Serum tumor markers may precede instrumental response to chemotherapy in patients with metastatic cancer

PURPOSE: Although serum tumor markers (STMs) are widely used in clinical practice, their predictive role for the response to anticancer treatment is still controversial. The correlation of CEA, CA 15.3, CA 19.9, CA 125 (only with peritoneal involvement) and NSE levels with imaging response and clinical benefit was investigated in 60 non-selected patients with metastatic epithelial cancers treated by single-agent docetaxel chemotherapy. METHODS: STM measurement was performed at baseline and subsequently every three to four weeks. We applied the WHO criteria to evaluate both STM and instrumental responses. Concordance analysis was performed by the Cohen Kw index, and the significance of the results was established using the Fleiss, Cohen & Everitt test. Qualitative interpretation of data was obtained with the Landis & Koch scale. Correlations of STM response with clinical benefit (PS or pain improvement) were evaluated by the chi-square test. RESULTS: The primary tumors included breast cancers (38 patients), gastrointestinal non-colorectal cancers (12 patients), and lung cancers (10 patients). An overall significant good degree of agreement was observed between STM and instrumental response (p < 0.0005). The degree of agreement for each marker was as follows: excellent for CEA (p < 0.0005) and CA 125 (p = 0.006), good for CA 15.3 (p < 0.0005) and CA 19.9 (p = 0.011). Restricted analysis for the correlation of each marker with primary tumor origin showed good prediction of radiological response for CA 15.3 and CEA in breast cancer patients (p<0.0005 for both), for CEA and CA 19.9 in gastrointestinal cancer patients (p = 0.01 and 0.04, respectively), and for CEA+NSE in lung cancer patients (p = 0.01). Conversely, STM response did not correlate significantly with the clinical benefit for the patients, both in terms of PS and pain improvement (p = 0.24 and p=0.42, respectively). CONCLUSION: This study showed STMs to be good predictors of tumor response. Although STMs cannot replace diagnostic imaging, in metastatic cancer they might be useful to optimize the timing of radiological re-evaluation in the palliative setting.     

Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with fluorine-containing sulfonamides. The first subnanomolar CA IX inhibitor discovered

Polyfluorinated CAIs show very good inhibitory properties against different carbonic anhydrase (CA) isozymes, such as CA I, II, and IV, but such compounds have not been tested for their interaction with the transmembrane, tumor-associated isozyme CA IX. Thus, a series of such compounds has been obtained by attaching 2,3,5,6-tetrafluorobenzoyl- and 2,3,5,6-tetrafluorophenylsulfonyl- moieties to aromatic/heterocyclic sulfonamides possessing derivatizable amino moieties. Some of these compounds showed excellent CA IX inhibitory properties and also selectivity ratios favorable to CA IX over CA II, the other physiologically relevant isozyme with high affinity for sulfonamide inhibitors. The first subnanomolar and rather selective CA IX inhibitor has been discovered, as the 2,3,5,6-tetrafluorobenzoyl derivative of metanilamide showed an inhibition constant of 0.8 nM against hCA IX, and a selectivity ratio of 26.25 against CA IX over CA II. Several other low nanomolar CA IX inhibitors were detected among the new derivatives reported here. The reported derivatives constitute valuable candidates for the development of novel antitumor therapies based on the selective inhibition of tumor-associated CA isozymes.     

Immunohistochemistry of CA 125. Unusual expression in normal tissues, distribution in the human fetus and questions around its application in diagnostic pathology

CA 125 is known as the marker that is most strongly associated with epithelial gynecological tumors. Compared to the number of publications on its use in serum assays, the application in immunohistochemistry is still limited. The availability of many good antibodies that perform well in formalin-fixed paraffin-embedded tissue opens good possibilities for a wider use. Outside the gynecological tract several other structures may react positive for CA 125. Among these are the lung and breast but also the epithelial cells of the conjunctiva and to some extent prostate glandular epithelium. In the fetus reactions can be found in the serosal linings of body cavities but also in the esophagus and skin. In diagnostic pathology CA 125 plays a role in identifying the primary locations of metastatic carcinoma of unknown origin. It is recommended to use CA 125 antibodies not in a solitary setting but in combination with CEA, BRST-2 and Vimentin to discriminate best between the most frequent sites of origin of metastatic carcinoma. Regular analysis of sensitivity/specificity ratios in a balanced population, representing the composition of the patient population seen in daily practice, should be performed to evaluate the position of CA 125 in diagnostic immunohistochemistry.     

