anthonyyazdaniml/gliner-biomed-curated-corpus huggingface dataset:
WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms1-5. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers.
OBJECTIVE: Which is superior, partial nephrectomy (PN) or radical nephrectomy (RN), for the treatment of complex renal tumours (RENAL or score ≥ 7)?
METHODS: This systematic review and meta-analysis was conducted in accordance with the PRISMA statement. A systematic search of the literature published before November 2023 was conducted using Pubmed, Embase, Cochran, and Web of Science libraries. We included studies comparing perioperative and oncologic outcomes of partial nephrectomy and radical nephrectomy for complex renal tumors.
RESULTS: A total of 2602 patients from six studies meeting the criteria were included. The PN group had a longer operative time, increased estimated blood loss, and major complications but a smaller reduction in renal function. There were no significant differences in complications, length of hospital stay, and blood transfusion. In terms of oncological outcomes, the PN group had longer OS, CSS, and no significant difference in RFS.
CONCLUSIONS: For complex renal tumours, PN requires more operative time and has a higher chance of complications in the short term. However, in long-term follow-up, PN has a small decrease in renal function with longer OS and CSS.
The primary intervention is a multi-phase, mixed methods, implementation research study that will investigate the feasibility and acceptability of the limited introduction of ultrasound via the Butterfly iQ device into routine ANC service delivery at health center level in Blantyre, Malawi. The study will occur in three phases: 1) Training, 2) Iterative Service Delivery, and 3) Final Evaluation.
Breast cancer is a heterogenous disease with at least 4 intrinsic subtypes including Luminal A, Luminal B, HER2 enriched, Basal-like and normal breast like. Different subtypes have different prognosis and treatment sensitivity. Thus, it would be more suitable to administer different chemo-regimen in different subtypes. This is especially true in neoadjuvant chemotherapy setting where no standard regimen has ever been established. Therefore, we designed this phase 2 randomized clinical trial to explore potential effective regimens in variable subtypes of breast cancer in neoadjuvant treatment. Patients were first classified into Luminal type, Her2 positive type and triple-negative type by immunohistochemistry exam of ER/PR/HER2 in core needle biopsy and then randomized to received either dose dense paclitaxel in Luminal type or dose dense paclitaxel plus carboplatin with or without trastuzumab in HER2 positive type or dose dense paclitaxel plus carboplatin in triple-negative type.The control groups in each subtype all receive paclitaxel plus epirubicin every 3 weeks. The duration of treatment is 4-6 cycles. Primary endpoint is the pathological CR rate in each subtypes. Secondary endpoints include disease free survival, objective response rate, safety. Tissue samples and blood samples will be collected at baseline and during treatment. There will be exploratory biomarkers analyses to identify predictive markers for efficacy in every subtypes.
The invention discloses a composition with oxidation resistance and anti-aging functions, a preparation method and application thereof, wherein the composition comprises the following components: fullerene, haematococcus extract, olive oil, linseed oil, borage oil, almond oil, and squalane. Preferably, the composition comprises the following components in parts by weight: 4-6 parts of fullerene, 4-6 parts of haematococcus extract, 30-40 parts of olive oil, 12-16 parts of flaxseed oil, 8-12 parts of borage oil, 15-20 parts of almond oil and 4-6 parts of plant squalane. The invention also provides a preparation method and application of the composition. The composition can be used for preparing skin care products. Preferably, the skin care product comprises a skin care oil. The composition with the functions of resisting oxidation and ageing, which is prepared by the invention, is suitable for skin ageing caused by various reasons, and can whiten the skin, preserve moisture and lock water, and keep the skin moist and healthy while improving the skin ageing problem.
PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC).
METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures.
RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS.
CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.
