Four new isomeric sesquiterpene lactone dimers, carpedilactones A–D (1–4), were isolated from the acetonic extract of Carpesium faberi. Among them, 1–3 are the first three 2,4-linked exo-Diels–Alder ...adducts between a eudesmanolide dienophile and a guaianolide diene. The absolute configurations of 1–4 were unambiguously established by Cu Kα X-ray crystallographic analyses. Compounds 1–4 exhibited potent cytotoxicities against human leukemia (CCRF-CEM) cells with IC50 value of 0.14, 0.32, 0.35, and 0.16 μM, respectively.
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IJS, KILJ, NUK, PNG, UL, UM
Sea ice hinders the navigability of the Arctic, especially in winter and spring. However, three Arc7 ice-class Liquefied Natural Gas carrying vessels safely transited the Northern Sea Route (NSR) ...without icebreaker assistance in January 2021. More and more Arc7 ice-class vessels are putting into the transit services in the NSR. Therefore, it is necessary to analyze sea-ice conditions and their impact on navigation during wintertime, and the future navigability of Arc7 ice-class vessels along the NSR during winter and spring. Based on sea ice datasets from satellite observations and a model using data assimilation, we explored the sea-ice conditions and their impact during the first three successful commercial voyages through the NSR in winter. In addition, we analyzed the sea ice variation and estimated navigability for Arc7 ice-class vessels in the NSR from January to June of the years 2021–2050 using future projections of the sea-ice cover by the Coupled Model Inter-comparison Project Phase 6 (CMIP6) models under two emission scenarios (SSP2-4.5 and SSP5-8.5). The results reveal lower sea ice thickness and similar sea ice concentration during these three transits relative to the past 42 years (from 1979 to 2020). We found the thickness has a larger impact on the vessels’ speeds than sea ice concentration. Very likely sea ice thickness played a larger role than the sea ice concentration for the successful transit of the NSR in winter 2021. Future projections suggest sea ice thickness will decrease further in most regions of the NSR from January to June under all scenarios enabling increased navigability of the NSR for Arc7 ice-class vessels. Such vessels could transit through the NSR from January to June under all scenarios by 2050, while some areas near the coast of East Siberian Sea remain inaccessible for Arc7 ice-class vessels in spring (April and May). These findings can support the strategic planning of shipping along the NSR in winter and spring.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Accessory breast cancer is very rare, particularly in men. Male accessory breast cancer on the abdominal wall has not been documented in the scientific literature so far. We describe a case of male ...accessory breast cancer on the abdominal wall.
We describe a male patient suffering a swelling and erosive, enlarged, and hardened abdominal wall mass with pain due to abdominal wall accessory breast cancer. The patient had no obvious disease history, and the initial clinical symptom was a small mass on the abdominal wall. B-ultrasound revealed a solid subcutaneous nodule in the right abdomen with a size of ~2.8 × 2.5 × 1.5 cm. The abdominal wall tumor resection was performed with local anesthesia. Pathological testing revealed a grade II infiltrating ductal carcinoma derived from the accessory mammary gland (right abdominal wall) with neuroendocrine characteristics, showing ER (100% strong positive), PR (100% strong positive), HER-2 (-), ki67 (40% positive), Syn (+), CgA (+), and GCDFP15 (+).
