bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer
Authors: Akıncılar Semih Can , Chua Joelle Yi Heng , Ng Qin Feng , Chan Claire Hian Tzer , Eslami-S Zahra , Chen Kaijing , Low Joo-Leng , Arumugam Surendar , Aswad Luay , Chua Clarinda , Tan Iain Beehuat , DasGupta Ramanuj , Fullwood Melissa Jane , Tergaonkar Vinay 
Published: June 2022

Abstract
Transcriptional reactivation of hTERT is the limiting step in tumorigenesis. While mutations in hTERT promoter present in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, remain unknown. Using primary colorectal cancers (CRC) we identified Tert INTeracting region 2 (T-INT2), the critical chromatin region essential for reactivating WT-hTERT promoter in CRCs. Elevated β-catenin and JunD level in CRC facilitates chromatin interaction between hTERT promoter and T-INT2 that is necessary to turn on hTERTexpression. Pharmacological screens uncovered salinomycin, which inhibits JunD mediated hTERT-T-INT2 interaction that is required for the formation of a stable transcription complex on the hTERT promoter. Our results showed for the first time how known CRC alterations, such as APC, lead to WT-hTERT promoter reactivation during stepwise-tumorigenesis and provide a new perspective for developing cancer-specific drugs.
Experimental paradigms revisited: oxidative stress-induced tRNA fragmentation does not correlate with stress granule formation but is associated with delayed cell death
Authors: Sanadgol Nasim , König Lisa , Drino Aleksej , Jovic Michaela , Schaefer Matthias R 
Published: June 2022

Abstract
tRNA fragmentation is an evolutionarily conserved molecular phenomenon. tRNA-derived small RNAs (tsRNAs) have been associated with many cellular processes, including improved survival during stress conditions. Here, we have revisited accepted experimental paradigms for modeling oxidative stress resulting in tRNA fragmentation. Various cell culture models were exposed to oxidative stressors followed by determining cell viability, the production of specific tsRNAs and stress granule formation. These experiments revealed that exposure to stress parameters commonly used to induce tRNA fragmentation negatively affected cell viability after stress removal. Quantification of specific tsRNA species in cells responding to experimental stress and in cells that were transfected with synthetic tsRNAs indicated that neither physiological nor non-physiological copy numbers of tsRNAs induced the formation of stress granules. Furthermore, the increased presence of tsRNA species in culture medium collected from stressed cells indicated that cells suffering from experimental stress exposure gave rise to stable extracellular tsRNAs. These findings suggest a need to modify current experimental stress paradigms in order to allow separating the function of tRNA fragmentation during the acute stress response from tRNA fragmentation as a consequence of ongoing cell death, which will have major implications for the current perception of the biological function of stress-induced tsRNAs.
RBFOX2-regulated TEAD1 alternative splicing plays a pivotal role in Hippo-YAP signaling
Authors: Choi Sunkyung , Lee Hyo Seong , Cho Namjoon , Kim Inyoung , Cheon Seongmin , Park Chungoo , Kim Eun-Mi , Kim Wantae , Kim Kee K 
Published: June 2022

Abstract
Alternative pre-mRNA splicing is key to proteome diversity; however, the biological roles of alternative splicing (AS) in signaling pathways remain elusive. Here, we focus on TEA domain transcription factor 1 (TEAD1), a YAP binding factor in the Hippo signaling pathway. Public database analyses showed that expression of YAP-TEAD target genes negatively correlated with the expression of a TEAD1 isoform lacking exon 6 (TEAD1ΔE6) but did not correlate with overall TEAD1 expression. We confirmed that the transcriptional activity and oncogenic properties of the full-length TEAD1 isoform were greater than those of TEAD1ΔE6, with the difference in transcription related to YAP interaction. Furthermore, we showed that RNA-binding Fox-1 homolog 2 (RBFOX2) promoted the inclusion of TEAD1 exon 6 via binding to the conserved GCAUG element in the downstream intron. These results suggest a regulatory mechanism of RBFOX2-mediated TEAD1 AS and provide insight into AS-specific modulation of signaling pathways.
Salivary potassium measured by genetically encoded potassium ion indicators as a surrogate for plasma potassium levels in hemodialysis patients—a proof-of-concept study
Authors: Deak Andras T , Belić Katarina , Meissl Anna-Maria , Artinger Katharina , Eller Kathrin , Rechberger Bernd , Niedrist Tobias , Graier Wolfgang F , Malli Roland , Bischof Helmut , Burgstaller Sandra , Blass Sandra , Avian Alexander , Rosenkranz Alexander R , Kirsch Alexander H 
Published: June 2022

