Effect of sequential vs. non-sequential early enteral nutrition therapy on nutritional status, recovery, and quality of life of patients with esophageal cancer.

OBJECTIVE: To study the effects of early sequential enteral nutrition (ESEN) therapy and early non-sequential enteral nutrition (EN) therapy on the nutritional status, recovery, and quality of life of patients who undergo postoperative chemotherapy for esophageal cancer. PATIENTS AND METHODS: The data of 90 patients who underwent postoperative chemotherapy for esophageal cancer in Gansu Provincial Cancer Hospital from January 2018 to June 2020 were analyzed retrospectively. Patients were divided the Test group and the Control group (n=45 each) based on the method of nutritional support. Patients in the Control group were treated with non-sequential early enteral nutrition and the Test group treated with sequential early enteral nutrition until the discharge. Nutritional status, recovery, and quality of life of the chemotherapy patients in the two groups were compared. RESULTS: After the intervention, the pre-protein, albumin and hemoglobin levels were higher in the Test group than in the control group (p<0.05). Postoperative exhaustion, incision healing and length of hospital stay were significantly lower in the Test group than in the Control group (p<0.05), while the scores on all dimensions of the short-form 36 health survey scale (SF-36) and the total score were higher than in the Control group (p<0.05). CONCLUSIONS: Sequential early enteral nutrition may be used for patients who undergo chemotherapy after esophageal cancer surgery to promote their early recovery and improve their quality of life and nutritional status.

Defective Central Immune Tolerance Induced by High-Dose D-Galactose Resembles Aging.

D-Galactose (D-Gal) promotes accumulation of reactive oxygen species and formation of advanced glycation end-products, ultimately resulting in oxidative stress. D-Gal has been widely used to induce accelerated aging in anti-aging medical research. Although thymic epithelial cells are particularly sensitive to oxidative stress, there are few reports on the thymus changes accompanying D-Gal-induced aging in mice. To study the effect of D-Gal on rodent thymus, we investigated the degree of thymus atrophy and changes in the atrophy relative index in C57BL/6J mice following subcutaneous injection of D-Gal at different doses (200, 500, 1000 mg/kg per day) for 60 days. Compared with the vehicle-treated (0.9% saline) and young controls, D-Gal at doses of 500 and 1000 mg/kg per day led to a significant thymic atrophy; the latter dose caused atrophy similar to that observed in naturally aged (18-20-month-old) mice. Mice treated with high-dose D-Gal exhibited greater immunosenescence, defective central immune tolerance, increased levels of activated splenic immune cell, and chronic low-grade inflammation, i.e., outcomes similar to those observed in natural aging in mice. Taken together, our results indicate that mice treated with high-dose D-Gal may be a valid model for studying induced thymic atrophy and effects of aging on the immune system.

[Study on radiation dose in different field of views of oral and maxillofacial cone-beam CT].

Objective: To analyze the absorptive radiation dose of non-target sensitive organs under the NewTomVGi oral and maxillofacial cone-beam CT scanning in different view fields. Methods: The thermoluminescence dosimeter chip was placed in the non-target sensitive organ of the simulated radiology head model, and 6 scanning fields were measured and analyzed (standard resolution: scanning range was 15 cm×15 cm, 15 cm×12 cm, 12 cm×8 cm, 8 cm×8 cm respectively). High definition resolution: the radiation absorption dose of thermoluminescence with the scanning range of 12 cm×8 cm, 8 cm×8 cm, respectively. Results: Under the same resolution, the absorptive dose increased with the expansion of scanning field, and the amount of absorbent during high resolution scanning was higher than that during the standard resolution with the same scanning field. Conclusions: New TomVGi oral and maxillofacial cone-beam CT has sighificant difference in radiation dose in different view fields. The appropriate view field should be selected according to the patient's clinical needs, so as to reduce unnecessary radiation dose during medical imaging examination.

Isotopic homogeneity of iron in the early solar nebula.

The chemical and isotopic homogeneity of the early solar nebula, and the processes producing fractionation during its evolution, are central issues of cosmochemistry. Studies of the relative abundance variations of three or more isotopes of an element can in principle determine if the initial reservoir of material was a homogeneous mixture or if it contained several distinct sources of precursor material. For example, widespread anomalies observed in the oxygen isotopes of meteorites have been interpreted as resulting from the mixing of a solid phase that was enriched in 16O with a gas phase in which 16O was depleted, or as an isotopic 'memory' of Galactic evolution. In either case, these anomalies are regarded as strong evidence that the early solar nebula was not initially homogeneous. Here we present measurements of the relative abundances of three iron isotopes in meteoritic and terrestrial samples. We show that significant variations of iron isotopes exist in both terrestrial and extraterrestrial materials. But when plotted in a three-isotope diagram, all of the data for these Solar System materials fall on a single mass-fractionation line, showing that homogenization of iron isotopes occurred in the solar nebula before both planetesimal accretion and chondrule formation.

Characterization of human lung cancer cells resistant to 4'-O-demethyl-4beta-(2"-nitro-4"-fluoroanilino)-4-desoxypodophyllotoxin , a unique compound in the epipodophyllotoxin antitumor class.

