Cancer-Associated Fibroblasts Induce Proliferation and Therapeutic Resistance to Everolimus in Neuroendocrine Tumors through STAT3 Activation.

INTRODUCTION: Cancer-associated fibroblasts (CAF) have been identified as relevant contributors to cancer progression and drug resistance in many tumors. Although neuroendocrine tumors (NET) are often associated with a strong stromal reaction, no study has addressed whether CAF are involved in progression and therapeutic resistance in NET. The aim of this study was to characterize the role of CAF in NET. METHODS: We established primary CAF cultures derived from NET liver metastases to study the effect on NET cell lines NT-3 and BON. Immunohistochemistry was performed on tissue sections of primary and metastatic NET tissue. RESULTS: Immunohistochemistry identified CAF dispersed in between tumor cells and within fibrotic bands separating tumor cell clusters in NET. Stimulating NET cells with CAF decreased expression of SSTR2 and chromogranin A and induced expression of CXCR4. CAF induced a 2.3-fold increase in proliferation and completely reversed the response to everolimus in NT-3 cells. We identified STAT3 as the main signaling pathway induced by CAF. STAT3 targeting by small interfering RNA knockdown and inhibitors prevented CAF-induced proliferation and restored everolimus responsiveness. STAT3 activation in NET tissue was associated with decreased chromogranin A expression, increased Ki-67 index, and decreased 5-year overall and progression-free survival. CAF directly influence proliferation and therapeutic response in NET cells. CONCLUSION: Identifying STAT3 as the contributing pathway of this so far neglected tumor-stroma interaction has the potential to become a new therapeutic target to halt tumor growth and to restore therapeutic responsiveness in NET.

How a GI Fellow Found a Following: Harnessing the Power of Social Media for Education and Fun.

Over the past fifteen years, social media has become a central part of nearly all aspects of society, including the broad field of healthcare. Over the past two years, I (the author) have created a social media platform on which I have produced video content that educates and entertains about numerous issues in healthcare and medicine. These videos have gained popularity, enabling me to develop a following of over 1 million people. With this social media platform, I have been able to educate both patients and medical trainees, dispel medical misinformation, and display a more human side of physicians in order to help patients and other healthcare workers gain a new, positive perspective on healthcare. Since users of social media typically have a limited attention span, education using social media can be challenging, though it can also be empowering since its reach can be far more extensive than what physicians typically experience in a clinical setting. Since the growing presence of social media can no longer be ignored by physicians and other healthcare professionals, it is imperative that it is understood as the powerful tool that it is for patient education and wellness.

Combined Use of Aspirin and Statin is Associated With a Decreased Incidence of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related mortality worldwide. Studies have suggested that aspirin (ASA) and statins may be associated with a decrease in incident HCC. GOALS: We aimed to evaluate the effect of ASA and statin use on the incidence of HCC in a prospective cohort of patients with liver cirrhosis and to identify if there was an increased risk of esophageal variceal hemorrhage (VH) in patients with ASA use. STUDY: We conducted a retrospective study of 521 patients with data collected from July 1, 2012 to December 31, 2017. We used competing risk analysis to assess the association between risk factors and HCC; and the association between ASA and VH. RESULTS: ASA use alone was associated with a decreased incidence of HCC in the univariate and multivariate models; [hazard ratio (HR) confidence interval (CI): 0.348 (0.124-0.976); P=0.0448] and [HR (CI): 0.266 (0.094-0.755); P=0.0129, respectively]. The combination of ASA and statin use was associated with a decreased hazard of HCC [HR (CI): 0.15 (0.036-0.624); P=0.0090] and this remained statistically significant in the multivariable model [HR (CI): 0.113 (0.026-0.483); P=0.0033]. Among daily ASA users compared with non-users, there was not a significant increase in risk of VH. CONCLUSIONS: Daily ASA use was associated with a decrease risk of incident HCC. The combination of daily ASA use and statin use decreased the risk of incident HCC suggesting there is beneficial interaction. Finally, no excess VH was observed in daily ASA users compared with non-users.

Characterizing round spheres using half-geodesics.