Nonaxillary accessory breast cancer in males is very rare, with no obvious clinical manifestations, and could be easily ignored. This disease requires great attention from clinicians.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BackgroundPulmonary cryptococcosis (PC) contributes to the ongoing global disease burden in human immunodeficiency virus (HIV)-negative populations. Since some PC patients are misdiagnosed under ...existing diagnostic guidelines, new diagnostic markers are needed to improve diagnostic accuracy and therapeutic efficacy and reduce disease risk.MethodsOur previously established sphingolipidomic approach was employed to explore the use of serum sphingolipids (SPLs) in diagnosing HIV-negative patients with PC. A clinical cohort of PC, pulmonary aspergillosis (PA), and tuberculosis (TB) patients and healthy controls was assessed to identify SPL biomarkers.ResultsA total of 47 PC, 27 PA, and 18 TB patients and 40 controls were enrolled. PC and TB patients had similar clinical features, laboratory test results and radiological features, excluding plural effusion. The serum ceramide Cer (d18:1/18:0) level showed a significant increase in PC patients compared to controls and PA and TB patients (P<0.05). Cer (d18:1/18:0) was identified as a specific diagnostic biomarker for PC. The optimal cut-off value of greater than 18.00 nM showed a diagnostic sensitivity of 76.60% and a specificity of 95.00% and better distinguished PC patients from PA and TB patients. Furthermore, the serum Cer (d18:1/18:0) level gradually decreased after 3 and 6 months of treatment, suggesting the prediction potential for therapeutic efficacy of this biomarker. In addition, Cer (d18:1/18:0) analysis presented a higher sensitivity than the cryptococcal antigen (CrAg) assay.ConclusionsThis is the first study to report the use of the SPL Cer (d18:1/18:0) as a serum biomarker for diagnosing Cryptococcus spp. infection in HIV-negative patients.
Aim. The aim of this study is to demonstrate the expression and clinicopathological significance of complement C1q B chain (C1QB) in cervical cancer. Methods. In total, 120 cervical cancer tissues, ...as well as 20 samples each of high-grade squamous intraepithelial lesions (HSILs), low-grade squamous intraepithelial lesions (LSILs), and benign cervical tissue, were collected to evaluate the expression of C1QB protein via immunohistochemical staining. We conducted an integrated analysis of C1QB mRNA expression in cervical cancer using public microarrays and RNA-seq data sets by calculating standard mean differences (SMDs). Simultaneously, we explored the relations of C1QB with clinicopathological parameters and the expression of P16, Ki-67, and P53. Results. The expression of C1QB protein was higher in cervical cancer samples than that in benign cervical tissue, LSIL, and HSIL samples (p<0.05). A combined SMD of 0.65 (95% CI: 0.52, 0.79, p<0.001) revealed upregulation of C1QB mRNA in cervical cancer. C1QB expression may also be related to the depth of infiltration, lymphovascular invasion, and perineural invasion in cervical cancer (p<0.05). We also found that C1QB protein expression was positively correlated with P16 and Ki-67 expression in cervical cancer (p<0.05). The gene set enrichment analysis showed that C1QB may participate in apoptosis and autophagy. A relationship was predicted between C1QB expression and drug sensitivity to cisplatin, paclitaxel, and docetaxel. Conclusion. We confirmed the overexpression of C1QB in cervical cancer at both mRNA and protein levels for the first time. C1QB may serve as an oncogene in the tumorigenesis of cervical cancer, but this possibility requires further study.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Impressed by the exceptional anticancer activity of cinnamon, the present study was conducted to elucidate the anticancer potential of essential oil of Cinnamon (EOC).
EOC was tested against various ...cell lines (FaDu, Detroit-562 and SCC-25) of head and neck squamous cell carcinoma (HNSCC) using MTT assay. The Hep-2 cell xenograft model was used to assess the positive bio-activity of EOC. EGFR-TK inhibitory assay was also carried out to explain the possible mechanism of action of EOC. Moreover, to rationalise the key contacts responsible for attenuating EGFR, the major component of EOC, i.e., trans-cinnamaldehyde, as identified by GC-MS analysis, was subjected to molecular docking experiments with the catalytic domain of EGFR protein model.
EOC exhibited significant anticancer activity with percent inhibition 66.12, 87.32, and 99.34%, against FaDu, Detroit-562 and SCC-25, respectively. Moreover, EOC reduced the tumor burden to 43.5% in Hep-2 cell xenograft model along with 89% inhibition of EGFR-TK activity in the EGFR-TK inhibitory assay. Docking experiments showed that trans-cinnamaldehyde was proficiently fitted into the inner grove of the active site of EGFR by making close inter-atomic contacts with the key catalytic residues Val702, Ala719, Lys721, Leu764, Thr766 and Leu820 and with inhibition constant Ki = 775.93 μM.
