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INTRODUCTION: Bladder cancer (BCa) with variant histology (VH) is notably aggressive and not as well studied as pure urothelial carcinoma (UC). The characteristics of variant BCa in the setting of metastatic disease may contribute to treatment response/resistance and subsequent disease progression. In this study, we sought to assess VH's impact on metastasis sites at presentation in metastatic BCa. METHODS: The National Cancer Database was queried from 2004 to 2019 to analyze cT1-4 cN0-3 cM1 patients with UC and VH BCa. The primary endpoint was the presence of metastasis to different organs. Binomial multivariable logistic regression was performed to determine the impact of VH on metastatic sites while controlling for multiple variables. RESULTS: Total 6005 eligible patients diagnosed with either UC or VH were included. Patients with small cell histology, the second most common VH, were more likely to have liver metastasis (OR: 4.335) while less likely to have lung metastases (OR: 0.521). Squamous cell carcinoma decreased the odds of bone metastasis (OR: 0.449). Adenocarcinoma increased the odds of lung metastases (OR: 1.690). Micropapillary VH is less likely to metastasize to the lungs (OR: 0.182) but more likely to spread to nonregional lymph nodes (OR: 2.623). Sarcomatoid subtype did not exhibit a statistically significant variation in the odds ratio for any of the metastatic sites. CONCLUSION: This study comprehensively analyzes the limited research regarding metastatic BCa and VH. Our analysis underscores each subtype exhibiting heterogeneous metastatic tropism. Importantly, these findings illustrate the role of routine somatic gene expression profiling to guide adequate staging and treatment intensification and to offer a foundation for future studies of VH BCa care.
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The associations between human concussions and subsequent sequelae of chronic neuropsychiatric and cardiovascular diseases such as hypertension have been reported; however, little is known about the underlying biological processes. We hypothesized that dietary changes, including a high-salt diet, disrupt the bidirectional gut-brain axis, resulting in worsening neuroinflammation and emergence of cardiovascular and behavioural phenotypes in the chronic period after repetitive closed head injury in adolescent mice. Adolescent mice were subjected to three daily closed head injuries, recovered for 12 weeks and then maintained on a high-salt diet or a normal diet for an additional 12 weeks. Experimental endpoints were haemodynamics, behaviour, microglial gene expression (bulk RNA sequencing), brain inflammation (brain tissue quantitative PCR) and microbiome diversity (16S RNA sequencing). High-salt diet did not affect systemic blood pressure or heart rate in sham or injured mice. High-salt diet increased anxiety-like behaviour in injured mice compared to sham mice fed with high-salt diet and injured mice fed with normal diet. Increased anxiety in injured mice that received a high-salt diet was associated with microgliosis and a proinflammatory microglial transcriptomic signature, including upregulation in interferon-gamma, interferon-beta and oxidative stress-related pathways. Accordingly, we found upregulation of tumour necrosis factor-alpha and interferon-gamma mRNA in the brain tissue of high salt diet-fed injured mice. High-salt diet had a larger effect on the gut microbiome composition than repetitive closed head injury. Increases in gut microbes in the families Lachnospiraceae, Erysipelotrichaceae and Clostridiaceae were positively correlated with anxiety-like behaviours. In contrast, Muribaculaceae, Acholeplasmataceae and Lactobacillaceae were negatively correlated with anxiety in injured mice that received a high-salt diet, a time-dependent effect. The findings suggest that high-salt diet, administered after a recovery period, may affect neurologic outcomes following mild repetitive head injury, including the development of anxiety. This effect was linked to microbiome dysregulation and an exacerbation of microglial inflammation, which may be physiological targets to prevent behavioural sequelae in the chronic period after mild repetitive head injury. The data suggest an important contribution of diet in determining long-term outcomes after mild repetitive head injury.