A half-geodesic is a closed geodesic realizing the distance between any pair of its points. All geodesics in a round sphere are half-geodesics. Conversely, this paper establishes that Riemannian spheres with all geodesics closed and sufficiently many half-geodesics are round.

Ultrasonic-Assisted Solid-Phase Peptide Synthesis of DOTA-TATE and DOTA-linker-TATE Derivatives as a Simple and Low-Cost Method for the Facile Synthesis of Chelator-Peptide Conjugates.

Peptides have been widely adopted as biological targeting vectors for applications in molecular imaging and peptide-receptor radionuclide therapy (PRRT). Somatostatin (SST) analogues such as octreotate (TATE) are exogenous ligands for somatostatin receptors (SSTRs), which are highly expressed on neuroendocrine tumors (NETs). Recently, both [68Ga]Ga-DOTA-TATE (NETSPOT) and [177Lu]Lu-DOTA-TATE (LUTATHERA) received U.S. Food and Drug Administration approval for positron emission tomography (PET) imaging and PRRT of NETs, respectively. However, to the best of our knowledge a well-described synthesis of DOTA-TATE has not been reported in the literature. Herein, we report a fully reoptimized DOTA-TATE synthesis, including the application of a simple ultrasonic bath to greatly improve yields, reduce coupling times, and decrease the amount of reagents required for each coupling step by a half. The most prevalently used cyclizing agents such as iodine, thallium(III) trifluoroacetate, hydrogen peroxide, and dimethyl sulfoxide were compared. On-resin cyclizations using mechanical agitation showed higher yields (23% and 25% using I2 and Tl(III), respectively) than off-resin (1.3% and 11% using DMSO and H2O2, respectively), and the total synthesis time of DOTA-TATE was ∼540 min excluding the cyclization step, with a total synthesis yield of ∼23%. The same manual SPPS methods/reagents were reoptimized with ultrasonic (US) agitation, resulting in an immense reduction in the total synthesis time by ∼8-fold to ∼70 min for DOTA-TATE with a higher yield (∼29% yield), and ∼13-fold to 105 min for DOTA-PEG4-TATE (∼29% yield). Also, the use of US agitation reduces the need for excess molar equivalents of the reagents to a half, which is particularly important when coupling expensive or custom-synthesized groups such as bifunctional chelators and linkers. Finally, the synthesized DOTA-TATE was successfully radiolabeled with [68Ga]Ga3+ (t1/2 = 68 min) with high radiochemical yields (30 min, 95 °C). We believe this work opens the door to the facile and low-cost synthesis of many new chelator-linker-peptide conjugates that were previously cumbersome or cost-prohibitive to produce with manual SPPS.

Incidence, Mortality, and Characteristics of 18 Pediatric Perioperative Cardiac Arrests: An Observational Trial From 22,650 Pediatric Anesthesias in a German Tertiary Care Hospital.

BACKGROUND: Recently, a very low incidence of 3 per 10,000 and a mortality of 30% were reported for pediatric perioperative cardiac arrest (POCA). However, high-risk patients, namely children already anesthetized on the intensive care unit (ICU), were excluded. This study investigates the incidence and mortality of POCA in children in whom anesthesia was induced in the ICU or in the operating room using real-world data. In addition, different classifications of POCA were compared with respect to outcome relevance. METHODS: This is a retrospective observational study conducted at a German level 1 perinatal center and tertiary care hospital between 2008 and 2018. Children ≤15 years who underwent an anesthetic procedure and suffered from POCA (defined as any condition requiring chest compressions and/or defibrillation) from the beginning of care provided by an anesthesiologist to 60 minutes after anesthesia or sedation were included. Primary end points were incidence and mortality of POCA in children with anesthesia induced in the ICU versus in the operating room. Secondary end points included incidences and outcomes with respect to the pathophysiological cause (respiratory versus circulatory associated). RESULTS: There were 18 POCA during 22,650 anesthetic procedures (incidence 7.9 per 10,000; 95% confidence interval [CI], 4.7-12.5). Thirty-day mortality was 3.5 per 10,000 (95% CI, 1.5-6.9). Incidence and mortality were higher in children in whom anesthesia was induced in the ICU versus in the operating room (incidence: 131.6; 95% CI, 57 to 257.6 versus 4.5; 95% CI, 2.2-8.3; P < .001; and mortality: 82.2; 95% CI, 26.7-190.8 versus 1.4; 95% CI, 0.3-3.9; P < .001). Mortality in circulatory-induced POCA (n = 8; 44%) was 100%, in respiratory-induced POCA (n = 9; 50%) 0% (P < .001). CONCLUSIONS: Children with anesthesia induction in the ICU represent a high-risk population for POCA and POCA-associated mortality. POCA classification should be based on the individual cause (respiratory versus circulatory) rather than on the perioperative phase or the responsible specialty.

