bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on the Mechanism of Qigu Capsule in Upregulating NF-κB/HIF-1α Pathway to Improve the Quality of Bone Callus in Mice at Different Stages of Osteoporotic Fracture Healing
Authors: Wang Peige , Ding Jie , Yang Guangyue , Sun Wen , Guo Hailing , Zhao Yongfang
Published: September 2021

Objective. The present study intends to investigate the effects and underlying molecular mechanism of Qigu Capsule (QG) on fracture healing in mice with osteoporosis. Methods. Ten-week-old female C57BL/6 mice were ovariectomized and three weeks later were evaluated for successful modeling. Then, all mice were prepared into models of transverse fracture in the right middle femoral shaft. Mice were treated daily using a gavage with normal saline (the NS group), Qigu Capsule (the QG group), or alendronate (the ALN group) postoperatively. Fracture callus tissues were collected and analyzed by X-ray, micro-CT, western blot (WB), and transmission electron microscope (TEM) on postoperation Day 14 (POD14), POD28, and POD42. Results. (1) X-ray results showed that on POD14, the QG group had the fracture healing score significantly higher than the NS and ALN groups, and on POD28, it had the fracture healing score higher than the NS group, suggesting that QG could promote fracture healing. (2) Micro-CT results showed that on POD14, the QG group had tissue bone density (TMD) significantly higher than the NS and ALN groups, and on POD28 and POD42, it had bone volume fraction, trabecular number, and TMD significantly higher than the NS group. (3) WB results showed that, compared with the NS group, the QG group had significantly increased expression of nuclear factor kappa-B (NF-κB), hypoxia-inducible factor-1α (HIF-1α), bone alkaline phosphatase (BALP), runt-related transcription factor 2 (Runx2), bone Gla protein (BGP) and collagen Iα1 (COLIα1) on POD14, significantly increased expression of NF-κB, HIF-1α, BALP and COLIα1 on POD28, and significantly increased expression of NF-κB, HIF-1α, and Runx2 on POD42. (4) TEM scanning results showed that, compared with the NS and ALN groups, the QG group had significantly increased numbers of autophagic vacuoles (AVs) in osteocytes on POD14, POD28, and POD42. Conclusion. QG could accelerate osteoporotic fracture healing by promoting bone formation and osteocyte autophagy, possibly through upregulating the NF-κB/HIF-1α signaling pathway.
Targeting Tumor–Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer
Authors: Dosch Austin R. , Singh Samara , Dai Xizi , Mehra Siddharth , Silva Iago De Castro , Bianchi Anna , Srinivasan Supriya , Gao Zhen , Ban Yuguang , Chen Xi , Banerjee Sulagna , Nagathihalli Nagaraj S. , Datta Jashodeep , Merchant Nipun B.
Published: September 2021

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense, desmoplastic stroma and the consequent altered interactions between cancer cells and their surrounding tumor microenvironment (TME) that promote disease progression, metastasis, and chemoresistance. We have previously shown that IL6 secreted from pancreatic stellate cells (PSC) stimulates the activation of STAT3 signaling in tumor cells, an established mechanism of therapeutic resistance in PDAC. We have now identified the tumor cell–derived cytokine IL1α as an upstream mediator of IL6 release from PSCs that is involved in STAT3 activation within the TME. Herein, we show that IL1α is overexpressed in both murine and human PDAC tumors and engages with its cognate receptor IL1R1, which is strongly expressed on stromal cells. Further, we show that IL1R1 inhibition using anakinra (recombinant IL1 receptor antagonist) significantly reduces stromal-derived IL6, thereby suppressing IL6-dependent STAT3 activation in human PDAC cell lines. Anakinra treatment results in significant reduction in IL6 and activated STAT3 levels in pancreatic tumors from Ptf1aCre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice. Additionally, the combination of anakinra with cytotoxic chemotherapy significantly extends overall survival compared with vehicle treatment or anakinra monotherapy in this aggressive genetic mouse model of PDAC. These data highlight the importance of IL1 in mediating tumor–stromal IL6/STAT3 cross-talk in the TME and provide a preclinical rationale for targeting IL1 signaling as a therapeutic strategy in PDAC.
Characterization of KRAS Mutation Subtypes in Non–small Cell Lung Cancer
Authors: Judd Julia , Abdel Karim Nagla , Khan Hina , Naqash Abdul Rafeh , Baca Yasmine , Xiu Joanne , VanderWalde Ari M. , Mamdani Hirva , Raez Luis E. , Nagasaka Misako , Pai Sachin Gopalkrishna , Socinski Mark A. , Nieva Jorge J. , Kim Chul , Wozniak Antoinette J. , Ikpeazu Chukwuemeka , de Lima Lopes Gilberto , Spira Alexander I. , Korn W. Michael , Kim Edward S. , Liu Stephen V. , Borghaei Hossein
Published: September 2021

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non–small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.

Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.

Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).

KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.
Epigenetic Regulation of Fanconi Anemia Genes Implicates PRMT5 Blockage as a Strategy for Tumor Chemosensitization
Authors: Du Changzheng , Li Steven W. , Singh Simranjit X. , Roso Kristen , Sun Michael A. , Pirozzi Christopher J. , Yang Rui , Li Jian-Liang , He Yiping
Published: September 2021

Strengthened DNA repair pathways in tumor cells contribute to the development of resistance to DNA-damaging agents. Consequently, targeting proteins in these pathways is a promising strategy for tumor chemosensitization. Here, we show that the expression of a subset of Fanconi anemia (FA) genes is attenuated in glioblastoma tumor cells deficient in methylthioadenosine phosphorylase (MTAP), a common genetic alteration in a variety of cancers. Subsequent experiments in cell line models of different cancer types illustrate that this reduced transcription of FA genes can be recapitulated by blockage of Protein Arginine Methyltransferase 5 (PRMT5), a promising therapeutically targetable epigenetic regulator whose enzymatic activity is compromised in MTAP-deficient cells. Further analyses provide evidence to support that PRMT5 can function as an epigenetic regulator that contributes to the increased expression of FA genes in cancer cells. Most notably and consistent with the essential roles of FA proteins in resolving DNA damage elicited by interstrand crosslinking (ICL) agents, PRMT5 blockage, as well as MTAP loss, sensitizes tumor cells to ICL agents both in vitro and in xenografts. Collectively, these findings reveal a novel epigenetic mechanism underlying the upregulated expression of FA genes in cancer cells and suggest that therapeutically targeting PRMT5 can have an additional benefit of chemosensitizing tumor cells to ICL agents.

Implications:

PRMT5 positively regulates the expression of FA genes. Inhibition of PRMT5 attenuates FA-dependent DNA repair pathway and sensitizes tumor cells to ICL agents.
Is There an Optimal Antiplatelet Strategy after Gastrointestinal Bleeding in Patients with Coronary Artery Disease?
Authors: Pickett Stephen J. , Levine Glenn N. , Jneid Hani , Bhatt Deepak L. , Nambi Vijay
Published: September 2021

Gastrointestinal bleeding after percutaneous coronary intervention (PCI) is a not too uncommon clinical situation and is associated with high morbidity and mortality. After initial treatment, a number of clinical decisions must be made weighing the risks of ischemic events and future bleeding. In particular, healthcare providers must carefully balance the effectiveness of antiplatelet therapy in the secondary prevention of coronary events, primarily future spontaneous myocardial infarction and stent thrombosis, against the risk of major, most commonly gastrointestinal bleeding. The first question is whether a dual antiplatelet therapy strategy is required or if a single antiplatelet agent will suffice. Then, if a single antiplatelet agent is adequate, which agent should be continued. Although there is some guidance to answer some of these questions, there are inadequate evidence-based data for others. Below, we review the various considerations and summarize our approach and rationale to manage patients who had gastrointestinal bleeding after PCI.
Opioids Cause Sex-Specific Vascular Changes via Cofilin-Extracellular Signal-Regulated Kinase Signaling: Female Mice Present Higher Risk of Developing Morphine-Induced Vascular Dysfunction than Male Mice
Authors: Cheon Soyoung , Tomcho Jeremy C. , Edwards Jonnelle M. , Bearss Nicole R. , Waigi Emily , Joe Bina , McCarthy Cameron G. , Wenceslau Camilla F.
Published: September 2021

Recent studies have shown that chronic use of prescription or illicit opioids leads to an increased risk of cardiovascular events and pulmonary arterial hypertension. Indices of vascular age and arterial stiffness are also shown to be increased in opioid-dependent patients, with the effects being more marked in women. There are currently no studies investigating sex-specific vascular dysfunction in opioid use, and the mechanisms leading to opioid-induced vascular damage remain unknown. We hypothesized that exposure to exogenous opioids causes sex-specific vascular remodeling that will be more pronounced in female. Acknowledging the emerging roles of cofilins and extracellular signal-regulated kinases (ERKs) in mediating actin dynamics, we investigated the effects of morphine on these molecules. Twenty-four hour exposure to morphine increased inactivated cofilin and activated ERKs in resistance arteries from female mice, which may promote stress fiber over-assembly. We also performed continuous intraluminal infusion of morphine in pressurized resistance arteries from male and female mice using culture pressure myographs. We observed that morphine reduced the vascular diameter in resistance arteries from female, but not male mice. These results have significant implications for the previously unexplored role of exogenous opioids as a modifiable cardiovascular risk factor, especially in women.
Association of the Degree of Erythroid Expansion and Maturation Arrest with the Clinical Severity of β0-Thalassemia/Hemoglobin E Patients
Authors: Suriyun Thunwarat , Kaewsakulthong Woratree , Khamphikham Pinyaphat , Chumchuen Sukanya , Hongeng Suradej , Fucharoen Suthat , Sripichai Orapan
Published: September 2021

Introduction: β-Thalassemia/hemoglobin E represents one-half of all the clinically severe β-thalassemias worldwide. Despite similar genetic backgrounds, patients show clinical heterogeneity ranging from nearly asymptomatic to transfusion-dependent thalassemia. The underlying disease modifying factors remain largely obscure. Methods: To elucidate the correlation between ineffective erythropoiesis and β0-thalassemia/hemoglobin E (HbE) disease severity, in vitro culture of erythroid cells derived from patients with different clinical symptoms was established. Cell proliferation, viability, and differentiation were investigated. To identify potential molecular mechanisms leading to the arrested erythroid maturation, the expression levels of erythropoiesis modifying factors were measured. Results: The β0-thalassemia/HbE cells exhibited enhanced proliferation, limited differentiation, and impaired erythroid terminal maturation but did not show accelerated erythroblast differentiation and increased cell death. Erythroblasts derived from mild patients showed the highest proliferation rate with a faster cell division time, while erythroblasts derived from severe patients displayed extremely delayed erythroid maturation. Downregulation of growth differentiation factor 11 and FOXO3a was observed in mild β0-thalassemia/HbE erythroblasts, while upregulation of heat shock protein 70 and activin receptor 2A was revealed in severe erythroblasts. Discussion/Conclusion: The degree of erythroid expansion and maturation arrest contributes to the severity of β0-thalassemia/HbE patients, accounting for the disease heterogeneity. The findings suggest a restoration of erythroid maturation as a promising targeted therapy for severe patients.
Neurosarcoidosis Mimicking the Recurrence of Malignant Lymphoma
Authors: Murakami Keishu , Koh Jinsoo , Taruya Junko , Ito Hidefumi
Published: September 2021

