bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhaled toxicants and pulmonary lipid metabolism: biological consequences and therapeutic interventions
Authors: Lovins Hannah B , Bathon Brooke E , Shaikh Saame Raza , Gowdy Kymberly M
Published: September 2023

Inhaled toxicants drive the onset of and exacerbate preexisting chronic pulmonary diseases, however, the biological mechanisms by which this occurs are largely unknown. Exposure to inhaled toxicants, both environmental and occupational, drives pulmonary inflammation and injury. Upon activation of the inflammatory response, polyunsaturated fatty acids (PUFAs) are metabolized into predominately proinflammatory lipid mediators termed eicosanoids which recruit immune cells to the site of injury, perpetuating inflammation to clear the exposed toxicants. Following inflammation, lipid mediator class-switching occurs, a process that leads to increased metabolism of hydroxylated derivates of PUFAs. These mediators, which include mono-hydroxylated PUFA derivatives and specialized proresolving lipid mediators, initiate an active process of inflammation resolution by inhibiting the inflammatory response and activating resolution pathways to return the tissue to homeostasis. Exposure to inhaled toxicants leads to alterations in the synthesis of these proinflammatory and proresolving lipid mediator pathways, resulting in greater pulmonary inflammation and injury, and increasing the risk for the onset of chronic lung diseases. Recent studies have begun utilizing supplementation of PUFAs and their metabolites as potential therapeutics for toxicant-induced pulmonary inflammation and injury. Here we will review the current understanding of the lipid mediators in pulmonary inflammation and resolution as well as the impact of dietary fatty acid supplementation on lipid mediator-driven inflammation following air pollution exposure.
Comprehensive analysis of JAZ family members in Ginkgo biloba reveals the regulatory role of the GbCOI1/GbJAZs/GbMYC2 module in ginkgolide biosynthesis
Authors: Du Jin-fa , Zhao Zhen , Xu Wen-bo , Wang Qiao-lei , Li Ping , Lu Xu
Published: September 2023

Ginkgo biloba L., an ancient relict plant known as a ‘living fossil’, has a high medicinal and nutritional value in its kernels and leaves. Ginkgolides are unique diterpene lactone compounds in G. biloba, with favorable therapeutic effects on cardiovascular and cerebrovascular diseases. Thus, it is essential to study the biosynthesis and regulatory mechanism of ginkgolide, which will contribute to quality improvement and medication requirements. In this study, the regulatory roles of the JAZ gene family and GbCOI1/GbJAZs/GbMYC2 module in ginkgolide biosynthesis were explored based on genome and methyl jasmonate-induced transcriptome. Firstly, 18 JAZ proteins were identified from G. biloba, and the gene characteristics and expansion patterns along with evolutionary relationships of these GbJAZs were analyzed systematically. Expression patterns analysis indicated that most GbJAZs expressed highly in the fibrous root and were induced significantly by methyl jasmonate. Mechanistically, yeast two-hybrid assays suggested that GbJAZ3/11 interacted with both GbMYC2 and GbCOI1, and several GbJAZ proteins could form homodimers or heterodimers between the GbJAZ family. Moreover, GbMYC2 is directly bound to the G-box element in the promoter of GbLPS, to regulate the biosynthesis of ginkgolide. Collectively, these results systematically characterized the JAZ gene family in G. biloba and demonstrated that the GbCOI1/GbJAZs/GbMYC2 module could regulate ginkgolides biosynthesis, which provides a novel insight for studying the mechanism of JA regulating ginkgolide biosynthesis.
The “Atypical Glandular Cells” Papanicolaou Test: Recent Updates
Authors: Li Zaibo , Zhao Chengquan
Published: September 2023

Atypical glandular cells are gynecologic cytology abnormalities representing glandular cells with morphologic changes that exceed obvious reactive/reparative changes, but fall short of an interpretation of adenocarcinoma either quantitatively or qualitatively. This cytological diagnosis occurs in less than 1% of the results of gynecologic cytology tests (0.2%–0.8%) but potentially reflects a wide range of conditions, from benign changes and cervical squamous/glandular precursor lesions, to invasive cervical or other gynecologic cancers. In this article, we aim at reviewing different subcategories, potential ancillary studies, histological follow-up results, and clinical management of atypical glandular cells.
Changes and Clarifications in the Eighth Edition of the AJCC Cancer Staging System for Breast Cancer
Authors: Sanders Mary Ann , Wong Stephanie M. , Iorgulescu Julian Bryan , Lester Susan C.
Published: September 2023

In the eighth edition of the American Joint Committee on Cancer staging system for breast cancer, the definitions for T (tumor), N (nodes), and M (metastases) remain substantially unchanged but with clarifications for certain categories that may have been problematic for pathologists and clinicians. The principal change is the decision to exclude lobular carcinoma in situ from T classification. In contrast, there is a major change in how stage is determined by introducing a new clinical prognostic stage and a new pathological prognostic stage. These prognostic stages incorporate information about grade, estrogen receptor expression, progesterone receptor expression, human epidermal growth factor receptor 2 expression, and, in some cases, the Oncotype Dx Recurrence Score, in addition to T, N, and M, to create groups of cancers predicted to have a similar survival at 3 years based on information from the National Cancer Database. This review highlights the changes and notable clarifications to the TNM system and how these relate to standard pathology reporting.
The American Joint Committee on Cancer Eighth Edition: Changes in Thyroid Carcinoma Staging and an Update on Reporting
Authors: Berg Aaron N. , Seethala Raja R.
Published: September 2023