In Situ Synthesis and Applications for Polyinterhalides Based on BrCl.

The use of neat BrCl in organic and inorganic chemistry is limited due to its gaseous aggregate state and especially its decomposition into Cl2 and Br2 . The stabilization of BrCl in form of reactive ionic liquids via a novel in situ synthesis route shifts this equilibrium drastically to the BrCl side, which leads to safer and easier-to-handle interhalogenation reagents. Furthermore, the crystalline derivatives of the hitherto unknown [Cl(BrCl)2 ]- and [Cl(BrCl)4 ]- anions were synthesized and characterized by single-crystal X-ray diffraction (XRD), Raman and IR spectroscopy, as well as quantum chemical calculations.

Polyhalogen and Polyinterhalogen Anions from Fluorine to Iodine.

This Review deals with the evolving field of polyhalogen chemistry, specifically polyhalogen anions (polyhalides). In addition to a historical outline, current progress in synthetic approaches towards the formation of polyfluorides, polychlorides, polybromides, and polyinterhalides is also illustrated. The structural diversity of polyhalides has substantially increased in the past decade, especially for polychlorides and polybromides, which are commonly characterized by single-crystal X-ray diffraction, Raman spectroscopy, and quantum-chemical calculations. Polyfluorides have been examined by sophisticated state-of-the-art quantum-chemical calculations and investigated spectroscopically in noble gas matrix-isolation experiments under cryogenic conditions at 4 K. The bonding in such polyhalide systems is also discussed. The last Section deals with applications of polyhalides in halogenation reactions and electrochemistry as well as their use as reactive ionic liquids, emphasizing the promising future of polyhalogen chemistry.

From Polyhalides to Polypseudohalides: Chemistry Based on Cyanogen Bromide.

Pseudohalogens are defined as molecular entities that resemble the halogens in their chemistry. While our understanding of polyhalogen chemistry has increased over the last years, research on polypseudohalogen compounds is lacking. The pseudohalogen BrCN possesses a highly pronounced σ-hole at the bromine side of the molecule, inducing strong halogen bonding. This allows the synthesis and characterization of new polypseudohalogen anions, as shown by the single-crystal X-ray diffraction of [PNP][Br(BrCN)] and [PNP][Br(BrCN)3 ]. Both the nearly linear anion [Br(BrCN)]- and the distorted pyramidal anion [Br(BrCN)3 ]- were characterized by Raman spectroscopy and quantum-chemical calculations. The behavior of the polypseudohalogen compounds in solution and as room-temperature ionic liquids (RT-ILs) using the [NBu4 ]+ cation was studied by 13 C and 15 N NMR spectroscopy. These types of ILs are capable of dissolving elemental gold and offer themselves as promising compounds in metal recycling.

Synthesis and Characterization of Nonclassical Interhalides Based on Bromine Monochloride.

Due to a more distinct σ-hole, BrCl is able to form stronger halogen bonds than those in polyhalogen anions based on Cl2 and Br2 . This stabilization allows the crystallographic characterization of a variety of new polyinterhalides, in which chloride functions as the central ion as shown by the molecular structures of [AsPh4 ][Cl(BrCl)3 ] and [CCl(NMe2 )2 ][Cl(BrCl)5 ]. Furthermore, the solid-state structure of an octahedrally coordinated nonclassical interhalide is reported for the first time. The tridecainterhalide monoanion [Cl(BrCl)6 ]- consists of a central chloride ion, which is coordinated by six BrCl molecules in a slightly distorted octahedral structure. All new compounds were characterized by single-crystal X-ray diffraction (XRD), NMR and Raman spectroscopy, as well as quantum-chemical calculations.