A 67-year-old woman with a recurrent history of malignant lymphoma (ML) presented with muscle weakness and paresthesia of the fingertips and feet. Due to the elevated level of serum soluble interleukin-2 receptor and increased 18F-fluorodeoxyglucose uptake in a mediastinal lymph node, neurolymphomatosis was initially suspected. Neurological and electrophysiological examinations were consistent with mononeuropathy multiplex. A diagnosis of neurosarcoidosis was made based on the presence of noncaseating epithelioid granulomas in the mediastinal lymph node, along with the presence of the uveitis, cardiac inflammation, and mononeuropathy multiplex. She was treated with glucocorticoids and azathioprine, and her symptoms disappeared. Sarcoidosis following ML is rare, and since biopsy of nervous systems is often improbable, differentiating neurosarcoidosis and neurolymphomatosis can be difficult as their clinical symptoms can be similar. Clinicians should consider systemic pathological investigations based on 18F-fluorodeoxyglucose positron emission tomography examination in addition to comprehensive evaluation to accurately diagnose neurosarcoidosis.
Ignored Papers, Invented Quotations: A History of Fetal Alcohol Syndrome
Authors: Obladen Michael
Published: September 2021

Given the high rate of alcoholism throughout history, its effects on the fetus may have existed for millennia. But, the claim that Greeks and Romans were aware of fetal alcohol syndrome rests on incorrect citations. From 1725, maternal alcohol consumption was associated with retarded fetal growth and neurological anomalies. From 1809, scientists followed Lamarck’s theory that the disorders parents acquire during their lifetime are passed on to their offspring. Fetal effects were thought to be inherited mainly from the father. During the 19th century, parental alcoholism became associated with malformations. In 1915, Ballantyne distinguished genetic influence via germ cells from toxin’s effect on the embryo. Fetal alcohol syndrome was characterized by Rouquette [Influence de la toxicomanie alcoolique parentale sur le développement physique et psychique des jeunes enfants] in 1957 and Lemoine et al. [Ouest Medical. 1968;21:476–482] in 1968 as consisting of 4 features: (A) facial anomalies (narrow forehead, retracted upper lip, and cupped ears), (B) severe growth retardation (prenatal and postnatal), (C) malformations (limbs, cardiac, and visceral), and (D) central nervous system anomalies (hyperexcitability and mental retardation). But, their studies, written in French, remained disregarded. In 1973, Jones et al. [Lancet. 1973;302:999–1001] reported “the first association between maternal alcoholism and aberrant morphogenesis in the offspring.” The history of fetal alcohol syndrome reveals shortcomings in citation practice. Alleged quotations remained unverified, non-English publications neglected, and short quotations taken out of context. Prejudiced by religious and abstinence groups, reports on alcohol damage to the unborn were fraught with emotions, moralizing, social implications, and presentism, the interpretation of past events with present knowledge.
LAight® Therapy Significantly Enhances Treatment Efficacy of 16 Weeks of Topical Clindamycin Solution in Hurley I and II Hidradenitis Suppurativa: Results from Period A of RELIEVE, a Multicenter Randomized, Controlled Trial
Authors: Schultheis Michael , Staubach Petra , Nikolakis Georgios , Grabbe Stephan , Ruckes Christian , von Stebut Esther , Kirschner Uwe , Matusiak Łukasz , Szepietowski Jacek C.
Published: September 2021

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, burdensome skin disease where medical first-line treatment is still limited to long-term, topical and/or systemic antibiotics. The RELIEVE study aimed at evaluating the efficacy of LAight® therapy – a combination of intense pulsed light and radiofrequency – as an adjunct treatment to first-line therapies in Hurley stage I and II HS. Methods: The RELIEVE study was performed as a two-period multicenter randomized controlled trial with blinded assessment. For period A from week 0 to week 16, the 88 participating subjects were randomized into either an intervention group (IG) or a control group (CG). The IG received topical clindamycin 1% solution combined with 8 additional bi-weekly treatments with LAight® therapy. The CG was treated with topical clindamycin 1% solution only. After 16 weeks, patients entered open-label period B and both groups were treated exclusively with LAight® therapy for an additional 16 weeks (8 sessions). The primary efficacy endpoint was the change in International Hidradenitis Suppurativa Score System (∆IHS4) at week 16 to baseline. Secondary endpoints were DLQI, HiSCR, Pain-NRS, and HADS. Results: In total, from the 88 patients enrolled in RELIEVE, 81 patients were included in the endpoint analysis after period A. After 16 weeks of treatment, the ∆IHS4 of the group treated with the combination of LAight® therapy and topical clindamycin 1% solution was −7.2 ± 6.7 (−60.0%), which was significantly higher in magnitude than the ∆IHS4 in the group treated with clindamycin 1% solution alone (−1.8 ± 5.6, −17.8%, p < 0.001). Secondary endpoints, including other clinical scores as well as patient-reported outcomes, confirmed that the efficacy of the combined treatment was superior to monotherapy. Conclusion: The results of the primary endpoint analysis of period A of the RELIEVE study show that the combined therapy with LAight® and topical clindamycin 1% solution, resulted in a significantly higher decrease in disease severity and an improvement of quality of life in comparison to topical clindamycin 1% solution monotherapy. Treatment was well tolerated, and side effects were all mild and transitory. These data speak for the implementation of the combined treatment as a first-line therapy in Hurley stage I and II HS. LAight® therapy as long-term monotherapy (results from period B), will be analyzed in a consecutive paper.
The Prediction of Inadequate Colon Capsule Cleansing: A Cohort Selection Guided by CC-CLEAR
Authors: de Sousa Magalhães Rui , Boal Carvalho Pedro , Rosa Bruno , Moreira Maria João , Cotter José
Published: September 2021

