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Estrogen and obesity synergistically suppress protein S via HIF1α, enhancing thrombosis potential
No full textVenous thromboembolism (VTE) is a leading cause of morbidity and mortality, with risk heightened in premenopausal women with obesity or use estrogen-based oral contraceptives. When both risk factors are present, the thrombosis risk increases substantially. Protein S (PS), an essential anticoagulant cofactor, is downregulated by both estrogen and obesity, but the molecular basis for this suppression remains poorly defined. We investigated the effect of estrogen and obesity on PS expression using plasma samples from 157 women stratified by BMI and contraceptive use, alongside 40 mice categorized as lean or obese with or without estrogen pellet treatment. The levels of PS were reduced by either estrogen or obesity alone, and the combined effect increased thrombin generation. In HepG2 hepatocytes, hypoxic conditions (1%-10% O2) mimicking obesity, with or without 17 β-estradiol, suppressed PROS1 transcription and promoter activity. ChIP confirmed direct binding of hypoxia-inducible factor 1α (HIF1α) to the PROS1 promoter, repressing gene expression. These findings define a mechanistic pathway through which estrogen and obesity converge to suppress PS synthesis, providing insight into the elevated thrombosis risk observed in women with obesity using estrogen-based contraceptives
Assessing the Tumor Suppressive Impact and Regulatory Mechanisms of SPDEF Expression in Breast Cancer
No full textBackground/Objectives: Breast cancer is a heterogeneous disease, and the role of the transcription factor SPDEF remains controversial. We aimed to clarify the prognostic value of SPDEF, explore demographic and molecular correlates of its expression, and investigate potential regulatory mechanisms underlying its dysregulation. Methods: Genomic and clinical data for 1218 breast cancer tumors were obtained from The Cancer Genome Atlas (TCGA). SPDEF mRNA expression was compared across intrinsic subtypes, age, and race, and prognostic significance was evaluated by Kaplan–Meier analysis. Promoter methylation patterns and DNA methyltransferase (DNMT) expression were examined as potential regulatory drivers. Co-expression analysis was performed using gene panels representing luminal differentiation, basal identity, EMT, proliferation, DNA repair, and immune signaling. Results: Low SPDEF expression was significantly associated with worse overall, relapse-free, and metastasis-free survival across all breast cancers. Expression was lowest in Basal tumors, as well as among younger and Black or African American patients. Promoter methylation at six CpG islands correlated with both reduced SPDEF expression and inferior survival, and DNMT1, DNMT3A, and DNMT3B overexpression also aligned with poor prognosis and Basal enrichment. Co-expression analysis revealed that SPDEF downregulation coincided with loss of luminal markers and increased EMT, proliferation, DNA repair, and immune pathways. Conclusions: SPDEF functions as a tumor suppressor in breast cancer, with reduced expression linked to poor outcomes, aggressive molecular features, and epigenetic regulation. These findings highlight SPDEF and DNMT-driven methylation as potential prognostic biomarkers for enhanced risk stratification and targets for novel therapies, particularly in Basal breast cancers
NLRC4 deficiency improves host protection during sepsis by regulating macrophage and T-cell responses
No full textSepsis followed by multiple organ failure is a leading cause of death in noncoronary intensive care units. While the NLRC4 inflammasome has been shown to play a crucial role in the innate immune response, the role of NLRC4 in sepsis remains unclear. Here, we used NLRC4 gene-deficient mice to explore its role in cecal ligation and puncture (CLP)-induced polymicrobial sepsis. Survival, bacterial clearance in the lung and extrapulmonary organs, and leukocyte influx to the peritoneum were determined. Chemokines and cytokines in the peritoneal fluid (PF) were quantified using ELISA. Mice were co-housed to compare the gut microbiota\u27s effect on bacterial burden following sepsis. Here, we report that NLRC4 deficiency improves host survival and bacterial clearance in mice with CLP-induced sepsis. Nlrc4-/- mice displayed reduced numbers of total leukocytes in the PF, including neutrophils compared to wild-type (WT) mice at 12 and 24 h post-CLP, although the recruitment of macrophages in NLRC4 knockout mice was higher at 12 h. Nlrc4-/- mice displayed lower levels of cytokines and chemokines in PF following sepsis. Co-housing of WT and Nlrc4-/- mice suggests that NLRC4 regulates host defense in CLP-induced sepsis independently of gut microbiota. Depletion of macrophages demonstrated that NLRC4 deficiency protects macrophages from sepsis-induced immune dysfunction. Moreover, we observed higher CD4+, CD8+, IFN-γ+CD8+, and NK cell subsets in the spleen and lower level of apoptosis of spleen cells of NLRC4-deficient mice after sepsis. Overall, these findings identify that NLRC4 activation has a detrimental role in sepsis through modulating macrophages and T-cell responses
Early Versus Late Venous Thromboembolism Prophylaxis Impact on Outcomes of Blunt Solid Abdominal Organ Injuries