Timing of adding blood to prime affects inflammatory response to neonatal cardiopulmonary bypass.

Complications from systemic inflammation are reported in neonates following exposure to cardiopulmonary bypass. Although the use of asanguinous primes can reduce these complications, in neonates, this can result in significant haemodilution, requiring addition of blood. This study investigates whether the addition of blood after institution of bypass alters the inflammatory response compared with a blood prime. Neonatal swine were randomised into four groups: blood prime, blood after bypass but before cooling, blood after cooling but before low flow, and blood after re-warming. All groups were placed on central bypass, cooled, underwent low flow, and then re-warmed for a total bypass time of 2 hours. Although haematocrit values between groups varied throughout bypass, all groups ended with a similar value. Although they spent time with a lower haematocrit, asanguinous prime groups did not have elevated lactate levels at the end of bypass compared with blood prime. Asanguinous primes released less tumour necrosis factor α than blood primes (p=0.023). Asanguinous primes with blood added on bypass produced less interleukin 10 and tumour necrosis factor α (p=0.006, 0.019). Animals receiving blood while cool also showed less interleukin 10 and tumour necrosis factor α production than those that received blood warm (p=0.026, 0.033). Asanguinous primes exhibited less oedema than blood primes, with the least body weight gain noted in the end cool group (p=0.011). This study suggests that using an asanguinous prime for neonates being cooled to deep hypothermia is practical, and the later addition of blood reduces inflammation.

Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition.

A recent gene expression classification of hepatocellular carcinoma (HCC) includes a poor survival subclass termed S2 representing about one-third of all HCC in clinical series. S2 cells express E-cadherin and c-myc and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between S2 and non-S2 HCC, this study investigated whether molecular subclasses of HCC predict sensitivity to FGFR inhibition. S2 cell lines were significantly more sensitive (p < 0.001) to the FGFR inhibitors BGJ398 and AZD4547. BGJ398 decreased MAPK signaling in S2 but not in non-S2 cell lines. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 44% or more in all five S2 cell lines (p < 0.05 for each cell line), a significantly greater decrease than seen with knockdown of FGFR1-3 with siRNA transfection. FGFR4 knockdown decreased MAPK signaling in S2 cell lines, but little effect was seen with knockdown of FGFR1-3. In conclusion, the S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4-MAPK signaling plays an important role in driving proliferation of a molecular subclass of HCC. This classification system may help to identify those patients who are most likely to benefit from inhibition of this pathway.

Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC)-associated mortality is increasing at an alarming rate, and there is a readily identifiable cohort of at-risk patients with cirrhosis, viral hepatitis, nonalcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention because it is inexpensive, has a favorable safety profile, and is well tolerated over long time periods. METHODS: The authors studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, in which tumors develop in the setting of chronic inflammation and cirrhosis. Repeated injections of diethylnitrosamine were used to induce sequential cirrhosis and HCC, and metformin was administered at the first signs of either fibrosis or cirrhosis. RESULTS: Prolonged metformin exposure was safe and was associated with decreases in fibrotic and inflammatory markers, especially when administered early at the first signs of fibrosis. In addition, early metformin treatment led to a 44% decrease in HCC incidence, whereas tumor burden was unchanged when metformin was administered at the first signs of cirrhosis. It is noteworthy that activation of the hepatic progenitor/stem cell compartment was first observed at the onset of cirrhosis; therefore, only early metformin treatment suppressed receptor for advanced glycation end products and inhibited the activation of hepatic progenitor cells. CONCLUSIONS: The current results are the first to demonstrate an effect on progenitor/stem cells in the setting of chemoprevention and provide further rationale to explore metformin as an early intervention in clinical trials of patients with chronic liver disease at high risk for HCC.

The landscape of biomedical research.