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Background: Muscle-invasive bladder cancer (MIBC) is a potentially fatal disease, especially in the setting of locally advanced or node-positive disease. Adverse outcomes have also primarily been associated with low-income status, as has been reported in other cancers. While the adoption of neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) and pelvic lymph node dissection (PLND) has improved outcomes, these standard-of-care treatments may be underutilized in lower-income patients. We sought to investigate the economic disparities in NAC and PLND receipt and survival outcomes in MIBC. Methods: Utilizing the National Cancer Database, a retrospective cohort analysis of cT2-4N0-3M0 BCa patients with urothelial histology who underwent RC was conducted. The impact of income level on overall survival (OS) and the likelihood of receiving NAC and PLND was evaluated. Results: A total of 25,823 patients were included. This study found that lower-income patients were less likely to receive NAC and adequate PLND (≥15 LNs). Moreover, lower-income patients exhibited worse OS (Median OS 55.9 months vs. 68.2 months, p < 0.001). Our findings also demonstrated that higher income, treatment at academic facilities, and recent years of diagnosis were associated with an increased likelihood of receiving standard-of-care modalities and improved survival. Conclusions: Even after controlling for clinicodemographic variables, income independently influenced the receipt of standard MIBC treatments and survival. Our findings identify an opportunity to improve the quality of care for lower-income MIBC patients through concerted efforts to regionalize multi-modal urologic oncology care.
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Lymph Node Excision , Neoadjuvant Therapy , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgery , Lymph Node Excision/methods , Female , Male , Neoadjuvant Therapy/methods , Aged , Middle Aged , Retrospective Studies , Income , Healthcare Disparities/statistics & numerical data , Pelvis , Cystectomy/methods , Neoplasm InvasivenessABSTRACT
INTRODUCTION: Concern for overtreatment in very low-, low-, and favorable intermediate-risk prostate cancer has promoted a more conservative approach through active surveillance (AS) with comparable survival outcomes. We analyzed the National Cancer Database (NCDB) to determine if delaying radical prostatectomy greater than 6 months is associated with an increase in the rate of adverse pathology or secondary treatment (adjuvant or salvage) at radical prostatectomy. METHODS: Utilizing the NCDB from 2004 to 2019, 40 to 75-year-old men with very low-, low-, and favorable-intermediate-risk prostate cancer, as defined by the National Comprehensive Cancer Network, were identified for this study. These individuals received radical prostatectomy either before or after 6 months following diagnosis. Clinical, demographic, and pathologic characteristics were obtained. Adverse pathologic outcomes were defined as pT3-4N0-1 and/or positive surgical margins. Multiple logistic regression models were used to predict delays in treatment, adverse pathologic outcomes, and receipt of secondary therapy. Survival analysis was performed using the Cox Proportional Hazards Model and the Kaplan-Meier Method. RESULTS: Of the 195,397 patients who met inclusion criteria, only 13,393 patients received surgery 6 months after diagnosis. The median time of delay was 7.5 months compared to 2.3 months in the immediate treatment group. Overall, delaying surgery had no statistically significant impact on adverse pathologic outcomes, regardless of risk category. However, when accounting for the interaction between race and delayed treatment, non-Hispanic black patients who received a delay in treatment were more likely to experience adverse features (OR 1.12, 95%CI 1.00-1.26, P = .041). Conversely, patients who had delayed surgery were less likely to receive additional therapy (either adjuvant or salvage) (OR 0.60, 95%CI 0.52-0.68, P < .001). Survival analysis showed that both groups fared well, with a 5-year survival of 97% for both groups. The treatment group was not predictive of survival. CONCLUSION: Overall, delaying surgery more than 6 months following diagnosis did not have a significant impact on adverse pathologic features or overall survival. However, when specifically looking at non-Hispanic black patients with a treatment delay, these patients were at increased risk for adverse features, suggesting that the negative impact of treatment delay depends on the patient's race. As race is a social construct, this finding likely points to the complex socioeconomic factors that contribute to overall health outcomes rather than any inherent disease characteristics. Lastly, delayed treatment patients were actually less likely to require secondary therapy, regardless of race, possibly reflecting high clinician acumen in selecting patients appropriate for treatment delay. The results suggest that patients who ultimately "fail" AS and require subsequent surgery have overall comparable survival outcomes. However, pathologic outcomes are dependent on the patient's underlying race, with non-Hispanic black patients experiencing an increased risk of adverse outcomes if treatment is delayed.
