bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Activity of Mitogen-Activated Protein Kinase–Targeted Therapies in Patients With Non–V600 BRAF-Mutant Tumors
Authors: Dankner Matthew , Wang Yifan , Fazelzad Rouhi , Johnson Benny , Nebhan Caroline A. , Dagogo-Jack Ibiayi , Myall Nathaniel J. , Richtig Georg , Bracht Jillian W.P. , Gerlinger Marco , Shinozaki Eiji , Yoshino Takayuki , Kotani Daisuke , Fangusaro Jason R. , Gautschi Oliver , Mazieres Julien , Sosman Jeffrey A. , Kopetz Scott , Subbiah Vivek , Davies Michael A. , Groover Anna L. , Sullivan Ryan J. , Flaherty Keith T. , Johnson Douglas B. , Benedetti Andrea , Cescon David W. , Spreafico Anna , Zogopoulos George , Rose April A.N. 
Published: August 2022

PURPOSENon-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.METHODSWe performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration–approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival.RESULTSA total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors.CONCLUSIONThis meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.
Hypothalamic Overexpression of Makorin Ring Finger Protein 3 Results in Delayed Puberty in Female Mice
Authors: Roberts Stephanie A , Naulé Lydie , Chouman Soukayna , Johnson Tatyana , Johnson Marciana , Carroll Rona S , Navarro Victor M , Kaiser Ursula B 
Published: August 2022

Abstract
Makorin ring finger protein 3 (MKRN3) is an important neuroendocrine player in the control of pubertal timing and upstream inhibitor of gonadotropin-releasing hormone secretion. In mice, expression of Mkrn3 in the hypothalamic arcuate and anteroventral periventricular nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if the persistence of hypothalamic Mkrn3 expression peripubertally would result in delayed puberty. Female mice that received neonatal bilateral intracerebroventricular injections of a recombinant adeno-associated virus expressing Mkrn3 had delayed vaginal opening and first estrus compared with animals injected with control virus. Subsequent estrous cycles and fertility were normal. Interestingly, male mice treated similarly did not exhibit delayed puberty onset. Kiss1, Tac2, and Pdyn mRNA levels were increased in the mediobasal hypothalamus in females at postnatal day 28, whereas kisspeptin and neurokinin B protein levels in the arcuate nucleus were decreased, following Mkrn3 overexpression, compared to controls. Cumulatively, these data suggest that Mkrn3 may directly or indirectly target neuropeptides of Kiss1 neurons to degradation pathways. This mouse model suggests that MKRN3 may be a potential contributor to delayed onset of puberty, in addition to its well-established roles in central precocious puberty and the timing of menarche.
Young Women Are Protected Against Vascular Insulin Resistance Induced by Adoption of an Obesogenic Lifestyle
Authors: Smith James A , Soares Rogerio N , McMillan Neil J , Jurrissen Thomas J , Martinez-Lemus Luis A , Padilla Jaume , Manrique-Acevedo Camila 
Published: August 2022

Abstract
Vascular insulin resistance is a feature of obesity and type 2 diabetes that contributes to the genesis of vascular disease and glycemic dysregulation. Data from preclinical models indicate that vascular insulin resistance is an early event in the disease course, preceding the development of insulin resistance in metabolically active tissues. Whether this is translatable to humans requires further investigation. To this end, we examined if vascular insulin resistance develops when young healthy individuals (n = 18 men, n = 18 women) transition to an obesogenic lifestyle that would ultimately cause whole-body insulin resistance. Specifically, we hypothesized that short-term (10 days) exposure to reduced ambulatory activity (from &gt;10 000 to &lt;5000 steps/day) and increased consumption of sugar-sweetened beverages (6 cans/day) would be sufficient to prompt vascular insulin resistance. Furthermore, given that incidence of insulin resistance and cardiovascular disease is lower in premenopausal women than in men, we postulated that young females would be protected against vascular insulin resistance. Consistent with this hypothesis, we report that after reduced ambulation and increased ingestion of carbonated beverages high in sugar, young healthy men, but not women, exhibited a blunted leg blood flow response to insulin and suppressed skeletal muscle microvascular perfusion. These findings were associated with a decrease in plasma adropin and nitrite concentrations. This is the first evidence in humans that vascular insulin resistance can be provoked by short-term adverse lifestyle changes. It is also the first documentation of a sexual dimorphism in the development of vascular insulin resistance in association with changes in adropin levels.
Patients’ Choice, Consent, and Ethics in Patient Blood Management
Authors: Isbister James P. , Pearse Bronwyn L. , Delaforce Alana S. , Farmer Shannon L. 
Published: August 2022