Introduction: In order to optimize the rate of adequate cleansing in colon capsule, it may be important to identify risk factors that can predict a suboptimal colon preparation. Aim:To define predictive factors for inadequate bowel preparation in colon capsule, according to CC-CLEAR (Colon Capsule CLEansing Assessment and Report). Methods: Retrospective, single center, cohort study. Patients’ demographics, data, and quality of bowel preparation, according to CC-CLEAR, were collected retrospectively. A univariate analysis tested the association between covariables and the outcome, inadequate cleansing. The statistically significant variables were included in multivariable logistic binary regression, and a receiver operating characteristic curve (ROC) assessment was performed. Results: We included 167 consecutive colon capsules. Sixty-eight percent (n = 114) of patients were female, with a mean age of 64 years. The main indication for colon capsule was previous incomplete colonoscopy, in 158 patients (94.6%). The colon capsules cleansing was graded as good or excellent in 96 patients (57.5%) and as inadequate in 71 (42.5%), according to CC-CLEAR. The variables inadequate previous colon cleansing (OR adjusted 41.72 [95% CI 12.57–138.57], p value < 0.001); chronic laxative (OR adjusted 4.86 [95% CI 1.08–21.79], p value = 0.039); antidepressant (OR adjusted 5.00 [95% CI 1.65–15.16], p value = 0.004), and impaired mobility (OR adjusted 5.54 [95% CI 1.17–26.31], p value = 0.031) were independently associated with the outcome inadequate cleansing, after adjusting for confoundment. The model presented an excellent discriminative power towards the outcome variable (AUC ROC 0.937 [CI 95% 0.899–0.975], p value < 0.001). Conclusion: A previous inadequate colon cleansing, the use of chronic laxative and antidepressant, or impaired mobility are predictors of inadequate colon capsule cleansing, as assessed by the CC-CLEAR. These 4 predictors come together as a model enabling an accurate categorization of the patients at major risk of inadequate bowel preparation for capsule colonoscopy, with an excellent discriminative power and performance, which seems useful for the selection of patients for tailored optimization of the colon cleansing protocol.
Does Oral Monosodium Glutamate Have a Cochleotoxic Effect? An Experimental Study
Authors: Guven Selis Gulseven , Ersoy Onur , Topuz Ruhan Deniz , Bulut Erdoğan , Kizilay Gulnur , Uzun Cem
Published: September 2021

Introduction: The effect of orally consumed monosodium glutamate (MSG), which is a common additive in the food industry, on the cochlea has not been investigated. The present study aimed to investigate the possible cochleotoxic effects of oral MSG in guinea pigs using electrophysiological, biochemical, and histopathological methods. Methods: Thirty guinea pigs were equally divided into control and intervention groups (MSG 100 mg/kg/day; MSG 300 mg/kg/day). At 1 month, 5 guinea pigs from each group were sacrificed; the rest were observed for another month. Electrophysiological measurements (distortion product otoacoustic emission [DPOAE] and auditory brainstem response [ABR]), glutamate levels in the perilymph and blood samples, and histopathological examinations were evaluated at 1 and 2 months. Results: Change in signal-to-noise ratio at 2 months was significantly different in the MSG 300 group at 0.75 kHz and 2 kHz (p = 0.013 and p = 0.044, respectively). There was no statistically significant difference in ABR wave latencies of the guinea pigs given MSG compared to the control group after 1 and 2 months; an increase was noted in ABR thresholds, although the difference was not statistically significant. In the MSG groups, moderate-to-severe degeneration and cell loss in outer hair cells, support cells, and spiral ganglia, lateral surface junction irregularities, adhesions in stereocilia, and partial loss of outer hair cell stereocilia were noted. Conclusion: MSG, administered in guinea pigs at a commonly utilized quantity and route of administration in humans, may be cochleotoxic.
Talker Adaptation and Lexical Difficulty Impact Word Recognition in Adults with Cochlear Implants
Authors: Tamati Terrin N. , Moberly Aaron C.
Published: September 2021