No full textBACKGROUND: Venous thromboembolism (VTE) following solid, blunt, isolated abdominal organ injuries remains a common posttrauma complication in adults. Accordingly, gaining a better understanding of the effect of early versus late VTE prophylaxis to reduce rates of this complication is prudent. OBJECTIVE: The purpose of this study is to evaluate the impact of early versus late VTE prophylaxis on clinical outcomes in adult trauma patients with isolated blunt solid abdominal organ injuries. METHODS: This retrospective cohort study utilized the American College of Surgeons Trauma Quality Improvement Program Participant Use File database between 2017 and 2021 to compare clinical outcomes between early ( ≤ 48 hours) and late ( \u3e 48 hours) VTE prophylaxis, including deep vein thrombosis (DVT), pulmonary embolism (PE), and other secondary outcomes. This study included adult (age ≥ 16) trauma patients with severe (ISS \u3e 15) and isolated Abbreviated Injury Scale (AIS) abdomen ≥ 3, all other body regions \u3c 3, blunt American Association for the Surgery of Trauma (AAST) grade ≥ 3 solid abdominal organ injuries without traumatic brain injury (TBI) (AIS head \u3c 2) who received early or late chemical VTE prophylaxis. RESULTS: A total of 3,365 non-TBI patients with isolated blunt solid abdominal organ injuries, with 2,033 patients (60.4%) receiving early VTE prophylaxis and 1,332 (39.6%) receiving late prophylaxis, were included. Early prophylaxis was associated with a 57% lower risk of DVT (OR 0.4, 95% CI [0.19, 0.98], p = .044). CONCLUSION: Adult non-TBI trauma patients with isolated, moderate-severe, blunt solid abdominal organ injuries receiving early VTE prophylaxis have significantly lower odds of developing specifically DVT compared to patients receiving late prophylaxis
Atypical abdominal pain: uncovering malignant peritoneal mesothelioma in suspected Crohn\u27s disease: a case report
No full textBACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer from the serosal membranes of the abdominal cavity. In the United States, MPM accounts for about 10-15% of all mesothelioma cases, and translates into approximately 600 new cases diagnosed annually. It is typically diagnosed in Caucasian individuals, and while asbestos exposure is a well-established risk factor for pleural mesothelioma, its association with peritoneal mesothelioma remains less clear. Clinical symptoms of MPM, such as abdominal pain, bloating, and weight loss, overlap with other gastrointestinal disorders, which often leads to delayed diagnosis. This case report presents a unique instance of MPM initially misdiagnosed as ileal Crohn\u27s disease (CD), highlighting the importance of differential diagnosis in such complex cases. CASE DESCRIPTION: A 62-year-old Caucasian male with a history of diverticulitis was referred to an inflammatory bowel disease (IBD) center for reported ileal CD. The patient experienced 3 years of persistent abdominal pain, constipation, fatigue, early satiety, and weight loss. Previous imaging, including computed tomography scans, suggested ileal thickening and inflammatory fat stranding, but no histologic confirmation of CD was obtained. He had been treated with Humira without improvement, and intermittent courses of prednisone provided temporary relief. Despite his diagnosis of CD, his symptoms were unresponsive to standard treatments. Upon further evaluation, Humira levels were undetectable, and magnetic resonance enterography (MRE) yielded no significant findings. A diagnostic laparoscopy was performed, revealing peritoneal mesothelioma, which was confirmed by biopsy as the diffuse, epithelioid type. The diagnosis was supported by positive immunohistochemical staining for calretinin, CK7, and CK5/6. CONCLUSIONS: This case underscores the importance of considering a broad differential diagnosis in patients with non-specific abdominal symptoms. Although CD was initially suspected, MPM was ultimately identified through diagnostic laparoscopy and histological analysis. The case highlights the need for comprehensive diagnostic evaluation, including histologic confirmation and objective markers, to accurately differentiate between conditions with similar presentations. Clinicians should maintain a high index of suspicion for rare etiologies, such as peritoneal mesothelioma, particularly in patients with a history of asbestos exposure, to ensure timely and appropriate management
The Clinical Anatomy of the Vascular System | Ch 15
No full textThe arterial supply to the thyroid gland is typically provided by two main arteries, the superior and inferior thyroid arteries. In a small proportion of individuals, an anomalous artery, the thyroidea ima artery, is present
The Clinical Anatomy of the Vascular System | Ch 42
No full textThe primitive mediastinum arises from mesenchyme during the fourth week of development. The intraembryonic coelom gives rise to the mesodermally lined pericardial cavity, peritoneal cavity, and two pericardioperitoneal canals, all of which contribute to the borders of the mediastinum (Ronson et al. 2000). Infoldings of the pericardial cavity, the pleuropericardial canals, grow medially from the lateral body wall and begin to create the division between the peritoneum and the pericardium (Schoenwolf et al. 2021). These pleuropericardial canals form the initial lateral borders of the mediastinum (Ronson et al. 2000). The mediastinal space is further defined as the bronchial lung buds extend into the pleuropericardial canals, pushing the superior and inferior surfaces of the canals away from each other (Ronson et al. 2000). The embryonic mediastinum is formed by the end of the seventh week of development when the pleuropericardial membranes growing from the lateral body wall fuse with mesoderm at the midline (Schoenwolf et al. 2021). This creates defined borders for the pericardial cavity and pleural cavities, forming a space for the mediastinum and its structures to extend from the sternum to the vertebral column and lie between the lungs (Ronson et al. 2000)
The Clinical Anatomy of the Vascular System | Ch 99
No full textAround the 26th day of embryo development, mesoderm cells replicate rapidly under the influence of morphogens, leading to the development of the upper limb (Guéro 2018). Initially, the upper limb contains only a capillary network, which develops into the overall vasculature (Al-Qattan et al. 2009). The development of the ulnar artery is preceded by a border vein that appears on day 14 (Al-Qattan et al. 2009). Subclavian–axillary–brachial axis arteries appear between days 33 and 36 of development, the brachial artery eventually giving rise to the median artery (Al-Qattan et al. 2009). Around 41 days of development, the ulnar artery appears, replacing part of the median artery (Al-Qattan et al. 2009)