The goal of patient blood management (PBM) is to optimize clinical outcomes for individual patients by managing their blood as a precious and unique resource to be safeguarded and managed judiciously. A corollary to successful PBM is the minimization or avoidance of blood transfusion and stewardship of donated blood. The first is achieved by a multidisciplinary approach with personalized management plans shared and decided on with the patient or their substitute. It follows that the physician-patient relationship is an integral component of medical practice and the fundamental link between patient and doctor based on trust and honest communication.
Central to PBM is accurate and timely diagnosis based on sound physiology and pathophysiology as the bedrock on which scientifically based medicine is founded. PBM in all disease contexts starts with the questions, “What is the status of the patient’s blood?” “If there are specific abnormalities in the blood, how should they be managed?” and “If allogeneic blood transfusion is considered, is there no reasonable alternative therapy?” There are compelling scientific reasons to implement a nontransfusion default position when there is clinical uncertainty and questionable evidence of clinical efficacy for allogeneic blood transfusion due to known potential hazards.
Patients must be informed of their diagnosis, the nature, severity and prognosis of the disease, and treatment options along with risks and benefits. They should be involved in decision-making regarding their management. However, as part of this process, there are multifaceted medical, legal, ethical, and economic issues, encompassing shared decision-making, patient choice, and informed consent. Furthermore, variability in patient circumstances and preferences, the complexity of medical science, and the workings of health care systems in which consent takes place can be bewildering, not only for the patient but also for clinicians obtaining consent.
Adding “patient” to the concept of blood management differentiates it from “donor” blood management to avoid confusion and the perception that PBM is a specific medical intervention. Personalized PBM is tailoring the PBM to the specific characteristics of each patient. With this approach, there should be no difficulty addressing the informed consent and ethical aspects of PBM. Patients can usually be reassured that there is nothing out of order with their blood, in which case the focus of PBM is to keep it that way. In some circumstances, a hematologist may be involved as a patient’s blood advocate when abnormalities require expert involvement while the primary disease is being managed.
H3K9 tri-methylation at Nanog times differentiation commitment and enables the acquisition of primitive endoderm fate
Authors: Dubois Agnès , Vincenti Loris , Chervova Almira , Greenberg Maxim V. C. , Vandormael-Pournin Sandrine , Bourc'his Déborah , Cohen-Tannoudji Michel , Navarro Pablo 
Published: August 2022

ABSTRACT
Mouse embryonic stem cells have an inherent propensity to explore gene regulatory states associated with either self-renewal or differentiation. This property depends on ERK, which downregulates pluripotency genes such as Nanog. Here, we aimed at identifying repressive histone modifications that would mark Nanog for inactivation in response to ERK activity. We found that the transcription factor ZFP57, which binds methylated DNA to nucleate heterochromatin, is recruited upstream of Nanog, within a region enriched for histone H3 lysine 9 tri-methylation (H3K9me3). Whereas before differentiation H3K9me3 at Nanog depends on ERK, in somatic cells it becomes independent of ERK. Moreover, the loss of H3K9me3 at Nanog, induced by deleting the region or by knocking out DNA methyltransferases or Zfp57, is associated with reduced heterogeneity of NANOG, delayed commitment into differentiation and impaired ability to acquire a primitive endoderm fate. Hence, a network axis centred on DNA methylation, ZFP57 and H3K9me3 links Nanog regulation to ERK activity for the timely establishment of new cell identities. We suggest that establishment of irreversible H3K9me3 at specific master regulators allows the acquisition of particular cell fates during differentiation.
Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas
Authors: Sun Chang , Estrella Jeannelyn S. , Whitley Elizabeth M. , Chau Gilda P. , Lozano Guillermina , Wasylishen Amanda R. 
Published: August 2022