Introduction: Talker-specific adaptation facilitates speech recognition in normal-hearing listeners. This study examined talker adaptation in adult cochlear implant (CI) users. Three hypotheses were tested: (1) high-performing adult CI users show improved word recognition following exposure to a talker (“talker adaptation”), particularly for lexically hard words, (2) individual performance is determined by auditory sensitivity and neurocognitive skills, and (3) individual performance relates to real-world functioning. Methods: Fifteen high-performing, post-lingually deaf adult CI users completed a word recognition task consisting of 6 single-talker blocks (3 female/3 male native English speakers); words were lexically “easy” and “hard.” Recognition accuracy was assessed “early” and “late” (first vs. last 10 trials); adaptation was assessed as the difference between late and early accuracy. Participants also completed measures of spectral-temporal processing and neurocognitive skills, as well as real-world measures of multiple-talker sentence recognition and quality of life (QoL). Results: CI users showed limited talker adaptation overall, but performance improved for lexically hard words. Stronger spectral-temporal processing and neurocognitive skills were weakly to moderately associated with more accurate word recognition and greater talker adaptation for hard words. Finally, word recognition accuracy for hard words was moderately related to multiple-talker sentence recognition and QoL. Conclusion: Findings demonstrate a limited talker adaptation benefit for recognition of hard words in adult CI users. Both auditory sensitivity and neurocognitive skills contribute to performance, suggesting additional benefit from adaptation for individuals with stronger skills. Finally, processing differences related to talker adaptation and lexical difficulty may be relevant to real-world functioning.
Fibrous Histiocytoma of Anterior Ethmoidal Sinus: Case Report and Review of the Literature
Authors: Sharifi Mohammad , Tafaghodi Yousefi Bahar
Published: September 2021

Benign fibrous histiocytoma of the para nasal sinus is a rare tumor of this region which originates from mesenchymal cells. A 9-year-old girl presented with gradually enlarging mass above the medial canthus over 3 months. Orbital computerized tomography scan showed a round well-differentiated homogeneous mass in the anterior ethmoidal sinus. Histology and immunohistochemistry analysis after excision revealed proliferation of spindle-shaped fibroblasts in storiform pattern and histiocytes without mitosis and anaplasia. After 9 months from surgical excision, recurrence occurred which resulted in total excision again. This is the first reported case of benign fibrous histiocytoma involving the ethmoid sinus in Iranian people. Rare sinus tumor should be considered in the differential diagnosis of sinus tumors.
Homozygous Germline APC p.I1307K Variants: A Case Series
Authors: Rosenblum Alexa , Springer Michelle , Eppolito Amanda , Axell Lisen , Mohler Lisa
Published: September 2021

Approximately 10% of all colorectal cancer is estimated to be due to an inherited predisposition. Identification of a germline pathogenic variant can aid in treatment, screening, and surveillance and help stratify familial cancer risks based on gene-specific cancer associations. The APC gene contributes to a small percentage of hereditary colon cancer, with most pathogenic APC variants causing familial adenomatous polyposis syndrome. However, one specific variant in APC called p.I1307K, found in approximately 10% of Ashkenazi Jewish individuals, is associated with a moderate risk for colon cancer, but not polyposis. Heterozygous carriers of one p.I1307K variant are well documented in the literature, and guidelines recommend earlier and more frequent colonoscopies. Conversely, reports of homozygous carriers of 2 p.I1307K variants are limited, and guidelines for medical management are lacking. This case series describes 4 homozygous p.I1307K patients of Ashkenazi Jewish ancestry identified in cancer genetics clinics. Case 1 is a 73-year-old pancreatic cancer patient with a family history of melanoma and colon cancer. Case 2 is a 62-year-old patient with a personal history of 4 adenomatous colorectal polyps and a family history of breast, pancreatic, colon, and prostate cancers. Case 3 is a 52-year-old patient with a personal history of early-onset breast cancer and uveal melanoma and a family history of breast, prostate, and stomach cancers. Case 4 is a 70-year-old patient with a personal history of gallbladder adenocarcinoma and a family history of breast cancer. These cases exhibit wide phenotypic variability and contribute to the limited reports of homozygous p.I1307K variant carriers.
Triamcinolone Acetonide in the Treatment of Perennial Allergic Rhinitis: A post hoc Efficacy Analysis of a Phase III Study Performed in Russia
Authors: Karaulov Alexander V. , Ilina Natalia I. , Shartanova Natalia , Maslakov Aleksandr , Lucio Luiz
Published: September 2021

Introduction: Allergic rhinitis (AR) is a disease which affects >24% of the population in Russia. Triamcinolone acetonide (TAA) is a corticosteroid used for treating AR. This post hoc analysis assesses the efficacy of intranasal TAA in improving perennial AR (PAR) symptom scores over 4 weeks. Methods: NASANIF (NCT03317015) was a double-blind, parallel-group, multicenter, prospective, non-inferiority, phase III clinical trial in which patients with PAR were randomized (1:1) to receive TAA or fluticasone propionate (FP) over 4 weeks. Our post hoc analysis evaluates weekly change in PAR symptoms using the reflective Total Nasal Symptom Score (rTNSS), overall and for individual symptoms (sneezing, nasal itching, rhinorrhoea, and nasal obstruction). Proportion of patients and time to achieve a ≥50 or ≥75% reduction in rTNSS were assessed. For rTNSS endpoints, a linear mixed-model methodology was used; for time-to-event endpoints, cumulative incidence functions were estimated using the Kaplan-Meier method, in the per-protocol population. Results: Of 260 patients, 128 each completed the study and were randomized to receive TAA or FP. From baseline to week 4, the changes in total rTNSS were −7.78 (95% CI: −8.1701 to −7.3967; p < 0.001) and −7.52 (−7.9053 to −7.1320; p < 0.001) for TAA and FP, respectively. Individual symptoms improved significantly from baseline. The proportion of patients achieving ≥50 and ≥75% reductions in total rTNSS was 88.0 and 67.2%, respectively in the TAA group. No significant differences were observed between the TAA and FP in any analyses. Conclusions: TAA produced effective and prolonged improvement of PAR symptoms over a 4-week treatment period.
Human Immunodeficiency Virus Infection Promotes Human Papillomavirus-Mediated Anal Squamous Carcinogenesis: An Immunologic and Pathobiologic Review
Authors: Bushara Omar , Krogh Katrina , Weinberg Samuel Edward , Finkelman Brian Steven , Sun Leyu , Liao Jie , Yang Guang-Yu
Published: September 2021

