Epithelial-mesenchymal transition (EMT) is a continuum that includes epithelial, partial EMT, and mesenchymal states, each of which is associated with cancer progression, invasive capabilities, and ...ultimately, metastasis. We used a lineage-traced sporadic model of pancreatic cancer to generate a murine organoid biobank from primary and secondary tumors, including sublines that underwent partial EMT and complete EMT. Using an unbiased proteomics approach, we found that organoid morphology predicts the EMT state, and the solid organoids are associated with a partial EMT signature. We also observed that exogenous TGFβ1 induces solid organoid morphology that is associated with changes in the S100 family, complete EMT, and the formation of high-grade tumors. S100A4 may be a useful biomarker for predicting EMT state, disease progression, and outcome in patients with pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. While immortalized cancer cell lines and genetically engineered murine models have increased our understanding of ...PDAC tumorigenesis, they do not recapitulate inter- and intra-patient heterogeneity. PDAC patient derived organoid (PDO) biobanks have overcome this hurdle, and provide an opportunity for the high throughput screening of potential new therapies. This review provides a summary of the PDAC PDO biobanks established to date, and discusses how they have advanced our understanding of PDAC biology. Looking forward, the development of coculturing techniques for specific immune or stromal cell populations will enable a better understanding of the crosstalk that occurs within the tumor microenvironment, and the impact of this crosstalk on treatment response.
Optimal treatment of intra-abdominal infections (IAIs) is multifaceted, typically requiring surgical intervention and antimicrobial therapy. Treatment of IAIs aligned with the 2017 revised Surgical ...Infection Society (SIS) guidelines may improve patient outcomes. Here we compare clinical outcomes of patients who received guideline concordant and discordant therapy for treatment of IAIs.
This was a retrospective observational study of patients admitted from January 2013 to June 2016 with IAIs. Guideline concordant treatment was based on three criteria: source control, antibiotic choice, and antibiotic duration. The primary outcome was a composite of in-hospital mortality and 30-day re-admission. Multivariable logistic regression was used to determine independent factors associated with the composite end point.
A total of 221 patients were included, with guideline concordant treatment occurring in 117 (53%) patients. In-hospital mortality or 30-day re-admission occurred in 15 (12.8%) patients in the guideline concordant group compared with 24 (23.1%) in the guideline discordant group (p = 0.046). Empiric antibiotic choice was the most common component of discordance to guidelines (61% of patients). In multivariable analysis, guideline concordant treatment was associated with a decrease in the composite outcome (adjusted odds ratio aOR = 0.461, p = 0.045). In contrast, the presence of empiric methicillin-resistant
(MRSA)/vancomycin-resistant
(VRE) coverage (aOR: 2.645, p = 0.030), and moderate-to-severe liver disease (aOR: 8.081, p = 0.027) were associated with an increased risk for the composite outcome.
Concordance to recommendations from the 2017 revised SIS guidelines is of critical importance in the optimal management of IAIs and further investigation of interventions to improve concordance are warranted.
Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure ...variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.9 8.2 SD), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aβ
(standardized ß = - 0.36 95% CI - 0.61, - 0.12; p = 0.005; adjusted R
= 0.28) and Aβ
: Aβ
ratio (ß = - 0.49 95% CI - 0.71, - 0.22; p < 0.001; adjusted R
= 0.28), and higher levels of total tau (ß = 0.27 95% CI 0.01, 0.54; p = 0.04; adjusted R
= 0.19) and Ptau
:Aβ
ratio (ß = 0.26 95% CI 0.02, 0.51; p = 0.04; adjusted R
= 0.22). Findings suggest higher blood pressure variability is linked to plasma biomarkers of increased Alzheimer's disease pathophysiology.
A better understanding of the relationship between the spread of head and neck squamous cell carcinoma (HNSCC) to regional lymph nodes (LNs) and the frequency and manner of treatment failure should ...help design better treatment intensification strategies. In this study, we evaluated the relationship between recurrence patterns, mortality, and number of pathologically positive (+) LNs in HNSCC in 3 prospective randomized controlled trials.
We performed a secondary analysis of 947 patients with HNSCC enrolled in RTOG 9501 (n = 410), RTOG 0234 (n = 203), and EORTC 22931 (n = 334) undergoing surgery and postoperative radiation ± systemic therapy. Multivariable models were constructed for overall survival (OS), disease-free survival (DFS), locoregional relapse (LRR), and distant metastases (DM). Restricted cubic splines were used to model the nonlinear relationship between +LN number and outcomes.
In multivariable analysis, OS and DFS decreased with each +LN without plateau, most pronounced up to 5 +LNs (OS: hazard ratio HR, 1.21 per +LN; 95% confidence interval CI, 1.10-1.34; P < .001; DFS: HR per +LN, 1.19; 95% CI, 1.08-1.30; P < .001) and more gradually beyond this (OS: HR per +LN, 1.02; 95% CI, 1.01-1.06; P < .001; DFS: HR per +LN, 1.04; 95% CI, 1.02-1.06; P < .001). In contrast to LRR risk, which increased sharply up to 5 +LNs (HR per +LN, 1.28; 95% CI, 1.10-1.50; P < .001) but plateaued beyond this (HR per +LN, 1.00; 95% CI, 0.96-1.04; P = .98), DM risk increased continuously with increasing +LNs (≤5 +LNs: HR per +LN, 1.10; 95% CI, 1.01-1.20; P = .04; >5 +LNs: HR per +LN, 1.05; 95% CI, 1.02-1.08; P = .003).