ABSTRACT
Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors; however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant preclinical models. Here, we used genetically engineered mouse models combined with environmental stress to evaluate the tumor suppressor functions of Daxx and Atrx in the mouse pancreas. Daxx or Atrx loss, alone or in combination with Men1 loss, did not drive or accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss did not cooperate with environmental stresses (ionizing radiation or pancreatitis) or with the loss of other tumor suppressors (Pten or p53) to promote pancreatic neuroendocrine tumorigenesis. However, owing to promiscuity of the Cre promoter used, hepatocellular carcinomas and osteosarcomas were observed in some instances. Overall, our findings suggest that Daxx and Atrx are not robust tumor suppressors in the endocrine pancreas of mice and indicate that the context of a human genome is essential for tumorigenesis.
This article has an associated First Person interview with the first author of the paper.
Case Report: Clinical outcome of prolonged cord prolapse
Authors: Karki Muna , Neupane Bibhushan , Bata Lokendra , Bam Shiba , Ghimire Rama , Maharjan Sujila , Pathak Bishnu Deep 
Published: August 2022

Abstract: Umbilical cord prolapse is an uncommon obstetric emergency with high neonatal morbidity and mortality. It is a rare entity with incidence ranging from 0.1 to 0.6%. Timely recognition and immediate interventions are needed for better outcome. Here, we present a case of 28-year-old multigravida of term pregnancy with cord prolapse of seven hours following rupture of membrane. She was experiencing vaginal leakage in the absence of abdominal pain, and was referred from the peripheral health center with the provisional diagnosis of cord prolapse. She finally underwent emergency caesarean section with good neonatal outcome at tertiary care center.
Knowledge and attitudes about obstructive sleep apnea among otorhinolaryngology trainee residents in Saudi Arabia: A survey-based cross-sectional study
Authors: Alsaif Abdulrahman , Aldilaijan Khalid , Almasoud Mai , Jebakumar Arulanantham Zechariah 
Published: August 2022

Background: Obstructive sleep apnea is a common disorder frequently encountered in otorhinolaryngology practice. This study was conducted to assess the knowledge and attitudes toward obstructive sleep apnea among otorhinolaryngology trainees in Saudi Arabia. Methods: This was a survey-based cross-sectional study. An online questionnaire was sent in July 2020 via email and WhatsApp instant messaging to all otorhinolaryngology trainee residents in Saudi Arabia. We utilized the previously validated obstructive sleep apnea knowledge and attitudes questionnaire (OSAKA). Results: 32.4% of all email recipients completed the questionnaire and met the inclusion criteria. 66.7% were males, thirty-two participants (53.3%) were at the junior level (R2–R3), and twenty-eight (46.7%) were at the senior level (R4–R5). The mean total knowledge score was 13.98/18. Senior residents had a higher mean total knowledge score than junior residents. Senior residents had a higher mean total attitude score than junior residents. Age, gender, residency program area, and years of previous otorhinolaryngology practice showed no significant differences in terms of knowledge levels and attitudes toward obstructive sleep apnea. Exposure to obstructive sleep apnea surgery and awareness of sleep disorders other than sleep apnea were found to be associated with an increased level of confidence in identifying patients at risk of obstructive sleep apnea and in the ability to manage them. Conclusions: This study describes the current condition of obstructive sleep apnea knowledge and attitudes among otorhinolaryngology residents in Saudi Arabia. Addressing studied elements may improve training outcomes.
Longitudinal assessment of blood-borne musculoskeletal disease biomarkers in the DE50-MD dog model of Duchenne muscular dystrophy
Authors: Riddell Dominique O. , Hildyard John C. W. , Harron Rachel C. M. , Wells Dominic J. , Piercy Richard J. 
Published: August 2022