ABSTRACTBackgroundHyperkalemia is a common complication in cardiorenal patients treated with agents interfering with renal potassium (K+) excretion. It frequently leads to discontinuation of potentially life-saving medication, which has increased the importance of K+ monitoring. Non-invasive means to detect hyperkalemia are currently unavailable, but would be of potential use for therapy guidance. The aim of the present study was to assess the analytical performance of genetically encoded potassium-ion indicators (GEPIIs) in measuring salivary [K+] ([K+]Saliva) and to determine whether changes of [K+]Saliva depict those of [K+]Plasma.MethodsWe conducted this proof-of-concept study: saliva samples from 20 healthy volunteers as well as plasma and saliva from 29 patients on hemodialysis (HD) before and after three consecutive HD treatments were collected. We compared [K+]Saliva as assessed by the gold standard ion-selective electrode (ISE) with GEPII measurements.ResultsThe Bland–Altmann analysis showed a strong agreement (bias 0.71; 95% limits of agreement from –2.79 to 4.40) between GEPII and ISE. Before treatment, patients on HD showed significantly higher [K+]Saliva compared with healthy controls [median 37.7 (30.85; 48.46) vs 23.8 (21.63; 25.23) mmol/L; P &lt; .05]. [K+]Plasma in HD patients decreased significantly after dialysis. This was paralleled by a significant decrease in [K+]Saliva, and both parameters increased until the subsequent HD session. Despite similar kinetics, we found weak or no correlation between [K+]Plasma and [K+]Saliva.ConclusionGEPIIs have shown an excellent performance in determining [K+]Saliva. [K+]Plasma and [K+]Saliva exhibited similar kinetics. To determine whether saliva could be a suitable sample type to monitor [K+]Plasma, further testing in future studies are required.
OFFICE BLOOD PRESSURE MEASUREMENT: MEAN OF TWO OR OF THREE VALUES?
Authors: Paini Anna , Aggiusti Carlo , Bertacchini Fabio , Capellini Sara , Arnoldi Chiara , Cannata Marco , Caletti Stefano , Gatta Roberto , Stassaldi Deborah , Muiesan Maria Lorenza , Salvetti Massimo 
Published: June 2022

Objective:
ESC/ESH 2018 hypertension guidelines recommend the calculation of the average of the last 2 blood pressure(BP) measurements(out of 3).This recommendation does not strictly correspond to previous recommendations of the ESC/ESH guidelines and to those of other international Societies.Furthermore, in several clinical trials mean BP values were calculated in different ways, more frequently by using the mean of three values(out of 3 measurements),or the mean of the last two (out of 2 or out of 3).
Aim of the study was to evaluate the effect of different methods for the calculation of the mean BP values on observed BP values and their relationship with hypertension mediated organ damage.

Design and method:
In 206 patients BP was measured by a physician with an automated validated oscillometric device(3 measurements at 1 min intervals after 5 minutes of rest).Mean values were computed by using a)the first two measurements (SAP1/2 and DAP1/2)or b)the last two(SAP2/3 and DAP2/3)or c)three measurements (SAP1/2/3 and DAP1/2/3).All patients also underwent an echocardiogram.

Results:
Mean age was 58 ± 15 years,57%F,BMI 27 ± 5,85% were hypertensives(78%treated).BP values were as follows:SAP1/2:135.5 ± 17.4; SAP1/2/3:134.0 ± 17.1;SAP2/3:132.4 ± 16.9 mmHg(ANOVA p < 0.01 for all comparisons);DAP1/2:77.4 ± 11.0;DAP1/2/3:77.0 ± 11.0;DAP2/3:76.7 ± 11.3(ANOVA p < 0.01 only for DAP1/2 vs DAP2/3).Left ventricular mass index(LVMI/h2.7) was correlated with all three means of SAP:(SAP1/2: r = 0.164, p < 0.05;SAP1/2/3:r = 0.168;SAP2/3:r = 0.185).Despite a trend for a better correlation between LVMI/h2.7 and SAP2/3,no difference between the correlation coefficients was observed at the Steiger’s Zeta test.Also the correlations between mean BP values and left atrial volume were similar (SAP1/2: r = 0.174;SAP1/2/3:r = 0.169;SAP2/3:r = 0.170,p < 0.05).