血清腺苷脱氨酶、糖类抗原199、红细胞沉降率与活动性肺结核患者病情严重程度及预后的关系研究

摘要 目的：探讨血清腺苷脱氨酶（ADA）、糖类抗原199（CA199）、红细胞沉降率（ESR）与活动性肺结核（ATB）患者病情严重程度及预后的关系。方法：选取2021年1月～2022年10月湖南省胸科医院收治的75例ATB患者作为观察组，另外选取60例同期在我院体检健康的体检者作为对照组。比较两组血清ADA、CA199及ESR水平。根据病情严重程度将ATB患者分为轻度组、中度组和重度组。比较不同病情严重程度ATB患者的血清ADA、CA199及ESR水平。观察组接受抗结核治疗，根据疗效分为预后良好组和预后不良组，比较不同预后ATB患者的血清ADA、CA199及ESR水平。收集ATB患者的临床资料，多因素Logistic回归分析ATB患者预后的影响因素。受试者工作特征（ROC）曲线分析血清ADA、CA199、ESR对ATB患者预后的预测价值。结果：观察组血清ADA、CA199、ESR均高于对照组（P＜0.05）。将观察组患者分为轻度组26例、中度组34例和重度组15例。中度组和重度组血清ADA、CA199、ESR高于轻度组（P＜0.05），重度组血清ADA、CA199、ESR高于中度组（P＜0.05）。治疗后，根据疗效将观察组患者分为预后良好组50例和预后不良组25例，预后良好组和预后不良组在性别、年龄、BMI、吸烟史、饮酒史、糖尿病史、居住地、哮喘、支气管扩张、乙型肝炎、胸片改变等方面比较差异无统计学意义（P＞0.05），预后不良组患者血清PCT、白细胞计数、ADA、CA199、ESR高于预后良好组（P＜0.05）。经多因素Logistic回归分析结果显示，血清ADA、CA199、ESR升高是ATB患者预后不良的危险因素（P＜0.05）。绘制ROC曲线结果显示，血清ADA、CA199、ESR单独预测ATB患者预后不良的AUC分别为0.655、0.675、0.699，血清ADA、CA199、ESR联合预测ATB患者预后不良的AUC为0.828，大于各指标单独检测。结论：血清ADA、CA199、ESR升高可提示ATB患者的病情严重程度，血清ADA、CA199、ESR联合检测对预测ATB患者预后不良具有较高的价值。     

Synthesis of glycoconjugate carbonic anhydrase inhibitors by ruthenium-catalysed azide-alkyne 1,3-dipolar cycloaddition

Carbonic anhydrase IX (CA IX) is a recently validated target for the development of new cancer therapies. In this Letter we describe the synthesis and CA inhibition of a novel series of carbohydrate-based 1,5-disubstituted-1,2,3-triazole benzenesulfonamides. The key step of our synthesis is the regioselective Huisgen's 1,3-dipolar cycloaddition reaction (1,3-DCR) from carbohydrate azide substrates and 4-ethynylbenzenesulfonamide using a ruthenium-catalysed azide-alkyne cycloaddition (RuAAC). Our findings identified a number of triazole inhibitors (compounds 18, 19, 21-23, and 26) that block CA IX activity with inhibition constants less than 10 nM. One inhibitor (compound 17) possessed very good selectivity for CA IX over off-target CAs. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.     

Effect of deacetylation on wicking behavior of co-electrospun cellulose acetate/polyvinyl alcohol nanofibers blend

Cellulose acetate (CA) nanofibers webs deserve a special attention because of their very good water retention properties. CA nanofibers based biosensor in certain application come into contact with various liquids and requires high degree of wicking rate to transport liquid to its destination. Cellulose acetate (CA)/polyvinyl alcohol (PVA) blended nanofibers were prepared via co-electrospinning using double nozzle for jetting cellulose acetate and polyvinyl alcohol independently. The CA/PVA blend nanofibers webs were deacetylated in aqueous alkaline solution to convert CA in to regenerated cellulose and to remove PVA nanofibers from the raw web. The resultant nanofibers webs were characterized by wicking rate, water contact angle, SEM and FTIR analysis. The results revealed that by varying concentration of PVA solution enhances the wicking rate. Such a nanofibers web may be used in biosensor strip and other medical applications where the high wicking rates are desired.     

Evaluation of the micronucleus test using a Chinese hamster cell line as an alternative to the conventional in vitro chromosomal aberration test.