Chronic wounds with high disability are among the most common and serious complications of diabetes. Angiogenesis dysfunction impair wound healing in patients with diabetes. Compared with traditional therapies that can only provide symptomatic treatment, stem cells-owing to their powerful paracrine properties, can alleviate the pathogenesis of chronic diabetic wounds and even cure them. Exosome-derived microRNAs (miRNAs), important components of stem cell paracrine signaling, have been reported for therapeutic use in various disease models, including diabetic wounds. Exosome-derived miRNAs have been widely reported to be involved in regulating vascular function and have promising applications in the repair and regeneration of skin wounds. Therefore, this article aims to review the current status of the pathophysiology of exosome-derived miRNAs in the diabetes-induced impairment of wound healing, along with current knowledge of the underlying mechanisms, emphasizing the regulatory mechanism of angiogenesis, we hope to document the emerging theoretical basis for improving wound repair by restoring angiogenesis in diabetes.
Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. 

Niacin extended-release should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of niacin extended-release. 

Niacin preparations have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to final daily niacin extended-release doses ranging from 500 to 3000 mg, 245 patients received niacin extended-release for a mean duration of 17 weeks. No patient with normal serum transaminase levels (AST, ALT) at baseline experienced elevations to more than 3 times the upper limit of normal (ULN) during treatment with niacin extended-release. In these studies, fewer than 1% (2/245) of niacin extended-release patients discontinued due to transaminase elevations greater than 2 times the ULN.

Liver-related tests should be performed on all patients during therapy with niacin extended-release. Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the first year, and periodically thereafter (e.g., at approximately 6-month intervals). Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 times ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise, the drug should be discontinued.
Suicide is much higher in Veterans compared to non-Veterans and thus remains a major health crisis in the VA, but there are few treatments available that directly target core features of suicidal thoughts and behaviors. Rumination is the strong tendency to engage in self-critical repetitive thinking that is often difficult to interrupt and is associated with suicide attempts and the transition from suicidal ideation to intent above and beyond other suicide risk factors. Meta-analyses indicate that abnormalities in brain regions comprising the "default mode network," which play a role in daydreaming or mind-wandering, contribute to the maintenance of rumination. Although functional magnetic resonance imaging studies have provided key insights into the neurobiology of suicide, there has been little direct impact on clinical care thus far. With the advent of real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback, however, there is now the potential to implement personalized strategies for altering brain activity associated with rumination to reduce suicidal thoughts and behaviors. In the proposed study the investigators will determine the acceptability and feasibility of using rt-fMRI neurofeedback to reduce suicide-specific rumination, defined as "repetitive mental fixation on one's suicidal thoughts and intentions" in a transdiagnostic sample of 15 Veterans at elevated risk of suicide. The investigators will also assess pre- to post-treatment changes in measures of suicide-specific rumination, disability, functional impairment, and quality of life in Veterans with a suicide attempt history following 2 rt-fMRI neurofeedback sessions. Veterans will be provided signals from the brain to identify mental strategies (e.g., cognitive reappraisal) for altering brain connectivity. During a subsequent "transfer" period Veterans will be asked to utilize the mental strategy that worked best for altering this connectivity, but without receiving any neurofeedback signals from the brain. Post-treatment clinical assessments will occur following each of the 2 rt-fMRI neurofeedback sessions and at 1 month following the second fMRI neurofeedback session. The novelty of the proposed work is underscored by the paucity of work using rt-fMRI neurofeedback in a Veteran population and the lack of studies to date targeting a brain network to reduce suicide-specific rumination. In this study the investigators will test the following specific aims: (1) to determine the acceptability and feasibility of implementing rt-fMRI neurofeedback in a Veteran population experiencing suicide-specific rumination; (2) to identify changes in suicide-specific rumination following rt-fMRI neurofeedback and (3) to identify changes in functional impairment and quality of life following rt-fMRI neurofeedback. The proposed study is consistent with the mission of RR\&D to maximize Veterans' functional independence, quality of life and participation in their lives and community.
