Sulfur-Mediated Decarboxylative Amidation of Cinnamic Acids via C═C Bond Cleavage.

A new strategy for the synthesis of amides has been developed using sulfur-mediated decarboxylative coupling of cinnamic acids with amines via oxidative cleavage of the C═C bond.

Late-Stage Pancreatic Cancer Detected During High-Risk Individual Surveillance: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Identification and resection of successful targets, that is, T1 N0M0 pancreatic ductal adenocarcinoma (PDAC) and high-grade precursors during surveillance of high-risk individuals (HRIs) confers improved survival. Late-stage PDACs refer to T2-4 N0M0 and nodal or distant metastatic PDAC stages diagnosed during the follow-up phase of HRI surveillance. This study aimed to quantify late-stage PDACs during HRI surveillance and identify associated clinicoradiologic factors. METHODS: A systematic search (PROSPERO:CRD42018117189) from Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science was last performed on April 18, 2021. Only original HRI surveillance manuscripts that specified follow-up strategies were included, and studies with only baseline information were excluded. Cumulative incidences of advanced neoplasia: high-grade precursors and all PDACs, and surveillance-detected/interval late-stage PDACs were calculated through random-effects model. Incidence of late-stage PDACs underwent metaregression to identify association with HRI clinicoradiologic features. Publication bias was assessed through the funnel plot and Egger's regression line. RESULTS: Thirteen original surveillance studies included 2169 HRIs followed over 7302.72 patient-years. Cumulative incidence of advanced neoplasia and late-stage PDACs was 3.3 (95% confidence interval [CI]: 0.6-7.4) and 1.7 (95% CI: 0.2-4.0) per 1000 patient-years, respectively. Late-stage PDACs lacked significant association with surveillance imaging, baseline pancreatic morphology, study location, genetic background, gender, or age. Limited information on diagnostic error, symptoms, timing of presentation, lesion site, and surveillance adherence precluded formal meta-analysis. CONCLUSION: A sizeable proportion of late-stage PDACs were detected during follow-up. Their incidence lacked association with baseline clinicoradiologic features. Further causal investigation of stage-based outcomes is warranted for overall improvement in HRI surveillance.

Benefit of Extended Surveillance of Low-Risk Pancreatic Cysts After 5-Year Stability: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) lacking worrisome features (WF) and high-risk stigmata (HRS) warrant surveillance. However, their optimal duration, especially among cysts with initial 5 years of size stability, warrants further investigation. We systematically reviewed the surveillance of low-risk BD-IPMNs and investigated the incidence of WF/HRS and advanced neoplasia, high-grade dysplasia, and pancreatic cancer during the initial (<5 years) and extended surveillance period (>5-years). METHODS: A systematic search (CRD42020117120) identified studies investigating long-term IPMN surveillance outcomes of low-risk IPMN among the Cochrane Library, Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, from inception until July 9, 2021. The outcomes included the incidence of WF/HRS and advanced neoplasia, disease-specific mortality, and surveillance-related harm (expressed as percentage per patient-years). The meta-analysis relied on time-to-event plots and used a random-effects model. RESULTS: Forty-one eligible studies underwent systematic review, and 18 studies were meta-analyzed. The pooled incidence of WF/HRS among low-risk BD-IPMNs during initial and extended surveillance was 2.2% (95% CI, 1.0%-3.7%) and 2.9% (95% CI, 1.0%-5.7%) patient-years, respectively, whereas the incidence of advanced neoplasia was 0.6% (95% CI, 0.2%-1.00%) and 1.0% (95% CI, 0.6%-1.5%) patient-years, respectively. The pooled incidence of disease-specific mortality during initial and extended surveillance was 0.3% (95% CI, 0.1%-0.6%) and 0.6% (95% CI, 0.0%-1.6%) patient-years, respectively. Among BD-IPMNs with initial size stability, extended surveillance had a WF/HRS and advanced neoplasia incidence of 1.9% (95% CI, 1.2%-2.8%) and 0.2% (95% CI, 0.1%-0.5%) patient-years, respectively. CONCLUSIONS: A lower incidence of advanced neoplasia during extended surveillance among low-risk, stable-sized BD-IPMNs was a key finding of this study. However, the survival benefit of surveillance among this population warrants further exploration through high-quality studies before recommending surveillance cessation with certainty.