The AJCC Cancer Staging Manual, Eighth Edition (AJCC 8th edition) contains a number of significant changes, many of which affect the reporting of clinicopathologic parameters in thyroid cancers. The first key change is the separation of medullary thyroid carcinoma into its own chapter. Within differentiated and anaplastic thyroid carcinomas, anaplastic carcinomas are now assigned a T stage similar to differentiated thyroid carcinomas. However, this is largely cosmetic because these are still assigned stage group IV. Perhaps the most significant alteration from a reporting standpoint is revision of extrathyroidal extension (ETE) in terms of T staging. Pathologic stage pT3 is now subdivided into pT3a (by size) and pT3b (by ETE). Under AJCC 8th edition, pT3b is now defined by gross (clinical, radiologic, and/or macroscopic) ETE. Other key changes are the inclusion of level VII (anterior mediastinal) lymph nodes as N1a and changes in stage groupings, particularly with a new age cutoff of 55 years, and a downshift in several stage groups. In medullary thyroid carcinoma, the potential prognostic value of nonanatomic factors (ie, serum calcitonin, carcinoembryonic antigen, RET mutation status) is officially recognized, although not yet part of staging. The advent of the new terminology noninvasive follicular thyroid neoplasm with papillary-like nuclear features will remove a subset of tumors that qualify for this new designation from formal AJCC staging altogether.
Ultrasound-Guided Fine-Needle Aspiration of Thyroid Nodules: Pearls and Potential
Authors: Jiang Xiaoyin “Sara” , Foo Wen-Chi
Published: September 2023

Thyroid nodules are a commonplace clinical problem. Ultrasound-guided fine-needle aspiration biopsy is often the first step in the diagnosis and management of these nodules. We provide a review of technical considerations, performance, and techniques for thyroid nodule ultrasound-guided biopsy.
Indeterminate Thyroid Cytology and Impact of Noninvasive Follicular Thyroid Neoplasm with Papillary-like Features on Preoperative Diagnosis
Authors: Elsheikh Tarik M.
Published: September 2023

Since the introduction of “noninvasive follicular thyroid neoplasm with papillary-like features” terminology, there has been much discussion and debate on how to best accommodate this new classification and its anticipated effect on cytologic preoperative risk of malignancy. Noninvasive follicular thyroid neoplasm with papillary-like features is a recently proposed terminology that was applied to a subset of noninvasive follicular variant of papillary thyroid carcinomas to avoid the label of “cancer.” In this review, the impact of noninvasive follicular thyroid neoplasm with papillary-like features on thyroid FNA diagnosis and risk of malignancy is discussed, as well as its impact on the 2017 updates to the Thyroid Bethesda system classification. Minimal cytologic criteria for establishing a definitive diagnosis of papillary thyroid carcinoma are discussed, as well as detailed diagnostic criteria of the indeterminate thyroid categories, which include atypia/follicular lesion of undetermined significance, follicular neoplasm/suspicious for follicular neoplasm, and suspicious for malignancy. The role of molecular testing in management is briefly visited.
Pseudomyxoma Peritonei: Pathology, a Historical Overview, and Proposal for Unified Nomenclature and Updated Grading
Authors: Bradley Robert F. , Carr Norman J.
Published: September 2023

Pseudomyxoma peritonei (PMP) is a clinically distinctive form of malignancy that typically arises from the appendix and is characterized by bulky accumulation of mucinous tumor deposits in the peritoneal cavity. It has defied stable pathologic categorization ever since first being described in the late 19th century. Since the early 20th century, many accounts have emphasized the bland histology of those cases arising from appendiceal precursors that had been considered benign, in contrast to higher-grade cases with more conventionally malignant histology. Beginning in the late 20th century, this was exemplified by divided nomenclature, with “carcinoma” phraseology being reserved for cases with clear-cut high-grade morphology. Such a divided approach is rendered problematic by the spectrum of atypia in many cases, including a significant subset with “intermediate” features. More recently, unified nomenclature has been favored for PMP of appendiceal origin, with an emphasis on tiers of grading. The goal is a clinically relevant and objectively reproducible grading scheme for what appears to be the spectrum of one clinicopathological entity (except perhaps for cases purely composed of signet-ring cells). Currently proposed consensus criteria focus on the distinction of cases of PMP as low grade, high grade, or high grade with signet-ring cells.
Low Grade Mesothelial Tumors of the Peritoneum: Multicystic Mesothelioma, Well-Differentiated Papillary Mesothelioma, and Adenomatoid Tumor
Authors: Carr Norman John
Published: September 2023

Low-grade neoplasms of the peritoneum are rare but include 2 entities that are more often encountered in the peritoneum than the pleura, namely, multicystic mesothelioma and well-differentiated papillary mesothelioma. Adenomatoid tumor is most common in the genital tract, but can occur in the peritoneum where it is sometimes found as a component of either multicystic mesothelioma or well-differentiated papillary mesothelioma. Indeed, all 3 tumors can occur in combination. The histological differential diagnosis of these neoplasms can include reactive mesothelial proliferations, malignant mesothelioma, and metastatic carcinoma. Cystic conditions such as lymphangioma can also enter the differential diagnosis. The question of whether cystic mesothelial lesions are neoplastic or reactive is controversial—multicystic lesions of the type that can recur after surgery and involve multiple sites are clinically neoplastic, and the presence of genetic abnormalities consistent with neoplasia has been described. However, the possibility that small, isolated mesothelial cysts are simple inclusions may be difficult to refute.
Gastric Polyposis Syndromes
Authors: Chiu Kenrry , Lee Lik Hang , Xiong Wei
Published: September 2023

