Dose-response studies on the effects of alpha-, beta-, and gamma-hexachlorocyclohexane on putative preneoplastic foci, monooxygenases, and growth in rat liver

Alpha-, beta-, and gamma-hexachlorocyclohexane (alpha-, beta-, gamma-HCH) isomers are widespread environmental pollutants; alpha-HCH can cause liver tumors in rats and mice. In the present study we have checked first the tumor-initiating activity of HCH using the appearance of phenotypically altered foci in female rat liver as an end point. Foci were identified by means of the gamma-glutamyltransferase (GGT) reaction and by morphological alterations. No evidence of initiating activity was found. Secondly, we have attempted to determine quantitatively the ability of HCH isomers to promote tumor development. For this purpose growth and phenotypic changes of foci were used as an end point. Rats received a single dose of N-nitrosomorpholine. Then five different doses of each HCH isomer or phenobarbital (PB) (as a positive control) were administered continuously via the diet for 4, 15, and 20 weeks. Both number and size of altered foci were enhanced by doses of 2 to 3 mg/kg or more of the three isomers; in addition, foci phenotypes showed a pronounced shift towards strong expression of GGT and sharp demarcation from the surrounding liver. Based on daily doses the three HCH isomers were approximately equipotent; based on concentrations in liver or adipose tissue, gamma-HCH was severalfold more effective than alpha- and beta-HCH. Thirdly, size and DNA and monooxygenase activities of the liver were determined. All three parameters were enhanced by HCH isomers and PB. However, no strict correlations were found. Rather, at the highest doses tested PB was the most effective inducer of monooxygenases, alpha-HCH was the most potent inducer of liver growth, and all three HCHs were more potent than PB as inducers of focal expansion. Thus, induction of liver growth appears to be associated with foci expansion (tumor promotion); however, neither liver growth nor monooxygenase induction can be used for quantitative predictions of foci expansion by chemical compounds. Finally, no-observed-effect levels were estimated for the parameters studied and are discussed in relation to human exposure.     

A synoptical approach to the diagnosis of candidosis, relying on serological antigen and antibody tests, on culture, and on evaluation of clinical data

Summary: In a prospective study from December 1985 to September 1986, we have tested 1153 sera from 516 patients suspected of candidosis. Serological data, clinical conditions and cultures indicated involvement of Candida in 190 cases. Among them, 36 patients probably suffered from invasive mucocutaneous candidosis. Deep-seated candidosis was diagnosed in 50 patients. Nearly half of the patients of each group had been subjected to systemic antifungal therapy, which did not improve the prognosis of patients suffering from invasive mucocutaneous candidosis. However, among patients with deep-seated candidosis, overall lethality was reduced by more than 50% when systemic antifungals were applied. Therefore, differentiation of severe candidosis into an invasive mucocutaneous type and into truly deep-seated mycosis is diagnostically important. The latex agglutination test for detection of Candida antigen in serum (Cand-Tec, Ramco) is suitable for excluding severe candidosis; it does not allow further differentiation. The enzyme immunoassay for detection of fungal proteinase antigen showed a higher specificity for deep-seated mycosis; however, proteinase antigen was detected only in 50% of the suspected cases. Titers of anti-candidal antibodies (including anti-proteinase) did not allow differentiation of severe mycosis. They were useful for confirmation of the diagnosis, provided the patient was able to mount a regular immune response. In immuno-compromised patients, the criteria of the antigen titers have to be adapted to the degree of neutropenia. Likewise, positive cultures and clinical presentation have to be interpreted differently in such patients. A fair degree of reliability of early diagnosis of deep-seated candidosis is only attained by synoptical evaluation of clinical, serological, and cultural data. Zusammenfassung: In einer prospektiven Studie, die zehn Monate von Dezember 1985 bis September 1986 umfaßte, haben wir 1153 Seren von 516 Patienten unter Mykoseverdacht untersucht. Serologische Titer, Klinik und Kulturisolate sprachen in 190 Fällen für Candida-Mykosen unterschiedlichen Schweregrads. 36 Patienten litten offenbar an invasivem Soor, während bei 50 Patienten eine tiefe Mykose diagnostiziert wurde. Patienten dieser beiden Gruppen wurden etwa zur Hälfte mit systemischen Antimykorika behandelt. In den Fällen von invasivem Soor änderte sich die Prognose dadurch nicht. Bei tiefer Mykose wurde hingegen die Letalität durch systemische Therapie um mehr als 50% vermindert. Die Unterscheidung von invasiver Schleimhautmykose und tiefer Mykose ist demnach von großer klinischer Bedeutung: zu diesem Zweck wurden zwei serologische Candida-Antigentests und vier Antikörpertests durchgeführt. Der Anti-gennachweis durch Latex-Agglutination (Cand-Tec, Ramco) war zum Ausschluß von Candida-Mykose geeignet, er erlaubte jedoch kaum eine Unterscheidung zwischen invasivem Soor und der tiefen Mykose. Der Nachweis von Candida-Proteaseantigen war hingegen fast immer ein Zeichen für tiefe Mykosen. Der Test war jedoch nur in etwa der Hälfte der Fälle positiv, Antikörpertiter waren zur Bestätigung der Diagnose nützlich, sofern der Patient über-haupt zu einer Immunantwort in der LAge war. Die Ergebnisse der serologischen Tests waren bei immunkompetenten Patienten zuverlässiger als bei immundefizienten oder neutropenischen Patienten. Bei letzteren sind die Bewertungs-grenzen der Antigentiter verschoben, außerdem sind in diesen Fällen Klinik und Kulturnachweise stärker zu berücksichtigen.     