Early Detection of Cancers in the Era of Precision Oncology.

PURPOSE OF REVIEW: The increasing global incidence of cancer demands innovative cancer detection modalities. The current population-based early cancer detection approaches focus on several major types of cancers (breast, prostate, cervical, lung and colon) at their early stages, however, they generally do not target high-risk individuals at precancerous stages. RECENT FINDINGS: Some cancers, such as pancreatic cancer, are challenging to detect in their early stages. Therefore, there is a pressing need for improved, accessible, noninvasive, and cost-effective early detection methods. Harnessing cell-free-based biomarker-driven strategies paves a new era of precision diagnosis for multicancer early detection. The majority of these tests are in the early stages and expensive, but these approaches are expected to become cost sensitive in the near future. SUMMARY: This review provides an overview of early cancer detection strategies, highlighting the methods, challenges, and issues to be addressed to revolutionize and improve global early cancer detection.

Copper-Catalyzed Thiolation of Hydrazones with Sodium Sulfinates: A Straightforward Synthesis of Benzylic Thioethers.

A facile and sustainable protocol for the thiolation of hydrazones with sodium sulfinates has been developed in the presence of CuBr2 and DBU in DMF to afford diverse benzylic thioethers. Control experiments reveal a radical pathway involving a thiyl radical as a key intermediate.

Easy access to α-carbonyl sulfones using cross-coupling of α-aryl-α-diazoesters with sulfonyl hydrazides.

A facile synthesis of α-carbonyl sulfones has been accomplished by the cross-coupling of α-aryl-α-diazoesters with sulfonyl hydrazides in the presence of CuI and DBU. The reaction employs inexpensive and bench stable sulfonyl hydrazides as a sulfonyl source, and facilitates the migratory insertion with α-aryl-α-diazoesters under mild reaction conditions.

A Comparison of Home Health Utilization, Outcomes, and Cost Between Medicare Advantage and Traditional Medicare.

BACKGROUND: Home health use is rising rapidly in the United States as the population ages, the prevalence of chronic disease increases, and older Americans express their desire to age at home. Enrollment in Medicare Advantage (MA) plans rather than Traditional Medicare (TM) has grown as well, from 13% of total Medicare enrollment in 2004 to 39% in 2020. Despite these shifts, little is known about outcomes and costs following home health in MA as compared with TM. OBJECTIVE: The objective of this study was to measure the association of MA enrollment with outcomes and costs for patients using home health. DESIGN: This was a retrospective cohort study. PARTICIPANTS: Patients enrolled in plans offered by 1 large, national MA organization and patients enrolled in TM, with at least 1 home health visit between January 1, 2017, and June 30, 2018. EXPOSURE: MA enrollment. MAIN MEASURES: We compared the intensity of home health services and types of care delivered. The main outcome measures were hospitalization, the proportion of days in the home, and total allowed costs during the 180-day period following the first qualifying home health visit during the study period. KEY RESULTS: Among patients who used home health, our models demonstrated enrollment in MA was associated with 14%, and 6% decreased odds of 60- and 180-day hospitalization, respectively, a 12.8% and 14.7% decrease in medical costs exclusive and inclusive of home health costs, respectively, and a 0.27% increase in the proportion of days at home during the 180-day follow-up, equivalent to an additional half-day at home. There were few differences in home health care delivered for MA and TM [mean number of visits in the first episode of care (17.1 vs. 17.3) and mean visits per week (3.2 vs. 3.3)]. The mean number of visits by visit type and percent of patients with each type was similar between MA and TM as well. CONCLUSIONS: Compared with enrollment in TM, enrollment in MA was associated with improved patient-centered outcomes and lower cost and utilization, despite few differences in the way home health was delivered. These findings might be explained by structural components of MA that encourage better care management, but further investigation is needed to clarify the mechanisms by which MA enrollment may lead to higher value home health care.