Most gastric polyps are fundic gland polyps and hyperplastic polyps. Adenomas, inflammatory fibroid polyps, and neuroendocrine tumors are other types of gastric polyps that occur less frequently. Rarely, a gastric polyp may be associated with a syndrome, including hereditary cancer syndromes. Some of these syndromes are also associated with an increased risk of gastric cancer. We present a case of a 50-year-old woman with known Cowden syndrome who presents with multiple gastric hamartomatous polyps. We then review the clinical, endoscopic, and pathologic features of various syndromes that are associated with gastric polyps. Fundic gland polyp–predominant syndromes include familial adenomatous polyposis, gastric adenocarcinoma and proximal polyposis of the stomach, andMUTYH-associated polyposis, all of which are hereditary cancer syndromes. Gastric hamartomatous polyps are found in patients with juvenile polyposis syndrome, Peutz-Jeghers syndrome,PTENhamartoma tumor syndrome including Cowden syndrome, and Cronkhite-Canada syndrome. Syndromic gastric polyps may be biopsied in patients with a previously established diagnosis of the underlying syndrome, such as surveillance endoscopies in familial adenomatous polyposis. On other occasions, the pathologic assessment of gastric polyps may prompt or contribute to a diagnostic workup of an underlying syndrome in conjunction with other clinical and endoscopic findings.
Pseudomyxoma Peritonei Arising From a Low-Grade Mucinous Neoplasm of the Urachus
Authors: Vora Chintan , Tzivanakis Alexios , Dayal Sanjeev , Carr Norman John
Published: September 2023

Urachal mucinous tumors range from low-grade lesions traditionally called cystadenomas to frankly invasive mucinous adenocarcinomas. Occasionally, they can lead to the syndrome of pseudomyxoma peritonei (PMP). We report a patient who presented with abdominal distension and had raised tumor markers. A computed tomography scan revealed a calcified cystic lesion of the bladder dome together with features of PMP. These findings were confirmed at laparotomy, and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy was performed. Histologically, the urachal lesion was a low-grade urachal mucinous tumor (mucinous cystic tumor of low malignant potential). The peritoneal disease was associated with ovarian involvement and omental cake and was designated low-grade mucinous carcinoma peritonei on histology. The immunoprofile was typical for lesions of this type, featuring expression of CK20, CEA, and CDX2, but no expression of CK7. We review the literature of PMP arising from urachal primary neoplasms and identify 58 cases reported previously. Based on the limited data available, it appears that urachal lesions account for about 1 in 200 cases of PMP. Owing to the clinical and pathological similarities between urachal and appendiceal mucinous tumors, we recommend a simple classification based on the principles applied to appendiceal lesions and argue this is more appropriate than a classification based on ovarian nomenclature.
Marginal Zone Lymphoma, Immune Dysregulation, and High-Grade Transformation
Authors: Crane Genevieve M. , Chadburn Amy
Published: September 2023

Marginal zone lymphoma (MZL) is a low-grade B-cell lymphoma, which includes mucosa-associated lymphoid tissue lymphoma, splenic MZL, and nodal MZL. Of these, mucosa-associated lymphoid tissue lymphoma is the most frequent. While all 3 subtypes are typically indolent, a subset undergoes transformation to an aggressive B-cell lymphoma resulting in treatment challenges and a worse prognosis. We present a patient with systemic lupus erythematosus and Sjögren disease who developed MZL while on cyclophosphamide and steroids for treatment of her autoimmune disease. Her MZL was associated with a relatively indolent initial course. Unfortunately, her systemic lupus erythematosus continued to progress, and she ultimately required a renal transplant for end-stage renal disease due to lupus nephritis. At transplant, her MZL was thought to be in remission, but shortly thereafter, she developed an enlarging neck mass. A biopsy demonstrated background MZL with focal transformation to diffuse large B-cell lymphoma. Evidence is emerging that the underlying biology of a subset of MZL based on mutational profile, gene expression, and/or cytogenetic factors may affect the risk of transformation. Immune status has not been linked to progression, but chronic inflammation and immune dysregulation in the setting of chronic infection or autoimmune disease may underlie MZL development. In addition, iatrogenic immunosuppression for solid organ transplant or acquired immunodeficiency in the setting of human immunodeficiency virus may also result in increased risk or unusual presentations of MZL. This article features a case-based approach to explore factors related to MZL progression in a patient with a complex history of autoimmunity and immune suppression.
Large B-Cell Lymphoma With IRF4 Rearrangement: From Theory to Practice
Authors: Vincent Gabriel , Richebourg Steven , Cloutier Stephanie , Fortin Melanie , Jacob Simon , Amin-Hashem Mohamed
Published: September 2023