Subject(s)
Prostatectomy , Prostatic Neoplasms , Time-to-Treatment , Humans , Male , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Prostatic Neoplasms/mortality , Prostatectomy/methods , Aged , Time-to-Treatment/statistics & numerical data , Middle Aged , Adult , Databases, Factual , Watchful Waiting/statistics & numerical data , United States , Salvage Therapy , Retrospective Studies , Treatment OutcomeABSTRACT
Heterogeneity in endothelial cell (EC) sub-phenotypes is becoming increasingly appreciated in atherosclerosis progression. Still, studies quantifying EC heterogeneity across whole transcriptomes and epigenomes in both in vitro and in vivo models are lacking. Multiomic profiling concurrently measuring transcriptomes and accessible chromatin in the same single cells was performed on six distinct primary cultures of human aortic ECs (HAECs) exposed to activating environments characteristic of the atherosclerotic microenvironment in vitro. Meta-analysis of single-cell transcriptomes across 17 human ex vivo arterial specimens was performed and two computational approaches quantitatively evaluated the similarity in molecular profiles between heterogeneous in vitro and ex vivo cell profiles. HAEC cultures were reproducibly populated by four major clusters with distinct pathway enrichment profiles and modest heterogeneous responses: EC1-angiogenic, EC2-proliferative, EC3-activated/mesenchymal-like, and EC4-mesenchymal. Quantitative comparisons between in vitro and ex vivo transcriptomes confirmed EC1 and EC2 as most canonically EC-like, and EC4 as most mesenchymal with minimal effects elicited by siERG and IL1B. Lastly, accessible chromatin regions unique to EC2 and EC4 were most enriched for coronary artery disease (CAD)-associated single-nucleotide polymorphisms from Genome Wide Association Studies (GWAS), suggesting that these cell phenotypes harbor CAD-modulating mechanisms. Primary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles. Surprisingly, the perturbations used here only modestly shifted cells between subpopulations, suggesting relatively stable molecular phenotypes in culture. Identifying consistently heterogeneous EC subpopulations between in vitro and ex vivo models should pave the way for improving in vitro systems while enabling the mechanisms governing heterogeneous cell state decisions.
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Atherosclerosis , Coronary Artery Disease , Humans , Atherosclerosis/metabolism , Chromatin/metabolism , Coronary Artery Disease/genetics , Endothelial Cells/metabolism , Genome-Wide Association StudyABSTRACT
Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1ß) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1ß activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.
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BACKGROUND: Recent studies have highlighted the overall survival (OS) benefit of cytoreductive radical cystectomy (CRC) in metastatic bladder cancer (mBCa). Cytoreductive surgery has been established in other urologic cancers. However, the efficacy of CRC and optimal criteria for patient selection in mBCa is unclear. This study investigated the oncologic efficacy of CRC, particularly emphasizing the location and number of metastasis sites as a predictor of survival and treatment response. METHODS: A retrospective analysis of cT2-4N0-3M1 mBCa patients treated with multiagent chemotherapy between 2004 and 2019 was conducted using the National Cancer Database. Patients were classified by additional treatment with CRC or conservative local treatment (CLT), consisting of transurethral resection of bladder tumor, radiation, or no local treatment and propensity score (PS) matched. Kaplan-Meier analysis and multivariate Cox Proportional Hazards model assessed the effect of CRC or CLT on OS within the matched cohort and in four subgroups (1) patients with only distant lymph node (LN) metastasis vs. any organ metastasis, (2) patients with single metastasis vs. multiple metastases. Sensitivity analysis estimated the influence of unmeasured confounders on CRC OS benefit. RESULTS: Propensity matching yielded 247 and 251 patients treated with CRC and CLT, respectively. Median OS in patients who received CRC was greater than that of patients treated with CLT (20.4 months vs. 12.0 months, P < 0.001). CRC was associated with reduced mortality risk in patients with only distant LN metastases (HRâ¯=â¯0.545, Pâ¯=â¯0.039), any organ metastasis (HRâ¯=â¯0.421, P < 0.001), and single visceral metastasis (HRâ¯=â¯0.483, Pâ¯=â¯0.002). However, CRC did not significantly improve OS in patients with multiple metastases (HRâ¯=â¯0.501, Pâ¯=â¯0.064). CONCLUSION: These findings demonstrate an OS benefit of CRC with multiagent chemotherapy and pinpoint multiple visceral metastases as a potential contraindication for CRC. Although limited by the influence of unmeasured confounders, these findings may inform future prospective investigations into CRC.