Quantitative assessment of the immune microenvironment in African American Triple Negative Breast Cancer: a case-control study.

PURPOSE: Triple negative breast cancer (TNBC) is more common in African American (AA) than Non-AA (NAA) population. We hypothesize that tumor microenvironment (TME) contributes to this disparity. Here, we use multiplex quantitative immunofluorescence to characterize the expression of immunologic biomarkers in the TME in both populations. PATIENTS AND METHODS: TNBC tumor resection specimen tissues from a 100-patient case: control cohort including 49 AA and 51 NAA were collected. TME markers including CD45, CD14, CD68, CD206, CD4, CD8, CD20, CD3, Ki67, GzB, Thy1, FAP, aSMA, CD34, Col4, VWF and PD-L1 we quantitatively assessed in every field of view. Mean expression levels were compared between cases and controls. RESULTS: Although no significant differences were detected in individual lymphoid and myeloid markers, we found that infiltration with CD45+ immune cells (p = 0.0102) was higher in TNBC in AA population. AA TNBC tumors also had significantly higher level of lymphocytic infiltration defined as CD45+ CD14- cells (p = 0.0081). CD3+ T-cells in AA tumors expressed significantly higher levels of Ki67 (0.0066) compared to NAAs, indicating that a higher percentage of AA tumors contained activated T-cells. All other biomarkers showed no significant differences between the AA and NAA group. CONCLUSIONS: While the TME in TNBC is rich in immune cells in both racial groups, there is a numerical increase in lymphoid infiltration in AA compared to NAA TNBC. Significantly, higher activated T cells seen in AA patients raises the possibility that there may be a subset of AA patients with improved response to immunotherapy.

Advances in microfluidic in vitro systems for neurological disease modeling.

Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to "Organ-on-chip" models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and "Organ-on-chip" systems have enabled new understanding of metabolic coupling and blood-brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from "Organ-on-chip" to "Disease-on-chip." This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases.

Iodine-catalyzed thioallylation of indoles using Bunte salts prepared from Baylis-Hillman bromides.

Metal-free iodine-catalyzed regioselective thioallylation of indoles has been accomplished at room temperature using Bunte salts prepared from Baylis-Hillman bromides. The resulting multi-functional C3 thioallylated indoles exhibit ample structural diversity and good functional group tolerance.

Synthesis of 3-acylindoles via copper-mediated oxidative decarbethoxylation of ethyl arylacetates.

An efficient regioselective C-3 acylation of free indoles (N-H) has been accomplished via oxidative decarbethoxylation of easily available ethyl arylacetates using Cu(OAc)2 and KOtBu in DMSO.

Diminished Cortical Thickness Is Associated with Impulsive Choice in Adolescence.

Adolescence is characterized by both maturation of brain structure and increased risk of negative outcomes from behaviors associated with impulsive decision-making. One important index of impulsive choice is delay discounting (DD), which measures the tendency to prefer smaller rewards available soon over larger rewards delivered after a delay. However, it remains largely unknown how individual differences in structural brain development may be associated with impulsive choice during adolescence. Leveraging a unique large sample of 427 human youths (208 males and 219 females) imaged as part of the Philadelphia Neurodevelopmental Cohort, we examined associations between delay discounting and cortical thickness within structural covariance networks. These structural networks were derived using non-negative matrix factorization, an advanced multivariate technique for dimensionality reduction, and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear developmental effects. We found that impulsive choice, as measured by greater discounting, was most strongly associated with diminished cortical thickness in structural brain networks that encompassed the ventromedial prefrontal cortex, orbitofrontal cortex, temporal pole, and temporoparietal junction. Furthermore, structural brain networks predicted DD above and beyond cognitive performance. Together, these results suggest that reduced cortical thickness in regions known to be involved in value-based decision-making is a marker of impulsive choice during the critical period of adolescence.SIGNIFICANCE STATEMENT Risky behaviors during adolescence, such as initiation of substance use or reckless driving, are a major source of morbidity and mortality. In this study, we present evidence from a large sample of youths that diminished cortical thickness in specific structural brain networks is associated with impulsive choice. Notably, the strongest association between impulsive choice and brain structure was seen in regions implicated in value-based decision-making; namely, the ventromedial prefrontal and orbitofrontal cortices. Moving forward, such neuroanatomical markers of impulsivity may aid in the development of personalized interventions targeted to reduce risk of negative outcomes resulting from impulsivity during adolescence.

