Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.
Whole-exome sequencing ...was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.
Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.
The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.
•In NSCLC, overall response rate to single-agent chemotherapy after anti-PD1 failure was 39%.•Eleven out of 28 patients achieved a response (8 confirmed, 3 unconfirmed).•Responses approached those ...from first-line chemotherapy and compare favorably to historical control in this setting.•Further investigation on timing of chemotherapy with immunotherapy is warranted.
Exploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in overall response rate (ORR) to chemotherapy after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if single-agent chemotherapy (3rd-line or beyond) would yield improved ORR when given after exposure to programmed death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer (NSCLC).
We queried the Thoracic GEMINI database of MD Anderson Cancer Center for patients treated between 06/12 and 11/16 who received at least one single-agent chemotherapy as 3rd-line or beyond, following progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy outcomes to each therapy, including ORR by RECIST version 1.1, progression-free survival (PFS), and overall survival (OS).
Out of 306 anti-PD1-treated patients registered in the database, 28 met eligibility criteria − 54% were male, median age was 66 years, 82% had adenocarcinoma, and 71% were former/current smokers. The anti-PD1 and single-agent chemotherapy most commonly used were nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis was the only factor associated with response to single-agent chemotherapy on univariate analysis (p<0.05).
In NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line platinum-based chemotherapy. Further investigation of a possible immunotherapy-induced chemosensitization effect is warranted.
The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.
For patients identified before hospital arrival with ST-segment-elevation myocardial infarction, bypassing the emergency department (ED) with direct transport to the catheterization laboratory may ...shorten reperfusion times.
We studied 12 581 ST-segment-elevation myocardial infarction patients identified with a prehospital ECG treated at 371 primary percutaneous coronary intervention-capable US hospitals participating in the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines, including those participating in the American Heart Association Mission: Lifeline program from 2008 to 2011. Reperfusion times with primary percutaneous coronary intervention and in-hospital mortality rates were compared between patients undergoing ED evaluation and those bypassing the ED. ED bypass occurred in 1316 patients (10.5%). These patients had a lower frequency of heart failure and shock on presentation and nonsystem reasons for delay in percutaneous coronary intervention. ED bypass occurred more frequently during working hours compared with off-hours (18.3% versus 4.3%); ED bypass rate varied significantly across hospitals (median, 3.3%; range, 0%-71%). First medical contact to device activation time was shorter (median, 68 minutes interquartile range, 54-85 minutes versus 88 minutes interquartile range, 73-106 minutes; P<0.0001) and achieved within 90 minutes more frequently (80.7% versus 53.7%; P<0.0001) with ED bypass. The unadjusted in-hospital mortality rate was lower among ED bypass patients (2.7% versus 4.1%; P=0.01), but the adjusted mortality risk was similar (adjusted odds ratio, 0.69; 95% confidence interval, 0.45-1.03; P=0.07).
Among ST-segment-elevation myocardial infarction patients identified with a prehospital ECG, the rate of ED bypass varied significantly across US hospitals, but ED bypass occurred infrequently and was mostly isolated to working hours. Because ED bypass was associated with shorter reperfusion times and numerically lower mortality rates, further exploration of and advocacy for the implementation of this process appear warranted.
Dissolved organic matter (DOM) is not only a vector for the migration of aquatic environmental pollutants, but is also key to the control of water pollution. Economic and effective DOM removal ...through coagulation is essential in water treatment processes. This work investigated the role of carboxylated magnetic metal organic frameworks (MMOFs) nanoparticles in polymeric iron-based coagulation for the removal of aquatic DOM using a MMOFs-doped polyferric iron-based coagulant (MMOF-PIC). Analytical methodologies and tools used in this research included scanning electron microscopy (SEM), zeta potential, molecular weight cut off (MWCO), vibrating sample magnetometer (VSM) measurement, excitation emission matrix spectroscopy (EEMs), and X-ray photoelectron spectroscopy (XPS). The results showed that MMOF-PIC had the potential to change the structure of the polyferric iron-based coagulant (PIC) and charge, as determined by a porous surface morphology, a higher medium polymeric species distribution, and a more positive zeta potential. The MMOFs consequently enhanced PIC action on the removal of UV254 exposed DOM species with molecular weight <30 kDa, including aromatic CC based compounds, org-N as primary amines and amide/peptide bound species, water containing microbial metabolites and protein-like materials. The coagulation of DOM was enhanced by improving charge neutralization, adsorption-bridging and sweep-flocculation in the presence of MMOFs nanoparticles. This was due to hydrogen bonds, π-π bonds and covalent bonds resulting from actions of nanoparticles and pollutants. These results indicate that magnetic MOF nanoparticles can improve PIC coagulation for DOM, enhancing future removal of target pollutants.
