Age-specific cancer mortality in the U.S. during the COVID-19 pandemic, March-December 2020.

BACKGROUND: It is important to understand the impact of the COVID-19 pandemic on cancer death rates in 2020 in the U.S. We estimated whether there were larger than expected changes in cancer mortality rates during March-December 2020 after accounting for temporal and seasonal patterns using data from January 2011-February 2020 by cancer type and age. METHODS: We obtained death counts and underlying cause of death by cancer type, month/year (2011-2020), and age group from the National Center for Health Statistics and population estimates from the Census Bureau. Poisson regression was used to test for significant changes in cancer death rates from March-December 2020 compared to prior years. RESULTS: After accounting for temporal trends and seasonal patterns, total cancer death rates were significantly lower than expected during March-December 2020 among 55-64-year-olds and ≥75-year-olds, but not in other age groups. Cancer death rates were 2% lower than expected from March-June among 55-64-year-olds, and 2-3% lower from March-July and December among ≥75-year-olds. Among ≥75-year-olds, colorectal cancer death rates were lower in March-June (RRs 0.94-0.96; p<0.05); however, lung cancer death rates were 5% lower across each month (all RRs 0.95, p<0.05). CONCLUSIONS: In the U.S., cancer death rates based on the underlying cause of death were broadly similar to expected rates during March-December 2020. However, cancer death rates were lower than expected among 55-64-year-olds and ≥75-year-olds, likely due to COVID-19 as a competing cause of death. IMPACT: Cancer mortality rates from 2020 should be interpreted with caution. .

Specific CaMKIIs mediate convergent extension cell movements in early zebrafish development.

BACKGROUND: Noncanonical Wnts are morphogens that can elevate intracellular Ca2+, activate the Ca2+/calmodulin-dependent protein kinase, CaMKII, and promote cell movements during vertebrate gastrulation. RESULTS: Zebrafish express seven CaMKII genes during embryogenesis; two of these, camk2b1 and camk2g1, are necessary for convergent extension (CE) cell movements. CaMKII morphant phenotypes were observed as early as epiboly. At the 1-3 somite stage, neuroectoderm and paraxial cells remained unconverged in both morphants. Later, somites lacked their stereotypical shape and were wider, more closely spaced, and body gap angles increased. At 24hpf, somite compression and notochord undulation coincided with a shorter and broader body axis. A camk2b1 crispant was generated which phenocopied the camk2b1 morphant. The levels of cell proliferation, apoptosis and paraxial and neuroectodermal markers were unchanged in morphants. Hyperactivation of CaMKII during gastrulation by transient pharmacological intervention (thapsigargin) also caused CE defects. Mosaically expressed dominant-negative CaMKII recapitulated these phenotypes and showed significant midline bifurcation. Finally, the introduction of CaMKII partially rescued Wnt11 morphant phenotypes. CONCLUSIONS: Overall, these data support a model whereby cyclically activated CaMKII encoded from two genes enables cell migration during the process of CE.

Marinobazzanan, a Bazzanane-Type Sesquiterpenoid, Suppresses the Cell Motility and Tumorigenesis in Cancer Cells.

Marinobazzanan (1), a new bazzanane-type sesquiterpenoid, was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was elucidated using NMR and mass spectroscopic data, while the relative configurations were established through the analysis of NOESY data. The absolute configurations of 1 were determined by the modified Mosher's method as well as vibrational circular dichroism (VCD) spectra calculation and it was determined as 6R, 7R, 9R, and 10R. It was found that compound 1 was not cytotoxic to human cancer cells, including A549 (lung cancer), AGS (gastric cancer), and Caco-2 (colorectal cancer) below the concentration of 25 µM. However, compound 1 was shown to significantly decrease cancer-cell migration and invasion and soft-agar colony-formation ability at concentrations ranging from 1 to 5 µM by downregulating the expression level of KITENIN and upregulating the expression level of KAI1. Compound 1 suppressed ß-catenin-mediated TOPFLASH activity and its downstream targets in AGS, A549, and Caco-2 and slightly suppressed the Notch signal pathway in three cancer cells. Furthermore, 1 also reduced the number of metastatic nodules in an intraperitoneal xenograft mouse model.

Marine Depsipeptide Nobilamide I Inhibits Cancer Cell Motility and Tumorigenicity via Suppressing Epithelial-Mesenchymal Transition and MMP2/9 Expression.

A cyclic depsipeptide, nobilamide I (1), along with the known peptide A-3302-B/TL-119 (2), was isolated from the saline cultivation of the marine-derived bacterium Saccharomonospora sp., strain CNQ-490. The planar structure of 1 was elucidated by interpretation of 1D and 2D NMR and MS spectroscopic data. The absolute configurations of the amino acids in 1 were assigned by using the C3 Marfey's analysis and comparing them with those of 2 based on their biosynthetic pathways. Nobilamide I (1) decreased cell motility by inhibiting epithelial-mesenchymal transition markers in A549 (lung cancer), AGS (gastric cancer), and Caco2 (colorectal cancer) cell lines. In addition, 1 modulated the expression of the matrix metalloproteinase (MMP) family (MMP2 and MMP9) in the three cell lines.