Conclusions:
BP values are lower when the mean of the last two values out of three is calculated as recommended by the 2018 ESC/ESH guidelines. Despite this, no difference in the correlations of mean BP values with cardiac organ damage were observed.
Trends in Primary Gallbladder Cancer Incidence and Incidence-based Mortality in the United States, 1973 to 2015
Authors: Low Soon Khai , Giannis Dimitrios , Thuong Nguyen D. , Nam Nguyen Hai , Alshareef Abdulmueti , Koulas Ioannis , Geropoulos Georgios , Moris Dimitrios , Molmenti Ernesto P. , Huy Nguyen Tien 
Published: June 2022

Objectives:
Primary gallbladder cancer (GBC) is the most common biliary tract cancer with poor survival despite aggressive treatment. This study aimed to investigate the trends of GBC incidence and incidence-based mortality (IBM) over the last 4 decades.

Materials and Methods:
GBC cases diagnosed between 1973 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Incidence rates, IBM rates, and annual percent changes (APCs) were calculated and stratified according to population and tumor characteristics.

Results:
The cohort consisted of 10,792 predominantly white (81%) and female (71%) GBC patients. The overall GBC incidence decreased by 1.65% (95% confidence interval [CI]: 1.45% to 1.84%) per year since 1973, but has plateaued since 2002. IBM decreased by 1.69% (95% CI: 1.22% to 2.16%) per year from 1980 to 2015; the rate of decrease in IBM rates was lower during 1997 to 2015 (APC: −1.19%, 95% CI: −1.68% to −0.71%) compared with 1980 to 1997 (APC: −3.13%, 95% CI: −3.68% to −2.58%).

Conclusions:
The incidence and IBM rates of GBC have been decreasing over the last 40 years, but the decrease plateaued over the last 2 decades. The effects of treatment modalities, including laparoscopic cholecystectomy, adjuvant chemotherapy, and radiation on the incidence and IBM of GBC need to be further investigated.
Periocular Pigmented Basal Cell Carcinomas: Clinicopathologic Features and Mutational Profile
Authors: Hassanin Fadi , Al Hussain Hailah , Maktabi Azza , Adly Nouran , Alsuabeyl Mohammad , Abedalthagafi Malak , Edward Deepak P. , Strianese Diego 
Published: June 2022

Purpose:
Pigmented basal cell carcinomas (PBCC) is an uncommon variant of basal cell carcinoma of the periocular region with limited information in the literature. We highlight the clinicopathological profile and somatic mutations in periocular PBCC.

Methods:
The clinicopathological features and somatic mutations in patients with periocular PBCC were examined and compared with periocular non-PBCC reported in the literature. Next-generation sequencing panel analysis for the excised tumors identified somatic mutations.

Results:
In a total of 31 patients, PBCC was common in females (54%; p = 0.03); as a unilateral lower eyelid (n = 22; 71%), solitary mass (n = 30; 98%). Pathologic subtypes were variable. Most were nodular or mixed variants (n = 23; 74%). During the follow up (2.5–4.5 years), 1 patient (3.5%) had a recurrence. The clinical and pathologic features of PBCC were similar to those reported in nonperiocular locations. Somatic mutations detected in 25/31 tumors. Variants in 50/161 genes in the panel were noted. PTCH1 (14/31), TERT (12/31), and SMO (7/31) variants were common. Fifteen patients had novel drivers, including POLE, FANCD2, and CREBBP. SMO mutations were significantly more common in females (7/7), lower eyelid (5/7), and TERT mutations were more common in nodular subtype (10/12).

Conclusions:
In this large cohort of a relatively uncommon variant of BCC, the clinicopathological features and tumor behavior of PBCC was similar to periocular non-PBCC. The somatic mutation spectrum of PBCC resembles that reported in nonperiocular cutaneous BCC with novel drivers identified. We identified several potential actionable mutations that could be targeted with molecular therapy.
Ophthalmic Presentation and Outcome for Sinonasal Mucoceles
Authors: Malik Mohsan , Vahdani Kaveh , Rose Geoffrey E. 
Published: June 2022

Purpose:
The purpose of this study was to evaluate ophthalmic features and outcomes for patients who present with sinonasal mucoceles expanding into the orbit.