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•Carboxyl magnetic MOFs (MMOFs) doped polymeric-iron was prepared.•MMOFs and PIC coexisting in the same system can enhance coagulation for DOM.•MMOFs changed PIC’s structure, charge and adsorption properties.•Chemical bond binding force contributed to enhanced adsorption.
Norepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in ...part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRABNE) sensors with a 230% peak ΔF/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRABNE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.
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•GRABNE sensors are genetically encoded GPCR activation-based norepinephrine sensors•GRABNE distinguishes norepinephrine from dopamine with 1,000-fold specificity•The norepinephrine measurements are sensitive, with high spatiotemporal resolution•Norepinephrine dynamics are observed during stressful behaviors in zebrafish and mice
Feng et al. develop and validate a pair of genetically encoded GPCR-activation-based norepinephrine sensors, which, for the first time, enable specific in vivo measurement of norepinephrine dynamics during stressful behaviors with high spatiotemporal resolution in zebrafish and mice.
Abstract Background Antithrombotic therapy for acute myocardial infarction (MI) with atrial fibrillation (AF) among higher risk older patients treated with percutaneous coronary intervention (PCI) ...remains unclear. Objectives This study sought to determine appropriate antithrombotic therapy for acute MI patients with AF treated with PCI. Methods We examined 4,959 patients ≥65 years of age with acute MI and AF who underwent coronary stenting (Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines). The primary effectiveness outcome was 2-year major adverse cardiac events (MACE) comprising death, readmission for MI, or stroke; the primary safety outcome was bleeding readmission. Outcomes with dual antiplatelet therapy (DAPT) or triple therapy (DAPT plus warfarin) were compared using Cox proportional hazard modeling with inverse probability-weighted propensity adjustment. Results Among 4,959 patients, 27.6% (n = 1,370) were discharged on triple therapy. Relative to DAPT, patients on triple therapy had a similar risk of MACE (adjusted hazard ratio HR: 0.99 95% confidence interval (CI): 0.86 to 1.16) but significantly greater risk of bleeding requiring hospitalization (adjusted HR: 1.61 95% CI: 1.31 to 1.97) and greater risk of intracranial hemorrhage (adjusted HR: 2.04 95% CI: 1.25 to 3.34). Of 1,591 Medicare Part D patients, 90-day post-discharge warfarin persistence among patients discharged on warfarin was 93.2% (n = 412). Results of 90-day landmark analyses comparing triple therapy versus DAPT in patients persistently on warfarin versus those not discharged on warfarin who had not filled a warfarin prescription were similar to our primary findings. Conclusions Approximately 1 in 4 older AF patients undergoing PCI for MI were discharged on triple therapy. Those receiving triple therapy versus DAPT had higher rates of major bleeding without a measurable difference in composite MI, death, or stroke.
Background Angiotensin II stimulates epithelial Na
channel (ENaC) by aldosterone-independent mechanism. We now test the effect of angiotensin II on ENaC in the distal convoluted tubule (DCT) and ...cortical collecting duct (CCD) of wild-type (WT) and kidney-specific mineralocorticoid receptor knockout mice (KS-MR-KO). Methods and Results We used electrophysiological, immunoblotting and renal-clearance methods to examine the effect of angiotensin II on ENaC in KS-MR-KO and wild-type mice. High K
intake stimulated ENaC in the late DCT/early connecting tubule (DCT2/CNT) and in the CCD whereas low sodium intake stimulated ENaC in the CCD but not in the DCT2/CNT. The deletion of MR abolished the stimulatory effect of high K
and low sodium intake on ENaC, partially inhibited ENaC in DCT2/CNT but almost abolished ENaC activity in the CCD. Application of losartan inhibited ENaC only in DCT2/CNT of both wild-type and KS-MR-KO mice but not in the CCD. Angiotensin II infusion for 3 days has a larger stimulatory effect on ENaC in the DCT2/CNT than in the CCD. Three lines of evidence indicate that angiotensin II can stimulate ENaC by MR-independent mechanism: (1) angiotensin II perfusion augmented ENaC expression in KS-MR-KO mice; (2) angiotensin II stimulated ENaC in the DCT2/CNT but to a lesser degree in the CCD in KS-MR-KO mice; (3) angiotensin II infusion augmented benzamil-induced natriuresis, increased the renal K
excretion and corrected hyperkalemia of KS-MR-KO mice. Conclusions Angiotensin II-induced stimulation of ENaC occurs mainly in the DCT2/CNT and to a lesser degree in the CCD and MR plays a dominant role in determining ENaC activity in the CCD but to a lesser degree in the DCT2/CNT.
Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor ...microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
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