Interferon regulatory factor 4 (IRF4) rearrangement is a common cytogenetic anomaly reported in various neoplastic lymphoproliferative disorders. IRF4 is a gene located on chromosome 6 that encodes for the IRF4 protein belonging to the IRF family of transcription factors. Large B-cell lymphoma with IRF4 rearrangement constitutes a novel provisional entity included in the classification of lymphoid tissue recently proposed by the World Health Organization in its fourth revised edition. This rare entity, with a specific clinical presentation, is defined by the presence of a rearrangement of the IRF4 gene. We report a rare case of a 19-year-old female patient presenting with a large B-cell lymphoma with IRF4 rearrangement located in the right tonsil, with characteristic histologic appearance and the phenotype of neoplastic cells. The presence of an IGH-IRF4 rearrangement was also confirmed, using a fluorescence in situ hybridization analysis with 2 successive hybridizations on the same slide. Patient was treated with 6 cycles of R-CHOP with no evidence of recurrence.
Gender-Affirming Mastectomy Trends and Surgical Outcomes in Adolescents
Authors: Tang Annie , Hojilla J. Carlo , Jackson Jordan E. , Rothenberg Kara A. , Gologorsky Rebecca C. , Stram Douglas A. , Mooney Colin M. , Hernandez Stephanie L. , Yokoo Karen M.
Published: September 2023

Background

There are more than 150,000 transgender adolescents in the United States, yet research on outcomes after gender-affirming mastectomy in this age group is limited. We evaluated gender-affirming mastectomy incidence and postoperative complications, including regret, in adolescents within our integrated health care system.

Methods

Gender-affirming mastectomies performed from January 1, 2013, to July 31, 2020, in adolescents 12 to 17 years of age at the time of referral were identified. The incidence of gender-affirming mastectomy was calculated by dividing the number of patients undergoing these procedures by the number of adolescents assigned female at birth aged 12 to 17 years within our system at the beginning of each year and amount of follow-up time within that year. Demographic information, clinical characteristics (comorbidities, mental health history, testosterone use), surgical technique, and complications, including mention of regret, of patients who underwent surgery were summarized. Patients with and without complications were compared to evaluate for differences in demographic or clinical characteristics using χ2 tests.

Results

The incidence of gender-affirming mastectomy increased 13-fold (3.7–47.7 per 100,000 person-years) during the study period. Of the 209 patients who underwent surgery, the median age at referral was 16 years (range, 12–17 years) and the most common technique was double incision (85%). For patients with greater than 1-year follow-up (n = 137; 65.6%), at least one complication was found in 7.3% (n = 10), which included hematoma (3.6%), infection (2.9%), hypertrophic scars requiring steroid injection (2.9%), seroma (0.7%), and suture granuloma (0.7%); 10.9% underwent revision (n = 15). There were no statistically significant differences in patient demographics and clinical characteristics between those with and without complications (P > 0.05). Two patients (0.95%) had documented postoperative regret, but neither underwent reversal surgery at follow-up of 3 and 7 years postoperatively.

Conclusions

Between 2013 and 2020, we observed a marked increase in gender-affirming mastectomies in adolescents. The prevalence of surgical complications was low, and of more than 200 adolescents who underwent surgery, only 2 expressed regret, neither of which underwent a reversal operation. Our study provides useful and positive guidance for adolescent patients, their families, and providers regarding favorable outcomes with gender-affirming mastectomy.
Short Stay Management of Locally Advanced Breast Cancer Using Immediate Local Thoracoabdominal Advancement Flap and Enhanced Recovery After Surgery Protocol
Authors: Fahradyan Artur , Liu Alice , Taylor Lesley , Jones Veronica , Li Wai-Yee
Published: September 2023

Background

Patients with locally advanced invasive breast cancer (LABC) are often considered inoperable, because of the anticipated chest wall defect and need for complex reconstruction. We present a series of patients who underwent mastectomy with extensive skin resection and immediate chest wall reconstruction using a local thoracoabdominal advancement flap (TAAF). All patients were managed after surgery with an ERAS (Enhanced Recovery After Surgery) protocol, to decrease length of stay in hospital. We also present 1 patient who subsequently had satisfactory bilateral delayed breast reconstruction with pedicled latissimus dorsi myocutaneous flaps with prepectoral silicone implants.

Methods

This is a single-surgeon, single-institution retrospective chart review of patients with LABC who underwent mastectomy with skin resection and local TAAF from May 2017 to October 2019, with minimum 3-month follow-up.

Results

Thirteen patients met inclusion criteria. Twelve of 13 patients presented with stage III or IV invasive breast cancer, with skin involvement. The mean chest wall defect measured 248.7 cm2 (140–336 cm2; SD, 63.2 cm2), and all were successfully reconstructed with immediate local TAAF. There were no intraoperative complications, but 1 patient developed a postop hematoma. The mean hospital stay was 1.3 nights, with 9 patients (69.2%) staying less than 23 hours and 4 patients (30.8%) staying 2 nights. Nine patients (69.2%) underwent adjuvant therapy, beginning on average 32 days (13–55 days; SD, 13.1 days) after surgery. The mean follow-up time was 13.8 months (4.5–31.6 months; SD, 9.2 months). One patient underwent successful delayed bilateral breast reconstruction with pedicled latissimus dorsi myocutaneous flaps and silicone implant placement.