Subject(s)
Carcinoma, Transitional Cell , Cyanoacrylates , Urinary Bladder Neoplasms , Humans , Cytoreduction Surgical Procedures , Cystectomy , Retrospective Studies , Urinary Bladder Neoplasms/pathology , Carcinoma, Transitional Cell/pathology , Lymphatic Metastasis , Treatment OutcomeABSTRACT
Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.
Subject(s)
Brain Injuries, Traumatic , Brain Injuries , Humans , Mice , Animals , Adolescent , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/diagnostic imaging , Disease Models, Animal , Cerebral Cortex/diagnostic imaging , CognitionABSTRACT
Objective: Endothelial cells (ECs), macrophages, and vascular smooth muscle cells (VSMCs) are major cell types in atherosclerosis progression, and heterogeneity in EC sub-phenotypes are becoming increasingly appreciated. Still, studies quantifying EC heterogeneity across whole transcriptomes and epigenomes in both in vitro and in vivo models are lacking. Approach and Results: To create an in vitro dataset to study human EC heterogeneity, multiomic profiling concurrently measuring transcriptomes and accessible chromatin in the same single cells was performed on six distinct primary cultures of human aortic ECs (HAECs). To model pro-inflammatory and activating environments characteristic of the atherosclerotic microenvironment in vitro, HAECs from at least three donors were exposed to three distinct perturbations with their respective controls: transforming growth factor beta-2 (TGFB2), interleukin-1 beta (IL1B), and siRNA-mediated knock-down of the endothelial transcription factor ERG (siERG). To form a comprehensive in vivo/ex vivo dataset of human atherosclerotic cell types, meta-analysis of single cell transcriptomes across 17 human arterial specimens was performed. Two computational approaches quantitatively evaluated the similarity in molecular profiles between heterogeneous in vitro and in vivo cell profiles. HAEC cultures were reproducibly populated by 4 major clusters with distinct pathway enrichment profiles: EC1-angiogenic, EC2-proliferative, EC3-activated/mesenchymal-like, and EC4-mesenchymal. Exposure to siERG, IL1B or TGFB2 elicited mostly distinct transcriptional and accessible chromatin responses. EC1 and EC2, the most canonically 'healthy' EC populations, were affected predominantly by siERG; the activated cluster EC3 was most responsive to IL1B; and the mesenchymal population EC4 was most affected by TGFB2. Quantitative comparisons between in vitro and in vivo transcriptomes confirmed EC1 and EC2 as most canonically EC-like, and EC4 as most mesenchymal with minimal effects elicited by siERG and IL1B. Lastly, accessible chromatin regions unique to EC2 and EC4 were most enriched for coronary artery disease (CAD)-associated SNPs from GWAS, suggesting these cell phenotypes harbor CAD-modulating mechanisms. Conclusion: Primary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles. Surprisingly, the perturbations used here, which have been reported by others to be involved in the pathogenesis of atherosclerosis as well as induce endothelial-to-mesenchymal transition (EndMT), only modestly shifted cells between subpopulations, suggesting relatively stable molecular phenotypes in culture. Identifying consistently heterogeneous EC subpopulations between in vitro and in vivo models should pave the way for improving in vitro systems while enabling the mechanisms governing heterogeneous cell state decisions.