Manual lymphatic drainage (MLD) + upper limb (UL) exercises + educational strategy + double compression bandage consisting of two layers, made up of a first rigid cotton bandage (11 cm Bande coton Short Stretch; Thuasne, France) and a second elastic bandage ("BiflexTM" 16 light; Thuasne, France). The two layers will be placed caudal to cranial in a circular manner, overlapping in one third the previous layer. The elastic bandage have squares drawn to help to the physiotherapist to control the stretch they given to the bandage. The two bandages could be cleaning without losing their properties. If there was any oedema concentration or a fibrous place, a paddle pad will be put in these places ("Mobiderm TM", Thuasne, France).
OBJECTIVE: Recently, the endoscopic superior eyelid transorbital approach (SETA) has emerged as a potential alternative to access the cavernous sinus (CS). Several previous studies have attempted to quantitatively compare the traditional open anterolateral skull base approaches with transorbital exposure; however, these comparisons have been limited to the area of exposure provided by the bone opening and trajectory, and fail to account for the main avenues of exposure provided by subsequent requisite surgical maneuvers. The authors quantitatively compare the surgical access provided by the frontotemporal-orbitozygomatic (FTOZ) approach and the SETA following applicable periclinoid surgical maneuvers, evaluate the surgical exposure of key structures in each, and discuss optimal approach selection.
METHODS: SETA and FTOZ approaches were performed with subsequent applicable surgical maneuvers on 8 cadaveric heads. The lengths of exposure of cranial nerves (CNs) II-VI and the cavernous internal carotid artery; the areas of the space accessed within the supratrochlear, infratrochlear, and supramaxillary (anteromedial) triangles; the total area of exposure; and the angles of attack were measured and compared.
RESULTS: Exposure of the extradural CS was comparable between approaches, whereas access was significantly greater in the FTOZ approach compared with the SETA. The lengths of extradural exposure of CN III, V1, V2, and V3 were comparable between approaches. The FTOZ approach provided marginally increased exposure of CNs IV (20.9 ± 2.36 mm vs 13.4 ± 3.97 mm, p = 0.023) and VI (14.1 ± 2.44 mm vs 9.22 ± 3.45 mm, p = 0.066). The FTOZ also provided significantly larger vertical (44.5° ± 6.15° vs 18.4° ± 1.65°, p = 0.002) and horizontal (41.5° ± 5.40° vs 15.3° ± 5.06°, p < 0.001) angles of attack, and thus significantly greater surgical freedom, and provided significantly greater access to the supratrochlear (p = 0.021) and infratrochlear (p = 0.007) triangles, and significantly greater exposure of the cavernous internal carotid artery (17.2 ± 1.70 mm vs 8.05 ± 2.37 mm, p = 0.001). Total area of exposure was also significantly larger in the FTOZ, which provided wide access to the lateral wall of the CS as well as the possibility for intradural access.
CONCLUSIONS: This is the first study to quantitatively identify the relative advantages of the FTOZ and transorbital approaches at the target region following requisite surgical maneuvers. Understanding these data will aid in selecting an optimal approach and maneuver set based on target lesion size and location.
OBJECTIVE AND AIMS: Identification of associations between the obese category of weight in the general US population will continue to advance our understanding of the condition and allow clinicians, providers, communities, families, and individuals make more informed decisions. This study aims to improve the prediction of the obese category of weight and investigate its relationships with factors, ultimately contributing to healthier lifestyle choices and timely management of obesity.
METHODS: Questionnaires that included demographic, dietary, exercise and health information from the US National Health and Nutrition Examination Survey (NHANES 2017-2020) were utilized with BMI 30 or higher defined as obesity. A machine learning model, XGBoost predicted the obese category of weight and Shapely Additive Explanations (SHAP) visualized the various covariates and their feature importance. Model statistics including Area under the receiver operator curve (AUROC), sensitivity, specificity, positive predictive value, negative predictive value and feature properties such as gain, cover, and frequency were measured. SHAP explanations were created for transparent and interpretable analysis.