Conclusions

Our study demonstrates that reconstruction with local TAAF is an outpatient procedure that reliably provides durable, immediate chest wall coverage, after mastectomy in patients with LABC. This technique has a short operative time, low blood loss, and low complication rate, allowing timely adjuvant therapy. Using an ERAS postop protocol we were able to reduce mean hospital stay to 1.3 days. Compared with other described techniques of reconstruction, the additional scars and donor site morbidity are minimal, allowing for delayed breast reconstruction. We also present survival outcomes data on these surgically managed patients.
Impact of Early Nutrition on the Gut Microbiome
Authors: Abad-Jorge Ana , Comess Jill E.
Published: September 2023

The gut microbiome develops in prenatal life and progresses through infancy and childhood. Identified factors that impact the quantity, quality, and diversity of the early gut microbiome include mode of delivery, early diet, environmental exposures, disease conditions, and treatment. Optimal gut health in childhood is impacted by microbiome stability and diversity. This narrative review provides an overview of the important factors including genetic, epigenetic, nutritional, and environmental exposures, playing a foundational role in establishing the early gut microbiome during the critical first “1000 days” of human life and its impact on pediatric obesity, allergy, and gastrointestinal disease.
Evaluation of the Effectiveness of Using Handgrip Strength in Determining Malnutrition in Adolescents
Authors: Doğan Gökcen , Yabanci Ayhan Nurcan , Tuna Kirsaçlioğlu Ceyda , Kuloğlu Zarife , Kansu Aydan
Published: September 2023

We aimed to evaluate the effectiveness of using handgrip strength (HGS) in determining malnutrition in adolescents. Sixty-two participants (10–18 years of age), 33 malnourished and 29 healthy participants, were recruited. A questionnaire was administered, and anthropometric parameters and HGS were measured. Dominant HGS was different in children with (11.6 ± 5.8 nkgF) or without (21.6 ± 5.7 kgF) malnutrition (P < .001). Body mass index, triceps/biceps skinfold, neck/waist/wrist circumferences, and arm muscle area were correlated with HGS. According to receiver operating characteristic analysis, dominant (area under the curve [AUC]: 85.9%), and nondominant HGSs (AUC: 83.9%) were possible predictors for malnutrition. HGS may be used as a tool for malnutrition assessment in adolescents.
The Association Between Serum Levels of Selenium With Inflammatory and Immunity Factors, and Mortality Rate in Patients Diagnosed With COVID-19
Authors: Keshani Parisa , Hassani Amirhossein , Arab-Moorchegani Maryam , Foroozanfar Zohre , Parvizi Fateme , Khadem Yasaman , Omidifar Navid , Davarpanah Mohammad Ali , Joulaei Hassan
Published: September 2023

Due to the potential role of selenium in enhancing the immune system, a cross-sectional study was conducted to investigate the association between selenium serum levels, mortality rate, and inflammatory and immunity factors in patients diagnosed with COVID-19. A total 179 patients (60.3% male) with COVID-19 were enrolled into this study. The serum level of selenium was significantly correlated with white blood cell count, neutrophils, lymphocytes, and erythrocyte sedimentation rate in patients with COVID-19. No significant association was seen between serum selenium levels and IL-6, IFN-γ, and mortality rate.
Vitamin D Concentrations in Pediatric Patients With COVID-19
Authors: Ekemen Keles Yildiz , Yilmaz Ciftdoğan Dilek , Colak Ayfer , Kara Aksay Ahu , Sahin Aslihan , Ustundag Gulnihan , Yilmaz Nisel
Published: September 2023

This study was conducted on 98 children with confirmed COVID-19 and 2112 patients in a healthy control group. Serum vitamin D levels were significantly lower in the patients with confirmed COVID-19 than in the control group (10.9 ng/dL vs 16.1 ng/dL; P < .001). Almost 65% of patients with inadequate serum vitamin D levels had symptomatic COVID-19, and 30% of patients with adequate vitamin D levels had symptomatic COVID-19 (P = .043). In the logistic model, inadequate vitamin D status was associated with symptomatic COVID-19 compared with asymptomatic COVID-19 (odds ratio = 4032; 95% confidence interval, 1.036-17.776; P = .045).
Real-World Experience With Teprotumumab in Patients With Dysthyroid Optic Neuropathy
Authors: Tamhankar Madhura A. , Pradeep Tejus , Chen Yuanyuan , Briceño César A.
Published: September 2023

Background:

Teprotumumab, an insulin-like growth factor I receptor inhibitory antibody, improved proptosis, diplopia, inflammatory signs/symptoms, and quality of life in patients with active thyroid eye disease (TED) in clinical trials. The trials excluded patients with dysthyroid optic neuropathy (DON). Recently, many case reports and case series have reported the successful use of teprotumumab to treat DON. Here, we review the data from published cases and our clinical experience in treating patients having DON with teprotumumab.

Methods:

A literature search was conducted of patients with DON treated with teprotumumab from January 2020 through September 2022. Data from DON patients from the authors' (M.A.T. and C.A.B.) clinical practice were included. Primary outcome measure was mean (SD) improvements for visual acuity, color vision, and visual fields. Improvements in proptosis and clinical activity score (CAS) and diplopia were compared before and after teprotumumab administration.

Results:

Ten observational studies/case reports were identified along with 2 patients in our practice. In all, there were 24 active TED patients with DON (37 eyes) who were treated with teprotumumab. Mean (SD) age was 66.5 (13.6) years and 13 (54%) were females, disease duration ranged from 2 months to >15 years. 22/24 patients had none, minimal improvement or progression of visual loss with intravenous/oral corticosteroids, orbital decompression (n = 9), and orbital radiation (n = 2). There were 2 patients who received teprotumumab as the only therapy. Overall, 88% (21/24) reported improvement in visual acuity after teprotumumab and in 75% (18/24), improvement in vision was observed after just 2 infusions of teprotumumab. Three eyes had decompression surgery in close proximity to teprotumumab infusions and were excluded from analyses. Mean (SD) improvement in visual acuity was 3.73 lines (SD 3.74), range 2–15 lines in 33 eyes. The mean (SD) improvement in the mean deviation on visual field testing in 15 eyes was 5.6 db (3.0 db). Mean (SD) improvement in proptosis was 4.37 mm (SD: 2.11) (20 patients, 32 eyes); and clinical activity score: mean reduction of 5.1 (1.3) for 18 patients. Teprotumumab was well tolerated in all but one patient. Adverse events reported included fatigue, dysgeusia, hearing loss, nausea, hyperglycemia, and muscle spasms.