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INTRODUCTION: Literature indicating that transcranial photobiomodulation (tPBM) may enable the brain to recover normal function after concussion, resulting in symptoms reduction, and improved cognitive function after concussion is limited by small sample sizes and lack of controls. METHODS: We conducted a randomized, double-blind, placebo-controlled trial examining the effect of 6 wk of tPBM in patients 11 yr or older who received care for persistent postconcussion symptoms between September 2012 and December 2015. Our primary outcome measure was the mean difference in Postconcussion Symptom Scale total score and the raw Immediate Postconcussion Assessment and Cognitive Testing composite scores between study entry and treatment completion. Participants received two, 10-min sessions either with tPBM units or via two placebo units, three times per week. We screened for potential confounding variables using univariable analyses. We entered covariables that differed between the two groups on univariable screening into a regression analysis. We considered adjusted odds ratio that did not cross one statistically significant. RESULTS: Forty-eight participants completed the study. Most were female (63%), and a majority sustained their injury during sports or exercise (71%). Despite randomization, those that received tPBM therapy reported a greater number of previous concussions. After adjusting for the effect of previous concussions and multiple comparisons, there were no significant differences between tPBM and placebo groups at 3 or 6 wk of treatment. CONCLUSIONS: Despite showing promise in previous investigations, our study did not show benefit to tPBM over placebo therapy in patients experiencing persistent postconcussion symptoms. Further investigation is needed to determine if varying the dose or timing alters the efficacy of tPBM after concussion.
Subject(s)
Athletic Injuries , Brain Concussion , Low-Level Light Therapy , Post-Concussion Syndrome , Sports , Female , Humans , Male , Athletic Injuries/radiotherapy , Athletic Injuries/diagnosis , Brain Concussion/radiotherapy , Brain Concussion/diagnosis , Neuropsychological Tests , Post-Concussion Syndrome/therapy , Child , Adolescent , Young AdultSubject(s)
Prostate , Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/radiotherapy , Pelvis , Iatrogenic Disease , Rectum/diagnostic imagingABSTRACT
Introduction: Adrenal cavernous hemangiomas are rare benign vascular tumors that pose significant diagnostic challenges. Despite their benign nature, features overlapping with malignancies often complicate management decisions. Case presentation: A 64-year-old male presented with a 4.4â cm necrotic left adrenal mass discovered incidentally on imaging. His medical history included papillary thyroid carcinoma, with subsequent thyroidectomy and radioactive iodine ablation. Evaluations for hiccups revealed multiple lung nodules, hypertrophic cardiomyopathy, and anemia. Given the patient's previous cancer history, elevated aldosterone/renin ratio, and mass size, our multidisciplinary tumor board decided to proceed with a left adrenalectomy. Post-surgical pathology confirmed a diagnosis of adrenal cavernous hemangioma. Conclusion: The occurrence of ambiguous adrenal mass with other pathologies, such as our patient's papillary thyroid carcinoma, complicates the diagnostic and therapeutic landscape. As demonstrated in our case, opting for surgery remains a viable solution for adrenal cavernous hemangiomas, especially for masses greater than 4â cm. Interdisciplinary collaboration, exemplified by our tumor board's decision-making process, is crucial for optimal management. This case underscores the need for a multifaceted approach when confronting adrenal masses with such diagnostic ambiguity.