Background: Anal squamous cell carcinoma (SCC) is a rare gastrointestinal malignancy with rising incidence, both in the United States and internationally. The primary risk factor for anal SCC is human papillomavirus (HPV) infection. However, there is a growing burden of disease in patients with human immunodeficiency virus (HIV) and HPV coinfection, with the incidence of anal SCC significantly increasing in this population. This is particularly true in HIV-infected men. The epidemiologic correlation between HIV-HPV coinfection and anal SCC is established; however, the immunologic mechanisms underlying this relationship are not well understood. Summary: HIV-related immunosuppression due to low circulating CD4+ T cells is one component of increased risk, but other mechanisms, such as the effect of HIV on CD8+ T lymphocyte tumor infiltration and the PD-1/PD-L1 axis in antitumor and antiviral response, is emerging as significant contributors. The goal of this article is to review existing research on HIV-HPV coinfected anal SCC and precancerous lesions, propose explanations for the detrimental synergy of HIV and HPV on the pathogenesis and immunologic response to HPV-associated cancers, and discuss implications for future treatments and immunotherapies in HIV-positive patients with HPV-mediated anal SCC. Key Messages: The incidence of anal squamous cell carcinoma is increased in human immunodeficiency virus (HIV)-infected patients, even in patients on highly active antiretroviral therapy. Locoregional HIV infection may enhance human papillomavirus oncogenicity. Chronic inflammation due to HIV infection may contribute to CD8+ T lymphocyte exhaustion by upregulating PD-1 expression, thereby blunting cytotoxic antitumor response.
Skin Lesions, Skin Care, and Characteristics of Pruritus in Patients Undergoing Haemodialysis
Authors: Sommer Rachel , Ständer Sonja , Augustin Matthias
Published: September 2021

Introduction: Pruritus has been shown to be a common and burdensome complaint in the general population. In some diseases, there is an even higher rate and intensity of pruritus such as in chronic kidney diseases. In particular, patients requiring dialysis commonly suffer from pruritus with proportions between 22.0 and 90.0%. Few data on the characteristics and burden of such pruritus have been published. Therefore, the aim of this study was to investigate the extent and profiles of pruritus in such patients related to skin lesions and care. Methods: A non-interventional cross-sectional study in 14 centres for haemodialysis across Germany was conducted. The survey explored the prevalence, severity, and resulting burden of pruritus and skin lesions. Results: In total, 302 patients with uraemia (56.5% male, mean age 66.0 ± 14.4 years, mean duration of dialysis 3.9 ± 4.8 years) were included. Skin lesions appeared since start of dialysis in 50.0% of patients, with xerosis (94.7%) and desquamation (25.8%) being the most frequent and disturbing findings. Pruritus was reported by 60.9% of patients undergoing dialysis with a current mean numerical rating scale of 5.1 ± 2.4 occurring most frequently in the back, legs, and arms. About 89.0% of patients with xerosis and 69.0% with desquamation reported self-medication. However, only 40.0% and 28.0% sought medical help, respectively, indicating a remarkable lack of healthcare. Discussion: The current data suggest a more intensive focus on the skin symptoms and signs related to uraemia in the patients with dialysis and thus underline claims from a previous German large-scale study. Recommendations for early treatment and prevention of skin lesions in dialysis patients should be developed. Further research should be conducted focusing on recognizing subgroups of patients of particular vulnerability to pruritus and skin lesions, which may facilitate identifying patients at risk in an early moment. Moreover, a more specific tool for screening of skin lesions as well as pruritus may be useful since the existing instruments lack such specificity.
Teatro e a condição de pós-autonomia da arte
Authors: Silva Heloisa Marina da
Published: September 2021

O propósito dessa comunicação é refletir acerca de modos de produção teatral os quais, pautados por pressupostos de democracia e dissidência às hegemonias culturais e aos modelos industriais de fabricação artística, se definem, não raro, como não comerciais. Este termo e outras nomenclaturas que buscam dar conta do fenômeno teatral mencionado serão discutidas à luz do conceito de pós-autonomia da arte, como proposto pelo antropólogo argentino Nestor Garcia Canclini. Pretende-se relativizar o entendimento de que é possível gerar fabricações artísticas que sejam, de fato, alheias a modelos mercadológicos. A metodologia adotada foi a de revisão bibliográfica sobre o tema, bem como a exploração de uma perspectiva autoetnográfica vinculada às minhas próprias experiências como atriz e produtora. Tendo como objeto de estudo fazeres teatrais latino-americanos, argumento que, ainda que se compreenda que há uma relação obrigatória entre produção teatral, economia, política e mercado, tal entendimento, ao invés de inviabilizar a defesa de um teatro dissidente, é fundamental para realização efetiva e consciente de produções cênicas críticas ao status quo e capazes de construírem esperanças de mundos outros.
Palavras-chave: Políticas culturais; Estado; atriz-produtora; teatro menor.
Viver de Dança
Authors: Anselmi Ádia da Silva Freitas
Published: September 2021