Background: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene. Due to their phenotypic similarity to human patients, large animal models are invaluable tools for pre-clinical trials. The DE50-MD dog is a relatively new model of DMD, and carries a therapeutically-tractable mutation lying within the hotspot for human patients, making it especially valuable. Prior to conducting therapeutic trials using this novel animal model, it is essential to establish a panel of viable biomarkers. Methods: We evaluated a panel of blood-borne biomarkers of musculoskeletal disease in the DE50-MD dog. Venous blood samples were obtained monthly throughout an 18-month study period in DE50-MD (N=18) and wild-type (WT) control (N=14) dogs. A panel of potential plasma/serum biomarkers of DMD was measured and their theoretical utility in future clinical trials determined using sample size calculations. Results: Compared to WT dogs, DE50-MD dogs had substantially higher circulating creatine kinase (CK) activities, myomesin-3 (MYOM3), and the dystromiRs miR-1, miR-133a and miR-206, but significantly lower serum myostatin concentrations. An age-associated pattern, similar to that observed in DMD patients, was seen for CK and MYOM3. Sample size calculations suggested that low cohort sizes (N≤3) could be used to detect up to a 50% improvement in DE50-MD results towards WT levels for each biomarker or a combination thereof (via principal component analysis); as few as N=3 animals should enable detection of a 25% improvement using a combined biomarker approach (alpha 0.05, power 0.8). Conclusions: We have established a panel of blood-borne biomarkers that could be used to monitor musculoskeletal disease or response to a therapeutic intervention in the DE50-MD dog using low numbers of animals. The blood biomarker profile closely mimics that of DMD patients, supporting the hypothesis that this DMD model would be suitable for use in pre-clinical trials.
Temporal integration of rod signals in luminance and chromatic pathways
Authors: Cormenzana Méndez Iñaki , Martín Andrés , O’Donell Beatriz , Cao Dingcai , Barrionuevo Pablo A. 
Published: August 2022

We assessed how rod excitation (R) affects luminance (L

+

M

+

S) and chromatic [L/(L

+

M)] reaction times (RTs). A four-primary display based on the overlapped images of two spectrally modified monitors, which allowed specific or combined [L

+

M

+

S

+

R, L/(L

+

M) + R] photoreceptor stimulation, was used to present a C-target stimulus differing from the background only by the selected stimulation. For the luminance pathway, rod input increased RTs, suggesting a suppressive rod–cone interaction. The responses of the chromatic pathway were faster when rods were involved, suggesting a major role of rods in mesopic color perception.
Infrared D-type photonic crystal fiber sensor for special drug detection and wide-range refractive index detection
Authors: Wang Shaofeng , Liu Chi , Liu Xin , Feng Yue , Zhang Zhiwen , Shen Tao , Han Wei 
Published: August 2022

In the field of drug inspection, the refractive indices (RIs) of many halogenated ethers and drugs are in the lower range; for example, the RI of anesthetic sevoflurane is approximately 1.27. Infrared spectral detection technology has significant advantages in the field of drug detection; to realize the RI sensing of such drugs in the infrared region, a D-shaped photonic crystal fiber sensor based surface plasmon resonance was investigated in this study. The side polishing adopted here can significantly shorten the distance between the core and metal layer, making the energy of the core easier to detect, reducing the difficulty of coating the metal layer, and improving the performance of the sensor. The structure is provided with two large-sized air holes on both sides of the fiber core, so that the sensor is suitable for sensing in the low RI range and has high wavelength sensitivity in the low RI range. The sensor works mainly in the infrared band, with a detection range of 1.20–1.34, maximum wavelength sensitivity of 24,000 nm/RIU, and resolution of