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The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimuli leads to an increase in mitochondrial metabolism; however, the function and regulation of elevated mitochondrial metabolism in EC in response to proinflammatory cytokines remain unclear. Studies using high-resolution metabolomics and 13C-glucose and 13C-glutamine labeling flux techniques showed that pyruvate dehydrogenase activity (PDH) and oxidative tricarboxylic acid cycle (TCA) flux are elevated in human umbilical vein ECs in response to overnight (16 h) treatment with TNFα (10 ng/mL). Mechanistic studies indicated that TNFα mediated these metabolic changes via mitochondrial-specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB-dependent mechanism. Using RNA sequencing following siRNA-mediated knockdown of the catalytically active subunit of PDH, PDHE1α (PDHA1 gene), we show that PDH flux controls the transcription of approximately one-third of the genes that are up-regulated by TNFα stimulation. Notably, TNFα-induced PDH flux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules. Metabolomics and ChIP sequencing for acetylated modification on lysine 27 of histone 3 (H3K27ac) showed that TNFα-induced PDH flux promotes histone acetylation of specific gene loci via citrate accumulation and ATP-citrate lyase-mediated generation of acetyl CoA. Together, these results uncover a mechanism by which TNFα signaling increases oxidative TCA flux of glucose to support TNFα-induced gene transcription through extramitochondrial acetyl CoA generation and histone acetylation.
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Protease La , Tumor Necrosis Factor-alpha , Humans , Tumor Necrosis Factor-alpha/pharmacology , Acetyl Coenzyme A , Endothelial Cells , Histones , CytokinesABSTRACT
Endoscopic management via retrograde ureteroscopic laser ablation of upper tract urothelial carcinoma (UTUC) has become the preferred treatment modality for low-risk tumors. The most popular ablative lasers over the past 15-20 years have been the holmium:yttrium-aluminum-garnet (Ho:YAG) and neodymium (Nd:YAG) lasers, but recently the thulium (Th:YAG) laser has emerged as a potential alternative. This review compares the mechanism of action, physiological properties and effects, and oncologic outcomes of Ho:YAG/Nd:YAG lasers versus the Th:YAG laser for UTUC treatment. Potential advantages of the Th:YAG laser over existing technologies are outlined, followed by a discussion of emerging laser technologies in UTUC management.
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Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.
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Brain Injuries, Traumatic , Contusions , Humans , Neuroinflammatory Diseases , Inflammation/metabolism , Brain/metabolism , Brain Injuries, Traumatic/metabolism , Contusions/metabolism , Mitochondria/metabolism , Microglia/metabolism , Astrocytes/metabolismABSTRACT
In this case report, we describe a patient who developed metastatic liver cancer of unknown primary origin one year following the surgical removal of a retroperitoneal adenocarcinoma. The retroperitoneal adenocarcinoma is considered a malignant transformation of teratoma (MTT), given the patient's distant history of testicular tumor excised 25 years prior and treated with chemotherapy. Despite no primary tumor being identified, the leading primary hypothesis is that the liver metastasis stemmed from the resected retroperitoneal adenocarcinoma from one year prior. We theorize that the patient's cisplatin-based chemotherapy 25 years ago may have triggered the MTT, as documented in the existing literature. Using TEMPUS gene testing on both the retroperitoneal adenocarcinoma and the recently discovered liver metastasis, we identified several genes with variants of unknown significance (VUS) that could potentially be linked to cisplatin chemotherapy resistance. While we cannot conclude that this patient definitively underwent MTT, it remains the most plausible explanation. Future research should investigate both the validity of the genes we have uncovered with respect to cisplatin resistance, as well as other genes associated with cisplatin resistance to further understand the pathogenesis of cisplatin resistance for better prediction of treatment response. As the world of medicine shifts towards individualized therapies and precision medicine, reporting and analyzing genetic mutations derived from tumors remains imperative. Our case report aims to contribute to the growing database of defined mutations and underscores the immense potential of genetic analysis in directing personalized treatment options.
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The transcription factor SREBP2 is the main regulator of cholesterol homeostasis and is central to the mechanism of action of lipid-lowering drugs, such as statins, which are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic disease. Recently, SREBP2 has been implicated in leukocyte innate and adaptive immune responses by upregulation of cholesterol flux or direct transcriptional activation of pro-inflammatory genes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and crucial to the pathogenesis of cardiovascular disease. Loss of SREBF2 inhibits the production of pro-inflammatory chemokines but amplifies type I interferon response genes in response to inflammatory stimulus. Furthermore, SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing of endogenous SREBP2 reveals that SREBP2 bound to the promoter regions of two nonclassical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. SREBP2 upregulation of KLF6 was responsible for the downstream amplification of chemokine expression, highlighting a novel relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.