A new semi-synthetic podophyllotoxin derivative, 4'-O-demethyl-4beta-2"-nitro-4"-fluoroanilino)-4-desoxypo dophyllotoxin (compound 1), an analog of GL-331 (compound 2), is a potent and broad-spectrum inhibitor of cultured human cancer and drug-resistant cell growth. In general, 4'-demethylepipodophyllotoxin analogs, including 2, exert anti-tumor activity by targeting the nuclear enzyme DNA topoisomerase II, but 1 is not an enzyme inhibitor. Unlike the cytotoxic activity of compound 2, cell killing by 1 is dose-limiting and a significant fraction of cells (30-40%) survive treatment. As an approach to investigate mechanism of action, 1-resistant A549 (human lung cancer) sub-lines were selected and characterized. Results of the work show that 1-resistant cells: (i) are moderately cross-resistant (2- to 3-fold) to various cytotoxic drugs via a P-glycoprotein-independent mechanism, (ii) have an altered growth habit, (iii) are deficient in normal attachment on plastic and collagen substrata, and (iv) have an altered plasma membrane protein composition including several proteins in the 140->200 kDa molecular mass range and a doublet of phosphoserine-containing proteins of about 135 kDa. Since 1 treatment of cells affects neither cellular attachment or membrane-protein phosphorylation, the changes observed in 1-resistant cells are interpreted as a survival response to drug action.

Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4beta-amino-4'-O-demethylepipodophyllotoxin conjugates.

Two compounds having a camptothecin (CPT) analog conjugated to the 4beta-amino-4'-O-demethylepipodophyllotoxin analog were evaluated for their biochemical and biological activities. W1[camptothecin-(para)-4beta-amino-4'-O-demethylepipodophyllotoxin] had no activity against topoisomerase II (TOP II), but inhibited topoisomerase I (TOP I) with an IC(50) value 2-fold higher than CPT. W2 [camptothecin-(ortho)-4beta-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with IC(50) values 1.5-fold higher than either CPT or etoposide (VP-16). Both conjugates had similar cytotoxicity against the KB cell line, although the protein-linked DNA breaks (PLDBs) generated by W2 in KB cells were about 4-fold more than those of W1. No cross-resistance with the two conjugates was seen in a VP-16-resistant KB subline, which showed down-regulation of TOP II and overexpression of the multiple drug resistance-associated protein, or in a vincristine-resistant KB subline with overexpression of gp-170/mdr-1. The CPT-resistant KB variant (KB CPT 100), which has a reduction in TOP I content and another mechanism that occurs post-PLDB formation, was partially resistant to both compounds. W1 was not affected by this post-PLDB resistance mechanism. Cell cycle analysis demonstrated that W1 and W1 had similar cell cycle effects on KB and KB CPT 100 cells, which accumulated in S-phase upon drug treatment. These results suggested that W1 and W2 exerted their cytotoxicity through TOP I. In CPT-resistant cells, however, an unidentified target also may be involved in the cytotoxic action of W1 and TOP II may still be a target for W1. In vivo, W1 was more effective against the growth of human prostate cancer cells in nude mice than VP-16, CPT, or W2. Given its antitumor activity and unique biochemical mechanism of action, W1 warrants exploration as an antitumor compound.

Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles.

As a continuation of our structure-activity relationship studies, several new 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Selected compounds were further evaluated as cytotoxic agents using a clonogenic survival assay. The target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '-yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '-(benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target series, 19, 21, and 24 displayed significant growth inhibitory action against a panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the prototype drug etoposide (VP-16). Compound 21 was the most active analogue, being 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 21 was effective against (P388/0) leukemia but not against the growth of a (MCF7) mammary tumor.

Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors.

Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against various human tumor cell lines and for their inhibitory effects on DNA topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes their biological profiles. Instead of displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only compounds with a larger side chain, such as 15a, 23a, and 24a, did not interfere with topoisomerase II enzymatic functions. The cytotoxicity of target compounds was reduced by 3 orders of magnitude compared to that of colchicine in most cell lines. The hydrophilicity of phenolic compounds might prevent drug passage through the cell plasma membrane and, thus, be responsible for the relatively weak cytotoxicity. To test this hypothesis, 27-30 were prepared from 16a by protecting all hydroxy groups with esters with an aim to facilitate drug transportation. In vitro cytotoxicity assays indicated that 27 was more potent than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect against KB cells (IC50 = 2.7 microg/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.

Antitumor agents. Part 186: Synthesis and biological evaluation of demethylcolchiceinamide analogues as cytotoxic DNA topoisomerase II inhibitors.

Demethylation of colchiceinamide (2) and its analogues (3-10) afforded a novel class of mammalian DNA topoisomerase II inhibitors (2a-10a) without displaying tubulin inhibitory activity. All target compounds inhibited the catalytic activity of topoisomerase II at drug concentrations at 100 microM. An in vitro cytotoxicity assay indicated that compounds 3a and 8a were strong and tissue-selective cytotoxic agents against the MCF-7 breast cancer cell line (IC50 = 0.36 and 0.48 microgram/mL, respectively) and the CAKI-1 renal cancer cell line (IC50 = 0.72 and 0.96 microgram/mL, respectively).