Patients and Methods:
Retrospective chart review for patients seen in a specialist orbital clinic over 25 years, with a review of demographics, clinical characteristics, imaging features, and outcomes after treatment.

Results:
Sixty patients (38 males; 63%) presented at a mean age of 51 years (range 3–89). Symptom duration was extremely variable (1 week–15 years) with a mean of 14 months and median of 4 months—the commonest being periorbital swelling (33/62 orbits) or ache (20 orbits), proptosis (30 orbits), and diplopia (19/50 patients without visual impairment; 38%). Of mucoceles affecting orbital function, 60/62 (97%) were of frontal and/or ethmoid sinus origin, and probable predispositions included past trauma (12/62 orbits) or prior ipsilateral sinus surgery (14 orbits). Forty-two of the 59 (71%) patients who underwent sinus surgery had complete resolution of symptoms within 6 months. Of 10 orbits presenting with moderate to severe visual loss (Snellen 20/60 or worse), the acuity improved in 7/10 (70%) of these after sinus surgery. Although 12/62 (19%) of eyes presented with epiphora, this persisted after sinus surgery in 9 orbits, and areas of occult malignant change were found in 3/9 (33%).

Conclusion:
Sinus mucoceles expanding into the orbit can cause significant globe displacement, dysmotility, or visual impairment. Symptoms usually resolve within several months after functional sinus surgery, but where symptoms persist (particularly periorbital swelling or epiphora) this might indicate underlying secondary causes, such as occult malignancy.
Meta-analysis and Systematic Review of Bronchoscopic Lung Volume Reduction Through Endobronchial Valves in Severe Emphysema
Authors: Patel Maulin , Chowdhury Junad , Zhao Huaqing , Lu Xiaoning , Roth Stephanie , Giovacchini Coral X. , Wahidi Momen M. , Criner Gerard 
Published: June 2022

Background:
Pharmacologic therapeutics for advanced emphysema have limited benefit. Bronchoscopic lung volume reduction with endobronchial valves (EBVs) have reported improvements in lung function, breathlessness, and quality of life through randomized clinical trials, with less morbidity as comparted to Surgical Lung volume Reduction. We here present a Meta-analysis and systematic review of bronchoscopic lung volume reduction in advanced chronic obstructive lung disease patients

Methods:
PubMed (NLM), Embase (Elsevier), and Web of Science (Clarivate Analytics) search was conducted using a combination of keywords and subject headings. The search was confined to the last 15 years and was completed on October 23, 2020. Only placebo-controlled randomized control trials of emphysema patients with EBV were included. Quality assessment was done by 2 independent reviewers.

Results:
Nine studies were included for the meta-analysis with a total number of 1383 patients of whom 888 received EBV and 495 standard of care (SOC) medications. Our Metanalysis show statistically significant improvement in forced expiratory volume in first second, percentage forced expiratory volume in first second, St. George’s respiratory questionnaire, and 6-minute walk distance in EBV group compared with SOC. Residual volume had statistically significant reduction after EBV placement compared with SOC. These differences continued to be present during short-term (<=6 mo) and long-term follow-up (>=6 mo). These improvements were even higher when the EBV patients’. Collateral ventilation was negative/fissure was intact (CV−/FI >90%). The rate of hemoptysis and pneumothorax was higher in the EBV group compared with SOC, however, did not lead to increased fatal outcomes.

Conclusion:
In conclusion, EBV has favorable effects on patients’ outcomes in patients who have heterogeneous emphysema particularly with no collateral ventilation.
Small molecule mediated stabilization of PP2A modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death
Authors: Avelar Rita A. , Armstrong Amy J. , Carvette Gracie , Puleo Noah , Gupta Riya , Colina Jose , Joseph Peronne , Sobeck Alex , O’Connor Caitlin M. , Gandhi Agharnan , Dziubinski Michele L. , Ma Daniel Shanhuai , Waggoner Steven , Zanotti Kristine , Nagel Christa , Resnick Kimberly , Singh Sareena , Thomas Daffyd , Skala Stephanie , Zhang Junran , Narla Goutham , DiFeo Analisa 
Published: June 2022