EOC exhibits significant anticancer activity against HNSCC cells in vitro. The mechanism underlying its anticancer action was attributed to the suppression of EGFR-TK. It also significantly suppressed the tumor growth in Hep-2 cell xenograft model.
The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity ...and potency is of necessity.
The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound
, they synthesized a series of 6-methyl-isoxazol3,4-
pyridine-3-amino derivatives and identified that compound
(IC
: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells.
The integrated biological activity results indicated that compound
deserves further development for therapeutic remedies for AML.
Insulin fibrillation provides a model for a broad class of amyloidogenic diseases. Conformational distortion of the native monomer leads to aggregation-coupled misfolding. Whereas β-cells are ...protected from proteotoxicity by hexamer assembly, fibrillation limits the storage and use of insulin at elevated temperatures. Here, we have investigated conformational distortions of an engineered insulin monomer in relation to the structure of an insulin fibril. Anomalous ¹³C NMR chemical shifts and rapid ¹⁵N-detected ¹H-²H amide-proton exchange were observed in one of the three classical α-helices (residues A1-A8) of the hormone, suggesting a conformational equilibrium between locally folded and unfolded A-chain segments. Whereas hexamer assembly resolves these anomalies in accordance with its protective role, solid-state ¹³C NMR studies suggest that the A-chain segment participates in a fibril-specific β-sheet. Accordingly, we investigated whether helicogenic substitutions in the A1-A8 segment might delay fibrillation. Simultaneous substitution of three β-branched residues (IleA² rightward arrow Leu, ValA³ rightward arrow Leu, and ThrA⁸ rightward arrow His) yielded an analog with reduced thermodynamic stability but marked resistance to fibrillation. Whereas amide-proton exchange in the A1-A8 segment remained rapid, ¹³Cα chemical shifts exhibited a more helical pattern. This analog is essentially without activity, however, as IleA² and ValA³ define conserved receptor contacts. To obtain active analogs, substitutions were restricted to A8. These analogs exhibit high receptor-binding affinity; representative potency in a rodent model of diabetes mellitus was similar to wild-type insulin. Although ¹³Cα chemical shifts remain anomalous, significant protection from fibrillation is retained. Together, our studies define an "Achilles' heel" in a globular protein whose repair may enhance the stability of pharmaceutical formulations and broaden their therapeutic deployment in the developing world.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Modeling three-dimensional (3D) underwater acoustic propagation is vital for underwater detection, localization, and navigation. This article introduces a novel model order reduction (MOR) technique ...to solve horizontal refraction equations (HREs) in the modeling of 3D underwater acoustic propagation. This approach relies on an adiabatic approximation of the 3D sound field, representing the field as a combination of local vertical modes with their modal coefficients governed by a system of two-dimensional (2D) HREs. Inspired by normal mode theory, the coefficients in the expansion over vertical modes are determined by projecting them onto a lower-dimensional, orthogonal space defined by their transverse eigenfunctions. By artificially truncating the horizontal domain in the transverse directions using two perfectly matched layers (PMLs), the eigenproblem associated with the transverse eigenfunctions of the modal coefficients is closed and thus can be solved through a modal projection method. The modal projection method enables fast computation of modal coefficients in a longitudinally invariant environment within seconds, offering a naturally wide-angle solution covering ±90°. The MOR method is extended to encompass fully 3D cases by introducing an admittance matrix, a memory-saving strategy that prevents numerical overflow when the longitudinal range is large. Moreover, the fact that the outer boundaries of the PMLs are range-independent allows the proposed MOR technique to perform well on a coarse grid when employing the Magnus scheme, significantly saving the numerical cost for the fully 3D simulation. Numerical simulations are provided for both longitudinally invariant and fully 3D scenarios, demonstrating the high accuracy and efficiency of the proposed MOR technique in solving HREs.
•A model order reduction technique is designed to solve horizontal refraction equations.•Only a few seconds are required for longitudinally invariant environments.•The solution provided by the proposed model is naturally a wide-angle solution.•The proposed model enables efficient and accurate solutions on a coarse grid.•A full-order, benchmark model for solving horizontal refraction equations is developed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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