“Viver de Dança” é uma produção independente dirigida por Ádia Anselmi durante sua residência artística em Buenos Aires, Argentina. O documentário se concentra em uma série de entrevistas que estabelece um diálogo entre bailarinos contemporâneos de diferentes nacionalidades. A linguagem cinematográfica integra-se com a ideia do projeto, aproximando as pessoas do corpo e contexto sociocultural dos artistas entrevistados. O trabalho abre um espaço de discussão e apoio por meio do conceito de que a diversidade é premissa do fazer arte. A série é um convite para pensar a profissão do artista, considerando temas como formas de ganhar a vida, escolhas de vida, interesses e experiências a compartilhar.
Neoliberalismo e modos de produção teatral no Brasil: da pós-ditadura ao neofascismo
Authors: Guenzburger Gustavo
Published: September 2021

O presente trabalho investiga relações entre o teatro brasileiro e a ideologia neoliberal. Para tanto, o texto faz um breve sumário de alguns modos de produção, circuitos teatrais e políticas culturais atuantes na cidade do Rio de Janeiro, desde o fim da ditadura militar até a presente ascensão do neofascismo. A hipótese a ser discutida é que, durante esse período, o meio teatral tem um papel importante na construção de sua própria crise, ao assumir para si alguns princípios e práticas do neoliberalismo.
Primeiras observações sobre os coletivos de teatro em São Luís: aspectos de uma territorialidade em processo de profissionalização
Authors: Oliveira Fernanda Areias
Published: September 2021

O artigo apresenta os primeiros dados referentes ao projeto de pesquisa O vídeo na Cena Teatral, realizado pelo Grupo de Pesquisa Laboratório de tecnologias Dramáticas (LabTecDrama). Na primeira etapa desta pesquisa discute-se as relações de Estado e políticas públicas para as artes cênicas no Maranhão, apresentando um breve diagnóstico sobre os coletivos em atuação da cidade de São Luís. Discute-se ainda alguns aspectos referentes a Semana do Teatro do Maranhão, evento de teatro profissional com maior continuidade em território ludovicente.
Nota Metodológica _ William I. Thomas & Florian Znaniecki
Authors: Eufrásio Mário Antônio
Published: September 2021

Uma das mais importantes características da evolução social é a crescente importância que uma técnica consciente e racional tende a assumir na vida social. Estamos cada vez menos dispostos a deixar qualquer processo social acontecer sem nossa ativa interferência e nos sentimos cada vez mais insatisfeitos com qualquer interferência ativa baseada no mero capricho de um indivíduo ou de um corpo social ou em generalizações filosóficas, religiosas ou morais preconcebidas.
Improving Outcome Predictions for Patients Receiving Mechanical Circulatory Support by Optimizing Imputation of Missing Values
Authors: Jaeger Byron C. , Cantor Ryan , Sthanam Venkata , Xie Rongbing , Kirklin James K. , Rudraraju Ramaraju
Published: September 2021

Background:

Risk prediction models play an important role in clinical decision making. When developing risk prediction models, practitioners often impute missing values to the mean. We evaluated the impact of applying other strategies to impute missing values on the prognostic accuracy of downstream risk prediction models, that is, models fitted to the imputed data. A secondary objective was to compare the accuracy of imputation methods based on artificially induced missing values. To complete these objectives, we used data from the Interagency Registry for Mechanically Assisted Circulatory Support.

Methods:

We applied 12 imputation strategies in combination with 2 different modeling strategies for mortality and transplant risk prediction following surgery to receive mechanical circulatory support. Model performance was evaluated using Monte-Carlo cross-validation and measured based on outcomes 6 months following surgery using the scaled Brier score, concordance index, and calibration error. We used Bayesian hierarchical models to compare model performance.

Results:

Multiple imputation with random forests emerged as a robust strategy to impute missing values, increasing model concordance by 0.0030 (25th–75th percentile: 0.0008–0.0052) compared with imputation to the mean for mortality risk prediction using a downstream proportional hazards model. The posterior probability that single and multiple imputation using random forests would improve concordance versus mean imputation was 0.464 and >0.999, respectively.

Conclusions:

Selecting an optimal strategy to impute missing values such as random forests and applying multiple imputation can improve the prognostic accuracy of downstream risk prediction models.
Characteristics and Quality of National Cardiac Registries: A Systematic Review
Authors: Dawson Luke P. , Biswas Sinjini , Lefkovits Jeffrey , Stub Dion , Burchill Luke , Evans Sue M. , Reid Christopher , Eccleston David
Published: September 2021

Background:

National cardiac registries are increasingly used for informing health policy, improving the quality and cost-effectiveness of patient care, clinical research, and monitoring the safety of novel treatments. However, the quality of registries is variable. We aimed to assess the characteristics and quality of national cardiac registries across all subspecialties of cardiac care.

Methods:

Publications relating to national cardiac registries across six cardiac subspecialty domains were identified by searching MEDLINE and the Google advanced search function with 26 438 citations and 4812 full-text articles reviewed.