A phase 1 trial of the oral DNA methyltransferase inhibitor CC-486 and the histone deacetylase inhibitor romidepsin in advanced solid tumors.

BACKGROUND: Epigenetic abnormalities are manifold in all solid tumors and include changes in chromatin configuration and DNA methylation. The authors designed a phase 1 study to evaluate the oral DNA methyltransferase inhibitor CC-486 combined with the histone deacetylase inhibitor romidepsin in advanced solid tumors with dose expansion to further evaluate pharmacodynamics and possible clinical benefit of the recommended phase 2 dose (RP2D). METHODS: This was a phase 1 study with a 3 + 3 dose-escalation design and an expansion phase for patients with virally mediated cancers. The disease control rate (DCR) was the primary outcome for the expansion cohort. Correlative studies included long interspersed nucleotide element 1 (LINE-1) methylation and drug exposure in blood samples (clinicaltrials.gov identifier NCT01537744). RESULTS: Fourteen patients were enrolled in the dose-escalation portion at 3 dose levels. Three patients experienced dose-limiting toxicities; the RP2D was oral CC-486 300 mg daily on days 1 through 14 and romidepsin 8 mg/m2 on days 8 and 15. Because of slow accrual into the expansion phase, the trial was closed after 4 patients enrolled. Common toxicities of the combination included nausea (83.3%), anorexia (72.2%), fatigue (61.1%), and constipation (55.6%). There were 12 patients evaluable for response, 5 with stable disease, of whom 2 received >4 cycles; there were no responses. Exposure to CC-486 and romidepsin was consistent with prior data. LINE-1 methylation on C1D8 was significantly reduced (mean, -6.23; 95% CI, -12.23, -0.24; P = .04). CONCLUSIONS: Although, at the RP2D, the combination of CC-486 and romidepsin was tolerable, no significant anticancer activity was observed. Significant demethylation in post-treatment circulating tumor DNA and biopsies provided proof of target acquisition.

Cu-Catalysed oxidative amidation of cinnamic acids/arylacetic acids with 2° amines: an efficient synthesis of α-ketoamides.

A new and convenient copper-catalysed synthesis of α-ketoamides has been accomplished using readily available cinnamic acids/arylacetic acids and 2° amines in an open atmosphere. The reaction between cinnamic acid and amine involves the formation of enamine followed by its aerobic oxidation, whereas the reaction of arylacetic acid with amine involves amide formation followed by benzylic methylene oxidation.

Epigenetic Therapeutics: A New Weapon in the War Against Cancer.

The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.

NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability.

The tumor protein 53 (TP53) tumor suppressor gene is the most frequently somatically altered gene in human cancers. Here we show expression of N-Myc down-regulated gene 1 (NDRG1) is induced by p53 during physiologic low proliferative states, and mediates centrosome homeostasis, thus maintaining genome stability. When placed in physiologic low-proliferating conditions, human TP53 null cells fail to increase expression of NDRG1 compared with isogenic wild-type controls and TP53 R248W knockin cells. Overexpression and RNA interference studies demonstrate that NDRG1 regulates centrosome number and amplification. Mechanistically, NDRG1 physically associates with γ-tubulin, a key component of the centrosome, with reduced association in p53 null cells. Strikingly, TP53 homozygous loss was mutually exclusive of NDRG1 overexpression in over 96% of human cancers, supporting the broad applicability of these results. Our study elucidates a mechanism of how TP53 loss leads to abnormal centrosome numbers and genomic instability mediated by NDRG1.