The in vitro micronucleus (MN) test was carried out simultaneously with the conventional chromosomal aberration (CA) test on 11 clastogenic chemicals or spindle poisons with different modes of action using a Chinese hamster cell line (CHL). The method of slide preparation for the MN test was the same as that for the conventional metaphase analysis, except that 1% acetic acid in methanol was used as the cell suspension medium for air-drying (to preserve the cytoplasm around the nucleus). All chemicals tested induced micronuclei reproducibly and dose-dependently in good agreement with the results of metaphase analysis (r = 0.99). Since the MN test methodology is simple and the observation of MN is less subjective than that of CA, we conclude that the in vitro MN test would be a good alternative to the conventional CA test for screening the genotoxicity of chemicals.     

Ferrier sulfonamidoglycosylation of D-glycals

A series of novel N-glycosyl sulfonamides were prepared via Ferrier sulfonamidoglycosylation of D-glycals with good to high alpha-stereoselectivity. Two new glycosylsulfamides were tested as carbonic anhydrase (CA II) inhibitors and showed good properties in the micromolar range.     

Kinetic analysis of the role of intersubunit interactions in human immunodeficiency virus type 1 capsid protein assembly in vitro

The human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) plays a crucial role in both assembly and maturation of the virion. Numerous recent studies have focused on either the soluble form of CA or the polymer end product of in vitro CA assembly. The CA polymer, in particular, has been used to study CA-CA interactions because it is a good model for the CA interactions within the virion core. However, analysis of the process of in vitro CA assembly can yield valuable insights into CA-CA interactions and the mechanism of core assembly. We describe here a method for the analysis of CA assembly kinetics wherein the progress of assembly is monitored by using turbidity. At pH 7.0 the addition of either of the isolated CA domains (i.e., the N or the C domain) to an assembly reaction caused a decrease in the assembly rate by competing for binding to the full-length CA protein. At pH 8.0 the addition of the isolated C domain had a similar inhibitory affect on CA assembly. However, at pH 8.0 the isolated N domain had no affect on the rate of CA assembly but, when mixed with the C domain, it alleviated the C-domain inhibition. These data provide biochemical evidence for a pH-sensitive homotypic N-domain interaction, as well as for an N- and C-domain interaction.     

Carbonic anhydrase inhibitors. Inhibition of transmembrane isozymes XII (cancer-associated) and XIV with anions

Metal complexing anions represent an important class of inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The first inhibition study of the transmembrane isozymes CA XII (tumor-associated) and XIV with anions is reported. These isozymes showed inhibition profiles with physiologic/non-physiologic anions quite distinct from any other cytosolic (CA I and II) or transmembrane isoforms (e.g., CA IX) investigated earlier. hCA XII has a good affinity for fluoride and bicarbonate but is not inhibited by heavier halides, perchlorate, nitrate, and nitrite. The best hCA XII inhibitors were cyanide (K(I) of 1 microM) and azide (K(I) of 80 microM). hCA XIV was on the other hand weakly inhibited by fluoride and not at all inhibited by perchlorate, but showed good affinity for most other anions investigated here. Chloride and bicarbonate showed K(I)s in the range of 0.75-0.77 mM for this isoform. The best hCA XIV anion inhibitors were sulfate, phenylarsonic, and phenylboronic acid (K(I) in the range of 10-92 microM).     

The role of CA 125 in screening for ovarian cancer

Ovarian cancer has the worst prognosis of any gynaecological malignancy, primarily because it tends to present at an advanced stage. The excellent survival rates of early stage disease have provided the rationale for efforts to detect ovarian cancer early by screening, in the hope that survival rates will be improved. Available data suggests that CA 125 is elevated in the majority of epithelial ovarian malignancies prior to clinical presentation. Large trials of screening for ovarian cancer indicate that using a CA 125 cutoff value of 30 U/mL has good sensitivity, but inadequate specificity for detecting preclinical disease. Use of transvaginal ultrasonography as a second-line test in women with elevated CA 125 levels improves specificity to acceptable levels, as does use of a mathematical algorithm which analyses rates of change of CA 125. Two major randomised controlled trials, investigating the effect of screening strategies incorporating CA 125 on mortality, are currently underway.     

Decreased total carbonic anhydrase esterase activity and decreased levels of carbonic anhydrase 1 isozyme in erythrocytes of type II diabetic patients