The number of publications in biomedicine and life sciences has grown so much that it is difficult to keep track of new scientific works and to have an overview of the evolution of the field as a whole. Here, we present a two-dimensional (2D) map of the entire corpus of biomedical literature, based on the abstract texts of 21 million English articles from the PubMed database. To embed the abstracts into 2D, we used the large language model PubMedBERT, combined with t-SNE tailored to handle samples of this size. We used our map to study the emergence of the COVID-19 literature, the evolution of the neuroscience discipline, the uptake of machine learning, the distribution of gender imbalance in academic authorship, and the distribution of retracted paper mill articles. Furthermore, we present an interactive website that allows easy exploration and will enable further insights and facilitate future research.

Does gamma-glutamyltransferase correlate with liver tumor burden in neuroendocrine tumors?

PURPOSE: In patients with neuroendocrine tumors (NETs) and liver metastases, increased gamma-glutamyltransferase (GGT) is commonly assumed as an indicator for progressive disease. To date, however, empirical data are lacking. This study aimed to investigate associations between GGT and liver tumor burden. In longitudinal analyses, associations of GGT and radiographic responses of liver metastases under therapy were investigated. METHODS: The cross-sectional sample consisted of 104 patients who were treated at the University Medical Center Hamburg-Eppendorf from 2008 to 2021 (mean age 62.3 ± 12.6 years, 58.7% male). GGT and liver imaging were identified in a time range of 3 months. Radiologic reassessments were performed to estimate liver tumor burden. In a separate longitudinal sample (n = 15), the course of GGT levels under chemotherapy was analyzed. Data were retrospectively analyzed with a univariate ANOVA, linear regression analyses, and Wilcoxon tests. RESULTS: Of 104 cross-sectionally analyzed patients, 54 (51.9%) showed a GGT elevation. GGT levels and liver tumor burden were positively correlated (p < 0.001), independently from age, gender, primary tumor location, grading, and cholestasis. Notably, GGT increase was associated with a liver tumor burden of >50%. In the longitudinal sample, 10 of 11 patients with progressive disease showed increasing GGT, whereas 4 of 4 patients with regressive disease showed declining GGT. CONCLUSION: Our findings indicate that GGT is associated with liver tumor burden. Over the course of therapy, GGT appears to change in line with radiographic responses. Further longitudinal studies with larger sample sizes are required to define GGT as a reliable marker for tumor response.

Overcoming evasive resistance from vascular endothelial growth factor a inhibition in sarcomas by genetic or pharmacologic targeting of hypoxia-inducible factor 1α.

Increased levels of hypoxia and hypoxia-inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged antiangiogenic therapy of tumors not only delays tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene Set Enrichment Analysis of microarrays from pretreatment biopsies found that the Gene Ontology category "Response to hypoxia" was upregulated in poor responders and that the hierarchical clustering based on 140 hypoxia-responsive genes reliably separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. In four sarcoma cell lines, HIF-1α shRNA or Dox at low concentrations blocked HIF-1α induction of VEGF-A by 84-97% and carbonic anhydrase 9 by 83-93%. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 with HIF-1α shRNA or metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, at least in part via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α target genes that may promote resistance to antiangiogenic and other therapies. HIF-1α inhibition blocks this evasive resistance and augments destruction of the tumor vasculature.

Measurement of brain activation during an upright stepping reaction task using functional near-infrared spectroscopy.

Functional near-infrared spectroscopy (fNIRS) is a non-invasive brain imaging technology that uses light to measure changes in cortical hemoglobin concentrations. FNIRS measurements are recorded through fiber optic cables, which allow the participant to wear the fNIRS sensors while standing upright. Thus, fNIRS technology is well suited to study cortical brain activity during upright balance, stepping, and gait tasks. In this study, fNIRS was used to measure changes in brain activation from the frontal, motor, and premotor brain regions during an upright step task that required subjects to step laterally in response to visual cues that required executive function control. We hypothesized that cognitive processing during complex stepping cues would elicit brain activation of the frontal cortex in areas involved in cognition. Our results show increased prefrontal activation associated with the processing of the stepping cues. Moreover, these results demonstrate the potential to use fNIRS to investigate cognitive processing during cognitively demanding balance and gait studies.