Conclusions:

Teprotumumab is an effective treatment for DON in our experience and in published cases in whom treatment with steroids, surgery, or orbital radiation was unsuccessful.
Transcriptome-based host epistasis and pathogen co-expression in barley-powdery mildew interactions
Authors: Velásquez-Zapata Valeria , Smith Schuyler , Surana Priyanka , Chapman Antony V.E. , Wise Roger P.
Published: September 2023

Mildew locus a (Mla) from the Triticeae grain crop barley (Hordeum vulgareL.) encodes a multi-allelic series of nucleotide-binding leucine-rich repeat (NLR) immune receptors. These variable NLRs recognize complementary secreted effectors from the powdery mildew fungus,Blumeria hordei(Bh), to block disease progression. We used a dynamic time-course transcriptome of barley infected withBhto infer gene effects and epistatic relationships governed by theMla6NLR, two other host loci critical to the interaction,Blufensin1(Bln1) andRequired for Mla6 resistance3 (Rar3),and genes that interact with them.Bln1is anR-gene independent regulator of immunity and the resistantbln1mutant exhibits enhanced basal defense to compatibleBh.Rar3is required for MLA6-mediated generation of H2O2and the hypersensitive reaction; therar3mutant contains an in-frame Lys-Leu deletion in the SGT1-specific domain that compromises immunity by a subset ofMlaalleles. Interactions ofMla6andBln1resulted in symmetric, suppression and masked epistasis on theBh-induced barley transcriptome. Likewise, dominant or equal effects were caused byMla6andSgt1.Of a total of 468 barley NLRs, 366 were expressed in our dataset and 115 of those were grouped under different gene effect models, which localized to several chromosome hotspots. The correspondingBhinfection transcriptome was classified into nine co-expressed modules, linking differential expression with pathogen development. Expression of most of 517Bheffectors exhibited dependence on disease phenotype and was associated with appressorial or haustorial structures, suggesting that disease is regulated by a host-pathogen intercommunication network that diversifies the response.
Geranylgeranyl pyrophosphate (GGPP) is associated with hepatic lipid accumulation and insulin resistance in MAO by prenylating Perilipin4
Authors: Zhao Yue , Jiang Shan , Nie Hong-Yu , Zhao Meng-Fei , Sun Peng , Zhang Jing-Zi , Wang Xiao-Chen , Tang Yi-Ping , Yuan Xian-Wen , Sun Xi-Tai , Shan Xiao-Dong , He Jian , Liu Jiang-Huai , Bi Yan , Fang Lei , Han Xiao , Li Chao-Jun
Published: September 2023

Metabolically Abnormal Obesity (MAO) is characterized by hepatic steatosis and type 2 diabetes (T2D), in contrast to Metabolically Healthy Obesity (MHO). In this study, we investigated the role of hepatic geranylgeranyl pyrophosphate (GGPP), a metabolite of the mevalonate (MVA) pathway, in regulating the differences in lipid metabolism between MAO and MHO. Our findings revealed that GGPP levels were significantly elevated in individuals with MAO, and deficiency of GGPP in the liver ameliorated the defects associated with MAO. Furthermore, we discovered that the prenylation of the lipid droplet-associated protein Perilipin 4 by GGPP enhances the formation of large lipid droplets, thereby exacerbating hepatic lipid accumulation and insulin resistance. Notably, the inhibitor DGBP, targeting the GGPP synthase Ggpps, effectively attenuated the traits of MAO, offering novel insights into the treatment of this condition.
Trial-to-trial similarity and distinctness of muscle synergy activation coefficients increases during learning and with a higher level of movement proficiency
Authors: Kaufmann Paul , Koller Willi , Wallnöfer Elias , Goncalves Basilio , Baca Arnold , Kainz Hans
Published: September 2023

Muscle synergy analyses are used to increase our understanding of motor control. Spatially fixed synergy vectors coordinate multiple co-active muscles through activation commands, known as activation coefficients. To better understand motor learning, it is crucial to know how synergy recruitment varies during a learning task and different levels of movement proficiency. Within one session participants walked on a line, a beam, and learned to walk on a tightrope – tasks that represent different levels of proficiency. Muscle synergies were extracted over all conditions and the number of synergies was determined through the knee-point of the total variance accounted for (tVAF) curve. We found that the tVAF of one synergy decreased with task proficiency (line < beam < tightrope). Additionally, trial-to-trial similarity and distinctness of synergy activation coefficients increased with proficiency and after a learning process. We conclude that precise adjustment and refinement of synergy activation coefficients play a crucial role in motor learning.
HybridMimulusflowers attract a new pollinator
Authors: Peng Foen , Sun Xiaohe , van Vloten Claudia , Correll Jude , Langdon Marlena , Ngochanthra Weerin , Johnson Karl , Kane Suzanne Amador
Published: September 2023