Histological Features of Methylene Blue-Induced Phototoxicity Administered in the Context of Parathyroid Surgery.

Methylene blue is a chromophore dye known for its photosensitizing properties. It is also administered intravenously as a tracer in parathyroid surgery to identify abnormal glands. We describe 2 cases of acute methylene blue-induced phototoxicity in patients who underwent parathyroidectomy. Both patients developed an acute vesiculopustular inflammatory rash on the anterior neck corresponding to the site exposed intraoperatively to overhanging surgical lights. One of the patients also developed a bulla on her finger at the site of attachment of the oxygen probe. Biopsies were taken from both patients at different time points. The histological findings included destruction of sebaceous glands and deposition of diastase-periodic acid-Schiff-positive hyaline material around dermal blood vessels. These features are similar to those seen in skin treated with photodynamic therapy and systemic photosensitivity disorders such as the porphyrias. The wavelengths of light emitted by the surgical lights and oxygen probe overlap with the absorption spectrum of methylene blue. This resulted in excitation of the systemically administered methylene blue at exposed sites, with resultant local tissue damage and a phototoxic reaction.

The role of death-associated protein 3 in apoptosis, anoikis and human cancer.

Death-associated protein 3 (DAP3) is a molecule with a significant role in the control of both apoptosis and anoikis. Apoptosis is the predominant type of programmed cell death (PCD) which may occur in response to irreparable damage to DNA, or in response to induction by inflammatory cells. Anoikis is subset of apoptosis which occurs in epithelial cells in response to detachment from the surrounding matrix. Both apoptosis and anoikis are of interest in the context of carcinogenesis. In this review, we shall discuss apoptosis and anoikis, and the recent literature regarding the role of DAP3 in both these pathways.

Enabling nanomaterial, nanofabrication and cellular technologies for nanoneuromedicines.

Nanoparticulate delivery systems represent an area of particular promise for nanoneuromedicines. They possess significant potential for desperately needed therapies designed to combat a range of disorders associated with aging. As such, the field was selected as the focus for the 2014 meeting of the American Society for Nanomedicine. Regenerative, protective, immune modulatory, anti-microbial and anti-inflammatory products, or imaging agents are readily encapsulated in or conjugated to nanoparticles and as such facilitate the delivery of drug payloads to specific action sites across the blood-brain barrier. Diagnostic imaging serves to precisely monitor disease onset and progression while neural stem cell replacement can regenerate damaged tissue through control of stem cell fates. These, taken together, can improve disease burden and limit systemic toxicities. Such enabling technologies serve to protect the nervous system against a broad range of degenerative, traumatic, metabolic, infectious and immune disorders. From the clinical editor: Nanoneuromedicine is a branch of nanomedicine that specifically looks at the nervous system. In the clinical setting, a fundamental hurdle in nervous system disorders is due to an inherent inability of nerve cells to regenerate after damage. Nanotechnology can offer new approaches to overcome these challenges. This review describes recent developments in nanomedicine delivery systems that would affect stem cell repair and regeneration in the nervous system.

Effect of Pore Size and Film Thickness on Gold-Coated Nanoporous Anodic Aluminum Oxide Substrates for Surface-Enhanced Raman Scattering Sensor.

A sensitive surface enhanced Raman scattering chemical sensor is demonstrated by using inexpensive gold-coated nanoporous anodic aluminum oxide substrates. To optimize the performance of the substrates for sensing by the Surface-enhanced Raman scattering (SERS) technique, the size of the nanopores is varied from 18 nm to 150 nm and the gold film thickness is varied from 30 nm to 120 nm. The sensitivity of gold-coated nanoporous surface enhanced Raman scattering sensor is characterized by detecting low concentrations of Rhodamine 6G laser dye molecules. The morphology of the SERS substrates is characterized by atomic force microscopy. Optical properties of the nanoporous SERS substrates including transmittance, reflectance, and absorbance are also investigated. Relative signal enhancement is plotted for a range of substrate parameters and a detection limit of 10(-6) M is established.