Areca nut-induced metabolic reprogramming and M2 differentiation promote OPMD malignant transformation.

BACKGROUND: Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive. METHODS: Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE. RESULTS: We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters. CONCLUSION: Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

Well controlled maternal inflammatory bowel disease does not increase the risk of abnormal neurocognitive outcome screening in offspring.

Background: Exposure to maternal inflammation is associated with an increased risk of neurocognitive and developmental disorders in offspring. Early diagnosis and intervention improves childhood motor and cognitive functioning. Neonatal cerebral MRI and remote app-based generalised movement assessments (GMAs) are both predictive of adverse neurocognitive outcomes but have only been used in infants at significantly increased risk for these outcomes, rather than following in utero exposure to maternal inflammatory disorders. Methods: Pregnant women with inflammatory bowel disease were assessed clinically and biochemically in each trimester of pregnancy in this single centre prospective study. Neonatal cerebral MRIs were performed at 6-12 weeks post-corrected term. Two GMA videos were filmed using the 'BabyMoves' app from 12 to 16 weeks of age. MRIs and GMAs were assessed by a blinded highly qualified practitioner using validated scoring systems. Results: 40/53 of invited maternal-infant dyads were recruited. C-reactive protein was elevated antenatally in less than 13%. 5/37 neonatal MRIs had incidental or obstetric trauma related gross anatomical abnormalities, with none abnormal on validated gross abnormality scoring. 3/35 GMAs were abnormal, with one GMA abnormality being clinically significant. Of those with abnormal GMAs, 2/3 were in exposed to severely active IBD in-utero. Conclusion: Neonatal cerebral MRI and GMA for neurocognitive screening is feasible in the setting of maternal inflammatory bowel disease, where the risk of cerebral palsy is poorly defined and thus burdensome screening interventions are less appealing to parents. Larger studies are required to stratify adverse neurocognitive outcome risk in infants born to women with maternal inflammatory disorders, but these data are reassuring for women with IBD in remission antenatally.

Neural-network-based solver for vesicle shapes predicted by the Helfrich model.

That a three-dimensional vesicle morphology can be modeled by an artificial neural network is proposed and demonstrated. In the phase-field representation, the Helfrich bending energy of a membrane is equivalently cast into field-based energy, which enables a more direct representation of a deformable, three-dimensional membrane surface. The core of our method is incorporating recent machine-learning techniques to perform the required energy minimization. The versatile ability of the method, to compute axisymmetric and nonsymmetric shapes, is discussed.

FISH Still a Very Important Tool to Monitor Breast Cancer: Review of Recent Literature, Alternative Methods, and Proposed Techniques.

OBJECTIVES: Fluorescent in situ hybridization has been the definitive modality in testing for overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2) for decades to guide the appropriate treatment for cancer patients. In more recent years innovation and new techniques have been developed to supplant or even replace FISH as a standard method for biomarker testing. Alternative testing methods such polymerase chain reaction (PCR), next-generation sequencing (NGS), and other in situ hybridization (ISH)-derived techniques such as chromogenic-ISH (CISH) have been shown in multiple publications to have high concordance with FISH in addition to advantages in economics, logistics and practicality to the point where CISH and derived methods appear to have eclipsed FISH as a testing method of choice after immunohistochemistry (IHC). This review assesses the status of FISH compared to other diagnostic techniques such as IHC, CISH, and less common and/or experimental methods. Also addressed are the updates to the guidelines from the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and National Comprehensive Cancer Network (NCCN) regarding FISH and IHC for HER2 testing with the updates reducing the number of equivocal diagnoses in the latest iteration. Though our findings show a constantly changing technological landscape, FISH remains an important primary tool to guide medical treatment and as a solid foundation to build upon for innovation in cancer research.

Multinuclear non-heme iron dependent oxidative enzymes (MNIOs) involved in unusual peptide modifications.

Multinuclear non-heme iron dependent oxidative enzymes (MNIOs), formerly known as domain of unknown function 692 (DUF692), are involved in the post-translational modification of peptides during the biosynthesis of peptide-based natural products. These enzymes catalyze highly unusual and diverse chemical modifications. Several class-defining features of this large family (>14 000 members) are beginning to emerge. Structurally, the enzymes are characterized by a TIM-barrel fold and a set of conserved residues for a di- or tri-iron binding site. They use molecular oxygen to modify peptide substrates, often in a four-electron oxidation taking place at a cysteine residue. This review summarizes the current understanding of MNIOs. Four modifications are discussed in detail: oxazolone-thioamide formation, ß-carbon excision, hydantoin-macrocycle formation, and 5-thiooxazole formation. Briefly discussed are two other reactions that do not take place on Cys residues.

Transcatheter Aortic Valve Replacement (TAVR) Versus Surgical Aortic Valve Replacement (SAVR): A Review on the Length of Stay, Cost, Comorbidities, and Procedural Complications.