In this exploratory study, we investigated total erythrocyte carbonic anhydrase (CA) estrase activity as well as CA I isozyme concentration in patients with diabetes mellitus type II (DM) and healthy individuals of Howard University Hospital community. Total estrase activity of CA was measured spectrophotometrically using p-nitrophenol acetate before and after inhibition with acetazolamide. CA I isozyme was measured by radial immunodiffusion using monoclonal antibody (CA I) in agarose plates. The study involved 20 consented participants; 10 normal (N) and 10 (DM), 21 to 84 years of age. The study was approved by the Howard University Institution Review Board. The CA activity was measured following lysis of cells as U/min/mL and CA I concentration as mg/l. We observed CA activity as 46.3±4(N) and 25±2.1 (DM) whereas CA I concentration as 1896±125 (N) and 1104 ±63 (DM). We speculate that the change in the CA activity may of fundamental importance in the regulation of intracellular; pH_i for the basic control of metabolism in diabetes mellitus. Further, we propose that CA activity is a good candidate for a biomarker of diabetes mellitus for the early detection of insulin resistance because the CA activity variation was proportional to the severity of the diabetes. Jehan Ornasir—these studies were undertaken as a partial requirement of her M.S. Degree, Graduate School, Howard University, Washington, DC, USA     

Prognostic value of CA125 kinetics and half-life in advanced ovarian cancer

This retrospective study was undertaken in order to assess the prognostic value of prechemotherapy serum CA125 level, CA125 kinetics, and CA125 half-life compared to the ten common clinicopathological variables in patients with advanced ovarian cancer (AOC). CA125 serum levels were determined before and during induction cisplatin polychemotherapy in 222 patients. A prechemotherapy CA125 level higher than 35 U/mL was found in 134 patients. Blood samples were further obtained before each course of chemotherapy (CT). CA125 half-life values were calculated in 112 patients with CA125 levels above 60 U/mL using van der Burg's exponential regression model. The prechemotherapy CA125 level had no prognostic value for survival. However, the median survival time of patients with CA125 levels below the upper normal limit of normality after two courses of CT was 101 months compared to a median survival of 21 months in patients without CA125 normalization (p=0.0000). Half-life calculation showed a significant correlation with survival. The median survival times of patients with T1/2 <20 days and T1/2 >20 days were 101+ and 18 months, respectively (p=0.0003). In a survival analysis using the Cox proportional hazard model, independent prognostic variables for survival included therapeutic response (p<0.0001), Karnofsky index (p<0.0001), residual disease (p<0.0001), tumor grade (p=0.0002), CA125 half-life (p=0.007), and CA125 kinetics (p=0.04). As a consequence, the possibility to predict treatment response by the CA125 half-life during chemotherapy and the time needed for normalization of CA125 levels can divide patients into good and poor prognostic groups early during chemotherapy.     

DR-70~(TM)和CA50肺癌免疫测定的应用价值

目的 :评价DR 70 TM和CA5 0两种肿瘤标志物在肺癌检测中的价值。方法 :应用DR 70 TMELISA和CA5 0IRMA对77例肺癌患者 ,42例健康者及 48例其它肺癌者进行对照检测。结果 :各组DR 70 TMCA5 0测定值比例显示肺癌组平均值显著其它两组 (P <0 .0 1)。DR 70 TM检测的敏感性和有效性高于CA5 0检测 (83.1%比 6 6 .2 % ,85 .7%比 75 .6 % )。两项联合检测的敏感性 ,有效性分别为 96 .1% ,93.1% ,优于单项DR 70 TM 检测的 83.1% ,85 .7% ,及CA5 0的 6 6 .2 9%、75 .6 %。结论 :DR 70 TM在肺癌检测中有较大应用价值。DR 70 TM 和CA5 0两项联合检测是较理想的肺癌检测组合     

Exploring the cardioprotective effects of canagliflozin against cisplatin-induced cardiotoxicity: Role of iNOS/NF-κB,Nrf2, and Bax/cytochrome C/Bcl-2 signals

Cardiotoxicity is a severe considerable side effect of cisplatin (CDDP) that requires much medical attention. The current study investigates the cardioprotective effects of canagliflozin (CA) against CDDP-induced heart toxicity. Rats were allocated to the control group; the CA group was administered CA 10 mg/kg/day orally for 10 days; the CDDP group was injected with 7 mg/kg, intraperitoneal as a single dose on the 5th day, and the CDDP + CA group. Compared to the CDDP-treated group, CA effectively attenuated CDDP-induced heart injury as evidenced by a decrease of serum aspartate aminotransferase, alkaline phosphatase, creatine kinase-MB, and lactate dehydrogenase enzymes and supported by the alleviation of histopathological changes in cardiac tissues. Biochemically, CA attenuated cardiac oxidative injury through upregulation of the nuclear factor-erythroid 2 related factor 2 (Nrf2) signal. CA suppressed inflammation by decreasing cardiac NO₂⁻, MPO, iNOS, nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha, and interleukin 1-beta levels. Besides, CA significantly upregulated cardiac levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and p-AKT proteins. Moreover, CA remarkably mitigated CDDP-induced apoptosis via modulation of Bax, cytochrome C, and Bcl-2 protein levels. Together, the present study revealed that CA could be a good candidate for preventing CDDP-induced cardiac injury by modulating iNOS/NF-κB, Nrf2, PI3K/AKT, and Bax/cytochrome C/Bcl-2 signals.     