RESULTS: There were 6,146 adults (age > 18) that were included in the study with average age 58.39 (SD = 12.94) and 3122 (51%) females. The machine learning model had an Area under the receiver operator curve of 0.8295. The top four covariates include waist circumference (gain = 0.185), GGT (gain = 0.101), platelet count (gain = 0.059), AST (gain = 0.057), weight (gain = 0.049), HDL cholesterol (gain = 0.032), and ferritin (gain = 0.034).
CONCLUSION: In conclusion, the utilization of machine learning models proves to be highly effective in accurately predicting the obese category of weight. By considering various factors such as demographic information, laboratory results, physical examination findings, and lifestyle factors, these models successfully identify crucial risk factors associated with the obese category of weight.
FIELD: pharmaceutical chemistry. SUBSTANCE: method is distinguished by that erythromycin is converted to oxime by hydroxylamine hydrochloride in presence of sodium carbonate in aqueous ethanol (20-40% water) medium at starting erythromycin-to-solvent g/ml ratio from 1:1.4 to 1:1.7 at temperature 50-80 C. Oxime product is isolated from reaction mixture by extraction with chlorinated hydrocarbon at pH 9-11 and subjected to Beckmann rearrangement by agency of arenesulfonic acid chloride in two-phase water-chlorinated hydrocarbon system to form erythromycin imino-ester. The latter is isolated by crystallization at pH 9-11 and temperature 60+-5 C and reduced in aqueous medium at room temperature with 0 to 0.2 molar excess of complex metal borohydride to give azaerythromycin. The latter is methylated, in the form of borate complex with mineral or organic acid (preferably, hydroxyacid), at pH 2.5, with formaldehyde in chloroform in presence of formic acid. Methylation product is isolated by reextraction with water at pH 4.5-5.5. Borate complex, if necessary, is hydrolyzed and product is precipitated form aqueous solution at pH 9-11 and 50-80 C and then recrystallized from acetone-water (2:1 to 1:2) mixture. EFFECT: simplified process and increased yield of final product. 4 cl, 5 ex
BACKGROUND: Atypical atrial flutters often involve complex circuits. Classic methods of identifying ablation targets, including detailed electroanatomical mapping and entrainment within a well-defined isthmus, may not always be sufficient to allow the critical isthmus to be delineated and ablated, with flutter termination and prevention of reinduction.
OBJECTIVES: This study sought a systematic method to classify conduction barriers and isthmuses as critical or noncritical that would improve understanding and ablation success. We also sought a construct unifying single- and dual-loop re-entry. Re-entrant circuits are bounded on 2 sides, although these are not consistently identified. We hypothesized 2 distinct critical boundaries, and a critical isthmus could be consistently defined without requiring entrainment, and ablation connecting these 2 boundaries would terminate tachycardia.
METHODS: Activation maps were created electroanatomically. Conduction barriers were classified as noncritical barriers or critical boundaries. Critical boundaries showed sequential activation around the barrier, spanning ≥90% of the cycle length. Noncritical barriers showed nonsequential, parallel, or colliding activation or <90% of the cycle length. Only tissue separating the 2 critical boundaries defined a critical isthmus (CI); all others were considered noncritical. The effect of ablation across a CI was assessed.
RESULTS: Complete maps were obtained in 128 cases in 121 patients (28 atypical right atrial, 100 left atrial). In all cases, 2 distinct critical boundaries were identified. Ablation across a CI connecting these critical boundaries terminated tachycardia in 123 of 128 cases (96.1%). Failures were due to inability to achieve block across the isthmus.
CONCLUSIONS: Activation mapping of atypical atrial flutter allows consistent identification of 2 critical boundaries. Successful ablation connecting the 2 critical boundaries reliably results in termination of atypical atrial flutter.
Irinotecan 65mg/m2/iv over 90min and cisplatin 30mg/m2/iv over 60min on day 1 and 8, repeat Q 3weeks. Four cycles.