This review provides an in-depth analysis of the effect of length of stay (LOS), comorbidities, and procedural complications on the cost-effectiveness of transcatheter aortic valve replacement (TAVR) in comparison to surgical aortic valve replacement (SAVR). We found that the average LOS was shorter for patients undergoing TAVR, contributing to lower average costs associated with the procedure, although the LOS varied between patients due to the severity of illness and comorbidities present. TAVR has also been found to improve the quality of life for patients receiving aortic valve replacement compared to SAVR. Although TAVR has a lower rate of most post-operative complications caused by SAVR, such as bleeding and cardiac complications, TAVR shows an increased rate of permanent pacemaker (PPM) implantation due to mechanical trauma on the heart's conduction system. In addition, our findings suggest that the cost-effectiveness of each procedure varies based on the types of valve, the patient history of other medical conditions, and the procedural methods. Our findings show that TAVR is preferred over SAVR in terms of cost-effectiveness across a variety of patients with other coexisting medical conditions, including cancer, advanced kidney disease, cirrhosis, diabetes mellitus, and bundle branch block. TAVR also appears to be superior to SAVR with fewer post-operative complications. However, TAVR appears to have a higher rate of PPM implantation rates as compared to SAVR. The comorbidities of the valve recipient must be considered when deciding whether to use TAVR or SAVR as cost-effectiveness varies with the patient background.

Forced extension of a wormlike chain in the Gibbs and Helmholtz ensembles.

A semiflexible polymer can be stretched by either applying a force to it or by fixing the positions of its endpoints. The two approaches generally yield different results and correspond to experiments performed in either the Gibbs or Helmholtz statistical ensembles. Here, we derive the Helmholtz force-extension relationship for the commonly used wormlike-chain model in the strongly stretched regime. By analyzing it in comparison with the Gibbs ensemble result, we show that equivalence between the two relationships is achieved only in the long-chain thermodynamic limit.

Sclerosing epithelioid fibrosarcoma associated with WRN gene variant presenting as chronic dyspnea and pathologic cervical fracture: a case report and review of the literature.

BACKGROUND: Sclerosing epithelioid fibrosarcoma is an aggressive sarcoma subtype with poor prognosis and limited response to conventional chemotherapy regimens. Diagnosis can be difficult owing to its variable presentation, and cases of sclerosing epithelioid fibrosarcoma are rare. Sclerosing epithelioid fibrosarcoma typically affects middle-aged individuals, with studies inconsistently citing gender predominance. Sclerosing epithelioid fibrosarcoma typically arises from the bones and soft tissues and often has local recurrence after resection and late metastases. Immunohistochemical staining typically is positive for mucin-4. Werner syndrome is due to an autosomal recessive mutation in the WRN gene and predisposes patients to malignancy. CASE PRESENTATION: A 37-year-old Caucasian female presented to the emergency department with 4 months of dyspnea and back pain. She had been treated for pneumonia but had persistent symptoms. A chest, abdomen, and pelvis computed tomography showed near-complete right upper lobe collapse and consolidation, mediastinal lymphadenopathy, lytic spinal lesions, and a single 15-mm hypodense liver nodule. The patient underwent a transthoracic right upper lobe biopsy, bronchoscopy, endobronchial ultrasound with transbronchial lymph node sampling, and bronchoalveolar lavage of the right upper lobe. The bronchoalveolar lavage cytology was positive for malignant cells compatible with poorly differentiated non-small cell carcinoma; however, the cell block materials were insufficient to run immunostains for further investigation of the bronchoalveolar lavage results. Consequently, the patient also underwent a liver biopsy of the liver nodule, which later confirmed a diagnosis of sclerosing epithelioid fibrosarcoma. Next-generation sequencing revealed a variant of unknown significance in the WRN gene. She was subsequently started on doxorubicin. CONCLUSION: Sclerosing epithelioid fibrosarcoma is a very rare entity, only cited approximately 100 times in literature to date. Physicians should be aware of this disease entity and consider it in their differential diagnosis. Though pulmonary involvement has been described in the context of sclerosing epithelioid fibrosarcoma, this malignancy may affect many organ systems, warranting extensive investigation. Through our diagnostic workup, we suggest a possible link between sclerosing epithelioid fibrosarcoma and the WRN gene. Further study is needed to advance our understanding of sclerosing epithelioid fibrosarcoma and its clinical associations as it is an exceedingly rare diagnosis.

The Incidence of Alopecia Areata in a COVID-19-Vaccinated Population: A Single-Center Review.

Background Cases of alopecia areata (AA) attributed to the coronavirus disease 2019 (COVID-19) vaccination have been reported in recent literature. However, these reports are reflective of specific geographic areas, and whether this phenomenon is observed in other regions remains to be investigated. This study focused on the association between AA and COVID-19 vaccination among patients from a large single-center safety net hospital in California. Methodology In this study, using electronic health records of patients and publicly available vaccination data, the demographics of patients including age group, sex, and race along with the vaccination status were carefully reviewed. Results A total of 73 cases of AA in the period from the release of the COVID-19 vaccination on December 17, 2020, to February 10, 2023, were identified. The odds ratios (ORs) for developing AA among the vaccinated and unvaccinated for each demographic level were calculated. Among all vaccinated individuals, the OR for developing AA was 0.58 (95% confidence interval (CI) = 0.35-0.94, p-value = 0.02). Conclusions This investigation noted no apparent increase in the incidence of AA among the vaccinated population compared to the unvaccinated population.