Hybridization is common in flowering plants and is believed to be an important force driving adaptation and speciation. The hybrid flowers often have new trait combinations, which, theoretically, could attract new pollinators. In this study, we found that the hybrids between a hummingbird-pollinated speciesMimulus cardinalisand a self-pollinated speciesMimulus parishiiattract bumblebees (Bombus impatiens), a pollinator not attracted to either of the progenitor species. This novel attraction is explained by several floral traits in hybrids, including petal color, nectar concentration, and corolla size. We also found that theYUPlocus, previously shown to be important in bee attraction in otherMimulusspecies, also played an important role in this novel attraction. Hybrid plants’ attraction to new pollinators could be an underexplored avenue for pollinator shift and speciation.
A simple statistical framework for small sample studies
Authors: Schwarzkopf D. Samuel , Huang Zien
Published: September 2023

Most studies in psychology, neuroscience, and life science research make inferences about how strong an effect is on average in the population. Yet, many research questions could instead be answered by testing for the universality of the phenomenon under investigation. By using reliable experimental designs that maximise both sensitivity and specificity of individual experiments, each participant or subject can be treated as an independent replication. This approach is common in certain subfields. To date, there is however no formal approach for calculating the evidential value of such small sample studies and to definea priorievidence thresholds that must be met to draw meaningful conclusions. Here we present such a framework, based on the ratio of binomial probabilities between a model assuming the universality of the phenomenon versus the null hypothesis that any incidence of the effect is sporadic. We demonstrate the benefits of this approach, which permits strong conclusions from samples as small as 2-5 participants and the flexibility of sequential testing. This approach will enable researchers to preregister experimental designs based on small samples and thus enhance the utility and credibility of such studies.
Shifting from correlations to dynamics in the study of human prehistorical resilience to extreme climatic shifts
Authors: Ben-Oren Yotam , Jaffe Yitzchak , Kolodny Oren
Published: September 2023

In recent years there has been a growing body of research on human resilience to extreme climatic shifts in the past. Most studies focus on comparing archaeological records prior to a perceived climatic shift with those after it, to investigate a causal relationship between the two. Although these comparisons are important, they are limited in their potential to facilitate causal understanding of the factors that determined the human response to climate change. We assert that for such understanding, it is necessary to explicitly consider prior processes that could have made certain populations more resilient to the extreme climatic shift. This assertion calls for a new focus on the cultural and demographicdynamicsin prehistorical populations, over the generations thatprecededthe climatic shift. In this article, we lay out several mechanisms of cultural evolution that – together with the experienced climatic dynamics prior to extreme climatic shifts – may have determined populations’ abilities to cope with them. This endeavor allows us to outline alternative hypotheses regarding what determined the fate of different human groups. These, in turn, may help direct the collection and analysis of archaeological data and to highlight modalities within it that may be helpful for inference of the mechanisms that determined populations’ resilience to climatic shifts.
InSituCor: a toolkit for discovering non-trivial spatial correlations in spatial transcriptomics
Authors: Danaher Patrick , McGuire Dan , Patrick Michael , Kroeppler David , Zhai Haiyan , Schmid Joachim , Beechem Joseph M.
Published: September 2023

Spatial transcriptomics presents the best kind of problem: how to find the many biological insights hidden within complex datasets. Spatially correlated genes can reveal high-interest phenomena like cell-cell interactions and latent variables. We introduce InSituCor, a toolkit for discovering modules of spatially correlated genes. A major contribution is that InSituCor returns only correlations not explainable by obvious factors like the cell type landscape; this spares precious analyst effort for non-trivial findings. InSituCor supports both unbiased discovery of whole-dataset correlations and knowledge-driven exploration of genes of interest. As a special case, it evaluates ligand-receptor pairs for spatial co-regulation.
Cardiac glycosides protect wormseed wallflower (Erysimum cheiranthoides) against some, but not all, glucosinolate-adapted herbivores
Authors: Younkin Gordon C. , Alani Martin L. , Capador Anamaría Páez , Fischer Hillary D. , Mirzaei Mahdieh , Hastings Amy P. , Agrawal Anurag A. , Jander Georg
Published: September 2023

The chemical arms race between plants and insects is foundational to the generation and maintenance of biological diversity. We asked how the evolution of a novel defensive compound in an already well-defended plant lineage impacts interactions with diverse herbivores.Erysimum cheiranthoides(Brassicaceae), which produces both ancestral glucosinolates and novel cardiac glycosides, served as a model.

We analyzed gene expression to identify cardiac glycoside biosynthetic enzymes inE. cheiranthoidesand characterized these enzymes via heterologous expression and CRISPR/Cas9 knockout. UsingE. cheiranthoidescardiac glycoside-deficient lines, we conducted insect experiments in both the laboratory and field.

EcCYP87A126 initiates cardiac glycoside biosynthesis via sterol side chain cleavage, andEcCYP716A418 has a role in cardiac glycoside hydroxylation. InEcCYP87A126 knockout lines, cardiac glycoside production was eliminated. Laboratory experiments with these lines revealed that cardiac glycosides were highly effective defenses against two species of glucosinolate-tolerant specialist herbivores but did not protect against all crucifer-feeding specialist herbivores in the field. Cardiac glycosides had lesser to no effect on two broad generalist herbivores.