Carbonic anhydrase inhibitors. Interaction of 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide with 12 mammalian isoforms: kinetic and X-ray crystallographic studies

2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide was tested for its interaction with 12 carbonic anhydrase (CA, EC 4.2.1.1) isoforms in the search of compounds with good inhibitory activity against isozymes with medicinal chemistry applications, such as CA I, II, VA, VB, VII, IX, and XII among others. This sulfonamide is a potent inhibitor of CA I and II (K(I)s of 7.2-7.5 nM), a medium potency inhibitor of CA VII, IX, XII, and XIV, and a weak inhibitor against the other ubiquitous isoforms, making it thus a very interesting clinical candidate for situations in which a strong inhibition of CA I and II is needed. The crystal structure of the hCA II adduct of this sulfonamide revealed many favorable interactions between the inhibitor and the enzyme which explain its strong low nanomolar affinity for this isoform but may also be exploited for the design of effective inhibitors incorporating bicyclic moieties.     

Dual targeting of cancer-related human matrix metalloproteinases and carbonic anhydrases by chiral N-(biarylsulfonyl)-phosphonic acids

A series of nanomolar phosphonate matrix metalloproteinase (MPP) inhibitors was tested for inhibitory activity against a panel of selected human carbonic anhydrase (CA, EC 4.2.1.1) isozymes, covering the cancer-associated CA IX and XII. None of the reported sulfonyl and sulfonylamino-derivatives sensitively affected the catalytic activity of the cytosolic isoforms CA I and II, which are considered off-target isoforms in view of their physiological role. The most active inhibitors were in the series of chiral N-(sulfonyl)phosphovaline derivatives, which showed good to excellent inhibitory activity over target CAs, with compound 15 presenting the best isoform-selectivity toward CA IX. We suggest here that the phosphonates have the potential as dual inhibitors of MMPs and CAs, both involved in tumor formation, invasion and metastasis.     

血清CA153、TK1、TSGF联合检测对乳腺癌诊断的价值

目的：探讨细胞表面糖蛋白（CA153）、胸苷激酶（TKl）、肿瘤生长因子（TSGF）等联合检测在乳腺癌诊断中的应用价值。方法：73例确诊为乳腺癌患者的血清标本作为实验组;66例乳腺良性疾病（包括乳腺纤维瘤、囊肿、增生等）及50例健康人群血清标本作为对照组。采用电化学发光法检测血清CAl53,免疫化学发光法检测TKl,化学显示法检测TSGF的表达。结果：血清CAl53、TKl及TSGF对乳腺癌的敏感性分别为54．8％、53．4％及79．5％,特异性分别为87．9％、81．8％及83．3％;血清CAl53、TKl、TSGF联合检测乳腺癌的敏感性为89．0％,特异性为92．4％。结论：与单项指标检测相比,多个指标联合检测提高了对乳腺癌早期诊断的敏感性．同时又有较好的特异性．有助于良、恶乳腺疾病的鉴别．具有一定的临床应用价值．     

Human biliary mucin binds to E-selectin: a possible role in modulation of inflammation

E-selectin, expressed on endothelial cells, mediates adhesion of leukocytes and tumor cells to endothelium. CA19-9 (sialyl-Lewis(a)) and sialyl-Lewis(x) are specific ligands for E-selectin. We have recently shown that mucin-rich culture media from human gallbladder epithelial cells contains CA19-9. In this study, we have tested whether human biliary mucin binds to E-selectin. The ability of mucins to inhibit the adhesion of HL-60 cells to immobilized E-selectin was taken as an index for E-selectin binding. Gallbladder bile, hepatic bile, and culture medium from human gallbladder epithelial cells completely inhibited the adhesion of HL-60 cells to E-selectin. The mucin-rich fractions of human bile exhibited strong inhibition, whereas mucin-free fractions had little effect. In contrast to human bile samples, CA19-9-free medium from cultured dog gallbladder epithelial cells failed to inhibit HL-60 binding. Furthermore, after CA19-9 immunoaffinity chromatography, which selectively extracted CA19-9 from bile, bile samples showed poor inhibition of HL-60 adhesion to immobilized E-selectin. A good correlation was observed between E-selectin binding and CA 19-9 concentrations in bile. Our results show that human bile has E-selectin binding activity that is mediated by the CA19-9 side chain of biliary mucin.