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Cytokines , Endothelial Cells , Humans , Transcriptional Activation , Endothelial Cells/metabolism , Cytokines/metabolism , Cholesterol/metabolism , Transcription Factors/metabolism , Sterol Regulatory Element Binding Protein 2/genetics , Sterol Regulatory Element Binding Protein 2/metabolism , Kruppel-Like Factor 6/genetics , Kruppel-Like Factor 6/metabolismABSTRACT
Introduction: As a composite immunonutritional biomarker, the Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) score has shown promise in assessing a patient's overall health status by integrating several routinely collected laboratory indicators. This biomarker has been examined in many different populations of patients and disease states (i.e., cancer), but an integrated, universal rubric using standardized thresholds has not thus far been developed. Pre-existing large population-based databases represent an ideal source to examine the distribution of HALP and the influence of diverse health statuses on this score. Methods: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) between 2017-2020, evaluating 8,245 participants across numerous demographic, socioeconomic, and health-related variables. Univariate and multivariate linear regression analyses assessed the associations between HALP scores and these factors. Results: Our findings revealed significant associations between HALP scores and various demographic, socioeconomic, and health conditions. The median HALP score among the representative population was 49.0, with varying median scores across different groups and normal reference ranges for males and females. Multivariate regression analysis showed that anemia treatment, age over 65 years, weak/failing kidneys, and cancer were independent risk factors associated with lower HALP scores. Male participants demonstrated higher HALP scores than female participants, and age was inversely related to HALP. Moreover, HALP scores were negatively associated with the number of comorbidities. Conclusion/discussion: This study set out to explore the HALP score from a population-based perspective, uncovering notable associations that offer vital insights into the score's clinical relevance and future applications. By determining a median HALP score of 49.0 and normal reference ranges within our diverse, representative sample, we establish a robust foundation for researchers to refine optimal HALP applications and thresholds. Considering the growing focus on personalized medicine, HALP holds promise as a prognostic tool, enabling clinicians to comprehend their patients' immunonutritional status better and deliver customized care.
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INTRODUCTION: Local tumor invasion depth has been associated with lymph node metastasis in urothelial carcinoma, and, for muscle-invasive bladder cancer (MIBC), pelvic lymph node dissection (PLND) is a critical step in curative surgery. Gold standard treatment includes radical cystectomy (RC), but partial cystectomy (PC) is an important bladder-preserving modality reserved for patients with certain favorable prognostic indicators. There is poor evidence concerning the utility of PLND in PC and we seek to further define its role by comparing survival outcomes when PLND was cursory or omitted. METHODS: A retrospective analysis of 13,652 cT2N0M0 patients who underwent PC or RC between 2004 and 2016 was performed using the National Cancer Database. Patients undergoing PC were stratified by the presence of PLND as well as by node yield >15. The primary outcome was overall survival, analyzed using the Kaplan-Meier Method and multivariable Cox-proportional hazards regression. Multivariable models were adjusted for confounding clinicopathologic variables. RESULTS: From 2004 to 2016, PLND in PC increased from 44% to 57% with RC remaining over 90%. Compared to RC, PC was approximately twice as likely to be performed at community centers and approached laparoscopically/robotically (P < .001). When stratifying PC PLND yield into 1 to 15 and > 15 compared to PC without PLND, the adjusted hazard ratios for overall mortality were 0.78 and 0.54, respectively (P < .05). CONCLUSIONS: PC patients had a significantly lower rate of PLND compared to RC and improved survival when performed versus PC alone. Furthermore, increased node yield was associated with a larger reduction of adjusted mortality hazard. For MIBC patients that are appropriately selected for PC, high-yield PLND should be prioritized given the significantly improved survival outcomes.