These results begin elucidation of theE. cheiranthoidescardiac glycoside biosynthetic pathway and demonstratein vivothat cardiac glycoside production allowsErysimumto escape from some, but not all, specialist herbivores.
Personality heterophily and friendship as drivers for successful cooperation
Authors: Bhattacharjee Debottam , Waasdorp Sophie , Middelburg Esmee , Sterck Elisabeth H.M. , Massen Jorg J.M.
Published: September 2023

Cooperation is widespread and arguably a pivotal evolutionary force in maintaining animal societies. Yet, proximately, what underlying motivators drive individuals to cooperate remains relatively unclear. Since ‘free-riders’ can exploit the benefits by cheating, selecting the right partner is paramount. Such decision rules need not be based on complex calculations and can be driven by cognitively less-demanding mechanisms, like social relationships (e.g., kinship, non-kin friendships, dyadic tolerance), social status (e.g., dominance hierarchies) and personalities (social and non-social traits); however, holistic evidence related to those mechanisms is scarce. Using the classical ‘loose-string paradigm’, we tested cooperative tendencies of a hierarchical primate, the long-tailed macaque (Macaca fascicularis). We studied three groups (n=32) in social settings, allowing free partner choice. We supplemented cooperation with observational and experimental data on social relationships, dominance hierarchies, and personality. Friendship and dissimilarity in a non-social ‘exploration’ personality trait predicted the likelihood of cooperative dyad formation. Furthermore, the magnitude of cooperative success was positively associated with friendship, low rank-distance, and dissimilarity in an ‘activity-sociability’ personality trait. Kinship did not affect cooperation. While some findings align with prior studies, the evidence of (non-social)personality heterophily promoting cooperation may deepen our understanding of the proximate mechanisms and, broadly, the evolution of cooperation.
Destabilization of mRNAs enhances competence to initiate meiosis in mouse spermatogenic cells
Authors: Pfaltzgraff Natalie G. , Liu Bingrun , de Rooij Dirk G. , Page David C. , Mikedis Maria M.
Published: September 2023

The specialized cell cycle of meiosis transforms diploid germ cells into haploid gametes. In mammals, diploid spermatogenic cells acquire the competence to initiate meiosis in response to retinoic acid. Previous mouse studies revealed that MEIOC interacts with RNA-binding proteins YTHDC2 and RBM46 to repress mitotic genes and promote robust meiotic gene expression in spermatogenic cells that have initiated meiosis. Here, we used the enhanced resolution of scRNA-seq, and bulk RNA-seq of developmentally synchronized spermatogenesis, to define how MEIOC molecularly supports early meiosis in spermatogenic cells. We demonstrate that MEIOC mediates transcriptomic changes before meiotic initiation, earlier than previously appreciated. MEIOC, acting with YTHDC2 and RBM46, destabilizes its mRNA targets, including transcriptional repressorsE2f6andMga, in mitotic spermatogonia. MEIOC thereby derepresses E2F6- and MGA-repressed genes, includingMeiosinand other meiosis-associated genes. This confers on spermatogenic cells the molecular competence to, in response to retinoic acid, fully activate transcriptional regulator STRA8-MEIOSIN, required for the meiotic G1/S phase transition and meiotic gene expression. We conclude that in mice, mRNA decay mediated by MEIOC-YTHDC2-RBM46 enhances the competence of spermatogenic cells to initiate meiosis.

SUMMARY STATEMENT

RNA-binding complex MEIOC-YTHDC2-RBM46 destabilizes its mRNA targets, including transcriptional repressors. This activity facilitates the retinoic acid-dependent activation ofMeiosingene expression and transition into meiosis.
Assessing molecular phylogenetics of Hydroptilidae (Trichoptera) subfamily lineages, with notes on biogeography
Authors: Murray-Stoker Kelly M. , McCauley Shannon J.
Published: September 2023

The microcaddisfly family Hydroptilidae is the most species-rich within the insect order Trichoptera and has a global distribution. The taxonomy and systematics of this group remains understudied in proportion to its diversity. Here, we present a phylogenetic assessment of subfamily relationships that includes five of the six Hydroptilidae subfamilies (Hydroptilinae, Leucotrichiinae, Ochrotrichiinae, Orthotrichiinae, and Stactobiinae) using publicly available molecular data. Our analyses recovered Leucotrichiinae, Ochrotrichiinae, and Stactobiinae as monophyletic and Hydroptilinae as paraphyletic. Based on the diversity and distribution of taxa, much more representation of species is needed to fully understand the relationships of subfamilies; however, our results suggest a need to revisit the placement ofIthytrichia, which concurs with other recent molecular work on Hydroptilidae. Further clarity into the relationships of Hydroptilidae will be important for understanding the variability and phylogenetic signal of ecological traits.
Looming detection in complex dynamic visual scenes by interneuronal coordination of motion and feature pathways
Authors: Gu Bo , Feng Jianfeng , Song Zhuoyi
Published: September 2023

Detecting looming signals for collision avoidance faces challenges in real-world scenarios due to interference from moving backgrounds. Astonishingly, animals, like insects with limited neural systems, adeptly respond to looming stimuli while moving at high speeds. Existing insect-inspired looming detection models integrate either motion-pathway or feature-pathway signals, remaining susceptible to dynamic visual scene interference. We propose that coordinating interneuron signals from the two pathways could elevate looming detection performance in dynamic conditions. We used artificial neural network (ANN) to build a combined-pathway model based onDrosophilaanatomy. The model exhibits convergent neural dynamics with biological counterparts after training. In particular, a multiplicative interneuron operation enhances looming signal patterns. It reduces background interferences, boosting looming detection accuracy and enabling earlier warnings across various scenarios, such as 2D animated scenes, AirSim 3D environments, and real-world situations. Our work presents testable biological hypotheses and a promising bio-inspired solution for looming detection in dynamic visual environments.