AbstractHigh-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, only ∼30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in Patient-Derived HGSC cells and Xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for transformation (B56α,B56γ and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061 stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and -deficient cells and in patient-derived xenograft models. Our studies identify PP2A as novel regulator of HR and introduces PP2A activators as a potential treatment for HGSC tumors. Our studies further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 has presented benefits in overcoming PARPi-resistance driven by BRCA1/2 mutation reversions.
Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS-CoV-2
Authors: Planchais Cyril , Reyes-Ruiz Alejandra , Lacombe Robin , Zarantonello Alessandra , Lecerf Maxime , Revel Margot , Roumenina Lubka T. , Atanasov Boris P. , Mouquet Hugo , Dimitrov Jordan D. 
Published: June 2022

AbstractSARS-CoV-2 infects cells by attachment to its receptor – the angiotensin converting enzyme 2 (ACE2). Regardless of the wealth of structural data, little is known about the physicochemical mechanism of interactions of the viral spike (S) protein with ACE2 and how this mechanism has evolved during the pandemic. Here, we applied experimental and computational approaches to characterize the molecular interaction of S proteins from SARS-CoV-2 variants of concern (VOC). Data on kinetics, activation- and equilibrium thermodynamics of binding of the receptor binding domain (RBD) from VOC with ACE2 as well as data from computational protein electrostatics revealed a profound remodeling of the physicochemical characteristics of the interaction during the evolution. Thus, as compared to RBDs from Wuhan strain and other VOC, Omicron RBD presented as a unique protein in terms of conformational dynamics and types of non-covalent forces driving the complex formation with ACE2. Viral evolution resulted in a restriction of the RBD structural dynamics, and a shift to a major role of polar forces for ACE2 binding. Further, we investigated how the reshaping of the physicochemical characteristics of interaction affect the binding specificity of S proteins. Data from various binding assays revealed that SARS-CoV-2 Wuhan and Omicron RBDs manifest capacity for promiscuous recognition of unrelated human proteins, but they harbor distinct reactivity patterns. These findings might contribute for mechanistic understanding of the viral tropism, and capacity to evade immune responses during evolution.
Unexpected death from hepatic abscess 16 months after toothbrush ingestion
Authors: Zhao Guoting , Zhao Shuquan , Wang Songjun , Liu Xia , Qi Qian , Li Yingmin , Zuo Min 
Published: June 2022

AbstractThe development of a hepatic abscess secondary to foreign body (FB) ingestion remains rare in forensic practice. Herein, we present a case of a prisoner who died in the hospital and a forensic autopsy was performed to confirm the cause of death. A 14.5‐cm‐long toothbrush handle was found in the duodenum and had penetrated the right lobe of the liver, consistent with the repeated abdominal pain in his clinical history. The clinical history and investigation confirmed that he had ingested the toothbrush handle 16 months prior. This case highlights a rare complication of intentional ingestion of foreign bodies, and pathologists should be aware of this rare entity which links hepatic abscess and FB ingestion.
Exsanguination from ruptured femoral artery pseudoaneurysm – A fatal complication of groin heroin injection
Authors: Leković Aleksa , Živković Vladimir , Nikolić Slobodan 
Published: June 2022

AbstractIntravenous drug users (IDUs) eventually encounter a common problem– a need to turn to a new vessel to inject drugs. Whether it is because no other spot is available due to scarring or convenience, the groin is the preferred spot for some. Chronic puncture of femoral vessels can lead to a rare but significant complication– femoral artery pseudoaneurysm (FAP). Its fatal consequence– rupture and bleeding is well recognized, but the forensic literature on this subject is limited. We present eight cases of exsanguination due to the ruptured FAP in IDUs who share most or all the following characteristics: long‐term heroin use and/or pronounced drug use stigmata, chronic groin injection‐related lesions, absence of significant precipitating pseudoaneurysm trauma, and no or minimal concentrations of heroin metabolites in blood. The FAP presentation varied greatly, from palpable fist‐sized mass or slight elevation under the skin defect to infundibular arterio‐cutaneous fistula that ruptured through the skin induration. In some, surrounding skin or soft tissue showed signs of inflammation but without suppuration. The most prominent FAP characteristic was smooth‐surface cavitation on cross‐sections. We performed microscopic evaluation in two cases and verified disruption of the artery wall (i.e., pseudoaneurysm) with elements of acute and chronic inflammation and fibrosis; foci of fibrinoid necrosis were noticed on the arterial wall. All subjects were pale, with faint hypostasis and organ anemia, consistent with reported massive hemorrhage. Because such sudden, unwitnessed, and suspicious deaths may raise the question of injury infliction, proper autopsy evaluation is crucial, for which we propose guidelines.