Results:

A total of 155 registries, representing 49 countries, were included in the study. Of these, 45 related to coronary disease or percutaneous coronary intervention, 28 related to devices, arrhythmia, and electrophysiology, 24 related to heart failure, transplant, and mechanical support, 21 related to structural heart disease, 21 related to congenital heart disease, and 16 related to cardiac surgery. Enrollment was procedure-based in 60% and disease-based in 40%. A total of 73.10 million patients were estimated to have been enrolled in cardiac registries. Quality scoring was performed using a validated registry grading system, with registries performing best in the use of explicit variable definitions and worst in assessment of data reliability. Higher quality scores were associated with government funding, mandated enrollment, linkage to other registries, and outcome risk adjustment. Quality scores and number of registries within a country were positively correlated with each other and with measures of national economic output, health expenditure, and urbanization.

Conclusions:

There has been remarkable growth in the uptake of national cardiac registries across the last few decades. However, the quality of processes used to ensure data completeness and accuracy remain variable and few countries have integrated registries covering multiple subspecialty domains. Clinicians, funders, and health policymakers should be encouraged to focus on the range, quality, and integration of these registries.

Registration:

URL:
https://www.crd.york.ac.uk/prospero
; Unique identifier: CRD42020204224.
NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis
Authors: Porritt Rebecca A. , Zemmour David , Abe Masanori , Lee Youngho , Narayanan Meena , Carvalho Thacyana T. , Gomez Angela C. , Martinon Daisy , Santiskulvong Chintda , Fishbein Michael C. , Chen Shuang , Crother Timothy R. , Shimada Kenichi , Arditi Moshe , Noval Rivas Magali
Published: September 2021

Rationale:

NLRP3 (NLR family pyrin domain containing 3) activation and IL-1β (interleukin-1β) production are implicated in Kawasaki disease (KD) pathogenesis; however, a detailed and complete characterization of the molecular networks and cellular subsets involved in the development of cardiovascular lesions is still lacking.

Objective:

Here, in a murine model of KD vasculitis, we used single-cell RNA sequencing and spatial transcriptomics to determine the cellular landscape of inflamed vascular tissues.

Methods and Results:

We observe infiltrations of innate and adaptive immune cells in murine KD cardiovascular lesions, associated with increased expression of
Nlrp3
and
Il1b
. Monocytes, macrophages, and dendritic cells were the main sources of IL-1β, whereas fibroblasts and vascular smooth muscle cells (VSMCs) expressed high levels of IL-1 receptor. VSMCs type 1 surrounding the inflamed coronary artery undergo a phenotype switch to become VSMCs type 2, which are characterized by gene expression changes associated with decreased contraction and enhanced migration and proliferation. Genetic inhibition of IL-1β signaling on VSMCs efficiently attenuated the VSMCs type 2 phenotypic switch and the development of cardiovascular lesions during murine KD vasculitis. In addition, pharmacological inhibition of NLRP3 prevented the development of cardiovascular inflammation.

Conclusions:

Our studies unravel the cellular diversity involved in IL-1β production and signaling in murine KD cardiovascular lesions and provide the rationale for therapeutic strategies targeting NLRP3 to inhibit cardiovascular lesions associated with KD.
Multiple Chronic Conditions Explain Ethnic Differences in Functional Outcome Among Patients With Ischemic Stroke
Authors: Jiang Xiaqing , Morgenstern Lewis B. , Cigolle Christine T. , Wang Lu , Claflin Edward S. , Lisabeth Lynda D.
Published: September 2021

Background and Purpose:

Mexican Americans (MAs) have worse stroke outcomes and a different profile of multiple chronic conditions (MCC) compared with non-Hispanic White people. MCC has implications for stroke treatment, complications, and poststroke care, which impact poststroke functional outcome (FO). We sought to assess the contribution of MCC to the ethnic difference in FO at 90 days between MAs and non-Hispanic White people.

Methods:

In a prospective cohort of ischemic stroke patients (2008–2016) from Nueces County, Texas, data were collected from patient interviews, medical records, and hospital discharge data. MCC was assessed using a stroke-specific and function-relevant index (range, 0–35; higher scores greater MCC burden). Poststroke FO was measured by an average score of 22 activities of daily living (ADLs) and instrumental ADLs at 90 days (range, 1–4; higher scores worse FO). The contribution of MCC to the ethnic difference in FO was assessed using Tobit regression. Effect modification by ethnicity was examined.

Results:

Among the 896 patients, 70% were MA and 51% were women. Mean age was 68±12.2 years; 33% of patients were dependent in ADL/instrumental ADLs (FO score >3, representing a lot of difficulty with ADL/instrumental ADLs) at 90 days. MAs had significantly higher age-adjusted MCC burden compared with non-Hispanic White people. Patients with high MCC score (at the 75th percentile) on average scored 0.70 points higher in the FO score (indicating worse FO) compared with those with low MCC score (at the 25th percentile) after adjusting for age, initial National Institutes of Health Stroke Scale, and sociodemographic factors. MCC explained 19% of the ethnic difference in FO, while effect modification by ethnicity was not statistically significant.

Conclusions:

MAs had a higher age-adjusted MCC burden, which partially explained the ethnic difference in FO. The prevention and treatment of MCC could potentially mitigate poststroke functional impairment and lessen ethnic disparities in stroke outcomes.