In high-risk resected HNSCC, increased mortality was associated with increased +LN count. LRR and DM risk both increased in parallel up to 5 +LNs, but only DM continued to increase for further +LN increases. These differing recurrence patterns can help inform design of future treatments.
Although imaging plays no role in diagnosing primary hyperparathyroidism (PHPT), preoperative localization is essential for a focused parathyroidectomy. We hypothesized that reviewing imaging ...obtained prior to PHPT diagnosis can identify enlarged parathyroid glands and provide information that might potentially impact the preoperative evaluation and intraoperative course of patients undergoing parathyroidectomy.
We included adult patients with PHPT who underwent parathyroidectomy between October 2015 and October 2020 and had contrast-enhanced computed tomography (CT) imaging of the lower neck and upper chest obtained prior to diagnosis for unrelated indications. A radiologist reviewed the prediagnosis CTs blinded to subsequent parathyroid localization imaging and operative findings. A surgeon assessed the radiologist's findings in the context of each case to determine the potential impact of information from old imaging on surgical decision-making.
We identified at least one enlarged parathyroid gland on prior contrast-enhanced CT in 30 (75%) of 40 included patients. Despite old imaging enabling correct localization, 60% of these 30 underwent dedicated parathyroid imaging prior to parathyroidectomy. Knowledge of the enlarged parathyroid(s) on prior imaging might have allowed a more focused approach in 10.0% and prompted a more thorough exploration in 13.3%. In the total cohort, reviewing prior imaging could have provided information capable of changing the preoperative evaluation in 52.5% and the operative course in 17.5%.
The identification of enlarged parathyroid glands on contrast-enhanced CT imaging that predates a diagnosis of PHPT is possible. Prospective studies might verify the impact of these findings on the preoperative evaluation and operative course of patients undergoing parathyroidectomy.
Central command is a feedforward neural mechanism that evokes parallel modifications of motor and cardiovascular function during arousal and exercise. The neural circuitry involved has not been ...elucidated. We have identified a cholinergic neural circuit that, when activated, mimics effects on tonic and reflex control of circulation similar to those evoked at the onset of and during exercise. Central muscarinic cholinergic receptor (mAChR) activation increased splanchnic sympathetic nerve activity (SNA) as well as the range and gain of the sympathetic baroreflex via activation of mAChR in the rostral ventrolateral medulla (RVLM) in anesthetized artificially ventilated Sprague-Dawley rats. RVLM mAChR activation also attenuated and inhibited the peripheral chemoreflex and somatosympathetic reflex, respectively. Cholinergic terminals made close appositions with a subpopulation of sympathoexcitatory RVLM neurons containing either preproenkephalin mRNA or tyrosine hydroxylase immunoreactivity. M2 and M3 receptor mRNA was present postsynaptically in only non-tyrosine hydroxylase neurons. Cholinergic inputs to the RVLM arise only from the pedunculopontine tegmental nucleus. Chemical activation of this region produced increases in muscle activity, SNA, and blood pressure and enhanced the SNA baroreflex; the latter effect was attenuated by mAChR blockade. These findings indicate a novel role for cholinergic input from the pedunculopontine tegmental nucleus to the RVLM in central cardiovascular command. This pathway is likely to be important during exercise where a centrally evoked facilitation of baroreflex control of the circulation is required to maintain blood flow to active muscle.
The aims of this study were to evaluate, using 3-dimensional superimposition techniques, the skeletal changes in Class II subjects with different vertical facial patterns treated with the Herbst ...appliance and to compare these skeletal changes to those of Class II controls treated with elastics.
Sixteen Herbst patients who met the inclusion criteria were divided into 2 equal groups based on vertical facial pattern as determined by the Frankfort mandibular plane angle (brachyfacial, ≤22°; mesofacial, 23°-29°) and had cone-beam computed tomographs taken before treatment, 8 weeks after Herbst appliance removal, and after subsequent fixed appliance treatment. Eleven Class II control patients treated with fixed appliances and elastics had cone-beam computed tomographs taken before and after treatment. Three-dimensional models were generated from the cone-beam computed tomography images, registered on the anterior cranial bases, and analyzed using color maps and point-to-point measurements.
There were minimal differences in treatment response between the 2 Herbst groups across all skeletal parameters measured. The Herbst subjects showed a greater inferior displacement of anterior nasal spine compared with the Class II controls (Herbst brachyfacial, −1.44 mm; Herbst mesofacial, −1.95 mm) with other maxillary changes being clinically insignificant. The Herbst subjects showed greater inferior displacement of B-point compared with the Class II controls (Herbst brachyfacial, −2.59 mm; Herbst mesofacial, −2.75 mm). There were no statistically significant differences in mean linear mandibular measurements. All groups showed a trend toward posterior displacement of the condyles and glenoid fossae from the start to the end of treatment, with no significant differences across the 3 groups. There were minimal differences in the changes in gonial angle and Frankfort mandibular plane angle across all groups.
Approximately 2 years after Herbst treatment, the Herbst subjects with different vertical facial patterns showed similar patterns of skeletal change compared with the Class II controls treated with elastics.
•Three-dimensional data allow accurate evaluation of skeletal changes with the Herbst appliance.•Differences in vertical facial pattern are proposed to modify treatment response.•Minimal differences in maxillary change were found in the Herbst groups vs the control.•Minimal differences in fossa remodeling were found in the Herbst groups vs the control.•Minimal differences in mandibular change were found in the Herbst groups vs the control.
TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF ...exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents.
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