4.1667

×

10

−
6

R
I
U

. The sensor has excellent performance and is easy to manufacture due to the simple structure; it has broad application prospects in low RI range detection fields such as biomedicine, drug detection, environmental monitoring, and water quality monitoring.
Depression, suicidal ideation and suicide risk in German veterinary medical students compared to the German general population
Authors: Schunter Nadine , Glaesmer Heide , Lucht Luise , Bahramsoltani Mahtab 
Published: August 2022

BackgroundVarious studies from different countries indicated that veterinarians have a significantly increased risk of depression, suicidal ideation and of death by suicide. For German veterinarians a recent study has demonstrated a three times higher rate for depression, two times higher rate for suicidal ideation and a five times higher suicide risk compared to the German general population. For veterinary students, recent studies in the US and UK indicated higher mental distress. To date, empirical studies on depression, suicidal ideation and suicide risk among veterinary students in Germany were lacking so far. This study investigates depression, suicidal ideation and suicide risk of veterinary students in Germany.Methods913 German veterinary students (14.3% response rate, 90.7% women, mean age 23.6 years) between 18 and 46 years were included and compared with representative German general population samples from 2007 (N = 1097, 55.4% women, mean age 33.9) and 2015 (N = 1033, 56.1% women, mean age 32.8) of the same age range using the depression module of the Patient Health Questionnaire (PHQ-9) and Suicide Behaviors questionnaire-Revised (SBQ-R). The general population samples were collected with the assistance of a demographic consulting company.ResultsThe prevalence of depression among German veterinary students was 45.9% (compared to 3.2% in the general population), suicidal ideation was 19.9% (compared to 4.5% in the general population) and suicide risk was 24.0% (compared to 6.6% in the general population).ConclusionIn this study, German veterinary students have a 22.1 times higher risk to be screened positive for depression, a 4 times higher risk for reporting current suicidal ideation and they are 4.2 times more likely to have an increased suicide risk compared with the general population in Germany of the same age range.
Impact of coronary bifurcation angle on the pathogenesis of atherosclerosis and clinical outcome of coronary bifurcation intervention–A scoping review
Authors: Murasato Yoshinobu , Meno Kyohei , Mori Takahiro , Tanenaka Katsuhiko 
Published: August 2022

BackgroundA coronary bifurcation stenting is still a challenging issue due to frequent restenosis and stent thrombosis even with drug-eluting stents. The bifurcation angle (BA) between a main vessel and a side branch is one of the crucial determinants of coronary flow and shear stress that affect the plaque distribution. Previous bench and clinical studies have evaluated the impact of the BA between the proximal main vessel and the side branch (Angle A) and the BA between the distal main vessel and the side branch (Angle B) on the clinical outcomes of bifurcation stenting. However, the impact has not yet been fully elucidated due to a lack of statistical power or different manner of the assessment of BA.ObjectivesTo analyze the published studies on coronary artery BA, the modalities used for assessment, and the impact of BA on interventions and attempt to define the pre-procedural protocols.Data sourcesA scoping review was performed using the Joanna Briggs Institute Methodology. A total of 52 relevant references were selected from PubMed, Cochrane Library, and CINAHL databases and categorized into three topic areas.Results and conclusionsA wider Angle A is associated with the increased likelihood of carina shift and a wider Angle B, with that of side branch occlusion. A wider Angle B promotes stent malapposition and deformation in the side branch ostium and has been reported as an independent predictor of major adverse cardiac events after bifurcation stenting; however, improvement of the drug-eluting stent, refinement of the stenting technique, and accurate 3-dimensional assessment may attenuate the adverse clinical impact of a wider BA.Implications of key findingsAssessment of the BA is necessary to predict the effect of bifurcation intervention procedure on the stent configuration and coronary flow at the bifurcated vessels. This will help to optimize stent selection and the stenting technique.