Acremonamide, a Cyclic Pentadepsipeptide with Wound-Healing Properties Isolated from a Marine-Derived Fungus of the Genus Acremonium.

Acremonamide (1) was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was established using MS, UV, and NMR spectroscopic data analyses. Acremonamide (1) was found to contain N-Me-Phe, N-Me-Ala, Val, Phe, and 2-hydroxyisovaleric acid. The absolute configurations of the four aforementioned amino acids were determined through acid hydrolysis followed by the advanced Marfey's method, whereas the absolute configuration of 2-hydroxyisovaleric acid was determined through GC-MS analysis after formation of the O-pentafluoropropionylated derivative of the (-)-menthyl ester of 2-hydroxyisovaleric acid. As an intrinsic biological activity, acremonamide (1) did not exert cytotoxicity to cancer and noncancer cells and increased the migration and invasion. Based on these activities, the wound healing properties of acremonamide (1) were confirmed in vitro and in vivo.

Bioactive natural products from the genus Salinospora: a review.

Actinomycetes are an important source for bioactive secondary metabolites. Among them, the genus Salinispora is one of the first salt obligatory marine species worldwide and is typically found in various types of substrates in tropical and subtropical marine environments including sediments and marine organisms. This genus produces a wide range of chemical scaffolds and bioactive compounds such as lomaiviticins, cyclomarins, rifamycins, salinaphthoquinones, and salinosporamides. This review arranged Salinispora derived secondary metabolites according to the three species that comprise the genus. Moreover, muta- and semi-synthesis analogs derived from salinosporamide were also described in this review.

Patterns of surveillance following curative intent therapy for gastroesophageal cancer.

PURPOSE: Our aims were to examine surveillance strategies after curative treatment of early gastroesophageal (GE) cancer and to evaluate the impact of different approaches on outcomes. METHODS: A total of 292 patients with non-metastatic GE cancer who were referred to the BC Cancer Agency from 2001 to 2010 for curative intent treatment were analyzed. Surveillance practices were classified into the following: cohort 1 (discharge to general practitioner), cohort 2 (follow-up by oncologist with clinical assessments), cohort 3 (specialist follow-up with laboratory investigations), and cohort 4 (specialist follow-up with imaging or endoscopy). Outcomes were compared across cohorts using Kaplan-Meier methods and Cox regression. RESULTS: In total, median age was 63 years and 76 % were men. Eighty-nine (30%), 18 (6%), 32 (11%), and 152 (53%) patients were classified into cohorts 1 to 4, respectively. Patients with primary lesions involving the distal esophagus were more likely to undergo intensive surveillance which involved imaging studies and endoscopic procedures (p = 0.001). Individuals affected by specific histological subtypes, such as squamous cell carcinoma and the signet cell variant, and those whose disease were managed with definitive chemoradiotherapy without surgery were also more inclined to receive intensive follow-up (p = 0.008 and p = 0.001, respectively) There were no significant differences in overall (p = 0.34) or relapse-free survival (p = 0.59) among the different surveillance strategies, even after adjusting for measured prognostic factors. CONCLUSION: In this population-based analysis, outcomes of GE cancer were comparable irrespective of surveillance strategy. Intensive follow-up with routine imaging and endoscopy may not be justified given the financial implications of these costly investigations.

ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase.

Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 Ser 14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in Caenorhabditis elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy-specific VPS34 complex and autophagy induction.

Readmission rates of patients discharged against medical advice: a matched cohort study.

OBJECTIVE: We compared the readmission rates and the pattern of readmission among patients discharged against medical advice (AMA) to control patients discharged with approval over a one-year follow-up period. METHODS: A retrospective matched-cohort study of 656 patients(328 were discharged AMA) who were followed for one year after their initial hospitalization at an urban university-affiliated teaching hospital in Vancouver, Canada that serves a population with high prevalence of addiction and psychiatric disorders. Multivariate conditional logistic regression was used to examine the independent association of discharge AMA on 14-day related diagnosis hospital readmission. We fit a multivariate conditional negative binomial regression model to examine the readmission frequency ratio between the AMA and non-AMA group. PRINCIPAL FINDINGS: AMA patients were more likely to be homeless (32.3% vs. 11%) and have co-morbid conditions such as psychiatric illnesses, injection drug use, HIV, hepatitis C and previous gastrointestinal bleeding. Patients discharged AMA were more likely to be readmitted: 25.6% vs. 3.4%, p<0.001 by day 14. The AMA group were more likely to be readmitted within 14 days with a related diagnosis than the non-AMA group (Adjusted Odds Ratio 12.0; 95% Confidence Interval [CI]: 3.7-38.9). Patients who left AMA were more likely to be readmitted multiple times at one year compared to the non-AMA group (adjusted frequency ratio 1.6; 95% CI: 1.3-2.0). There was also higher all-cause in-hospital mortality during the 12-month follow-up in the AMA group compared to non-AMA group (6.7% vs. 2.4%, p = 0.01). CONCLUSIONS: Patients discharged AMA were more likely to be homeless and have multiple co-morbid conditions. At one year follow-up, the AMA group had higher readmission rates, were predisposed to multiple readmissions and had a higher in-hospital mortality. Interventions to reduce discharges AMA in high-risk groups need to be developed and tested.