatic hypercholesterolemia in patients diagnosed with AGS is occasionally refractory and resistant to conventional treatments. We report the case of a 4-month-old boy diagnosed with AGS and refractory dyslipidemia due to cholestatic liver disease. He had repeated episodes of cyanosis due to pulmonary artery atresia since birth and underwent a Blalock-Taussig shunt procedure at age 3 months. At age 4 months, cholestatic hyperbilirubinemia deteriorated to a serum total bilirubin level of 19.9 mg/dL. At age 12 months, a laboratory test revealed severe dyslipidemia (serum total cholesterol, 1796 mg/dL; serum triglycerides [TGs], 635 mg/dL), and the presence of xanthomas. A pathogenic variant of the JAG1 gene (c.1326G &gt; A, p.Trp442X) was detected through genetic testing. Oral ursodeoxycholate normalized hyperbilirubinemia with a subtle improvement in dyslipidemia. Combination therapy with pravastatin and fenofibrate did not successfully improve dyslipidemia. At age 20 months, altering pravastatin to atorvastatin was effective in normalizing serum cholesterol and TGs with no adverse events.
Combination therapy with atorvastatin and fenofibrate was successful in improving refractory dyslipidemia in a child with AGS. Atorvastatin is a well-known strong statin that can lower serum cholesterol, and fenofibrate can lower serum TG levels. We propose that atorvastatin be taken into consideration for the treatment of persistent hyperlipidemia in patients diagnosed with AGS, because atorvastatin upregulates bile acid synthesis and lipoprotein scavenging, and inhibits intrinsic cholesterol production.