Effects of iron, copper, cobalt, and their chelators on the cytotoxicity of bleomycin

Bleomycin is widely used for treating several types of human tumors as well as a variety of experimental tumors. The ability of this antibiotic to bind and to damage DNA has been proposed to be responsible for its antitumor effect. Bleomycin is also a good chelator for several metals, e.g., iron, copper, and others. Bleomycin:metal complexes have been investigated in detail particularly for their action on isolated DNA. The conclusions from these studies indicate that metal-chelated bleomycin either is ineffective or more effective in damaging DNA. In this paper, we tested the effect of iron, copper, cobalt, and their chelators on bleomycin cytotoxicity. Our results suggest that chelating bleomycin with copper or adding an iron chelator (deferoxamine), diethylenetriamine pentaacetic acid, and a copper chelator (penicillamine) shows no effect on bleomycin cytotoxicity. On the other hand, iron dextran and a metal chelator, diethyldithiocarbamate (DDC), with bleomycin show enhanced cytotoxicity. Cobalt-chelated bleomycin is not cytotoxic but is cytotoxic when combined with DDC. We suggest that different mechanisms are contributing to the enhanced toxicity of bleomycin with iron dextran and DDC. Bleomycin acts as a ferrous oxidase which promotes the iron toxicity. In the case of DDC, it can act as a reducing agent or it can help to maintain the bleomycin:metal complex in the reduced form which can generate radicals.     

Consensus statement on definition,diagnosis, and management of high-risk prostate cancer patients on behalf of the Spanish Groups of Uro-Oncology Societies URONCOR,GUO, and SOGUG

Purpose

Prostate cancer (PCa) is the most prevalent malignancy in men and the second cause of mortality in industrialized countries.

Methods

Based on Spanish Register of PCa, the incidence of high-risk PCa is 29%, approximately. In spite of the evidence-based beneficial effect of radiotherapy and androgen deprivation therapy in high-risk PCa, these patients (pts) are still a therapeutic challenge for all specialists involved, in part due to the absence of comparative studies to establish which of the present disposable treatments offer better results.

Results

Nowadays, high-risk PCa definition is not well consensual through the published oncology guides. Clinical stage, tumour grade, and number of risk factors are relevant to be considered on PCa prognosis. However, these factors are susceptible to change depending on when surgical or radiation therapy is considered to be the treatment of choice. Other factors, such as reference pathologist, different diagnosis biopsy schedules, surgical or radiotherapy techniques, adjuvant treatments, biochemical failures, and follow-up, make it difficult to compare the results between different therapeutic options.

Conclusions

This article reviews important issues concerning high-risk PCa. URONCOR, GUO, and SOGUG on behalf of the Spanish Groups of Uro-Oncology Societies have reached a consensus addressing a practical recommendation on definition, diagnosis, and management of high-risk PCa.

     

In Vitro Studies on Phytochemical Content,Antioxidant, Anticancer,Immunomodulatory, and Antigenotoxic Activities of Lemon,Grapefruit, and Mandarin Citrus Peels

Background: In recent years, there has been considerable research on recycling of agroindustrial waste for production of bioactive compounds. The food processing industry produces large amounts of citrus peels that may be an inexpensive source of useful agents. Objective: The present work aimed to explore the phytochemical content, antioxidant, anticancer, antiproliferation, and antigenotxic activities of lemon, grapefruit, and mandarin peels. Materials and Methods: Peels were extracted using 98% ethanol and the three crude extracts were assessed for their total polyphenol content (TPC), total flavonoid content (TFC), and antioxidant activity using DPPH (1, 1diphenyl2picrylhydrazyl). Their cytotoxic and mitogenic proliferation activities were also studied in human leukemia HL60 cells and mouse splenocytes by CCK8 assay. In addition, genotoxic/ antigenotoxic activity was explored in mouse splenocytes using chromosomal aberrations (CAs) assay. Results: Lemon peels had the highest of TPC followed by grapefruit and mandarin. In contrast, mandarin peels contained the highest of TFC followed by lemon and grapefruit peels. Among the extracts, lemon peel possessed the strongest antioxidant activity as indicated by the highest DPPH radical scavenging, the lowest effective concentration 50% (EC50 42.97 ?g extract/ mL), and the highest Trolox equivalent antioxidant capacity (TEAC0.157). Mandarin peel exhibited moderate cytotoxic activity (IC50 77.8 ?g/mL) against HL60 cells, whereas grapefruit and lemon peels were ineffective antileukemia. Further, citrus peels possessed immunostimulation activity via augmentation of proliferation of mouse splenocytes (Tlymphocytes). Citrus extracts exerted noncytotoxic, and antigenotoxic activities through remarkable reduction of CAs induced by cisplatin in mouse splenocytes for 24 h. Conclusions: The phytochemical constituents of the citrus peels may exert biological activities including anticancer, immunostimulation and antigenotoxic potential.     

Influence of Rurality,Race, and Ethnicity on Non-Hodgkin Lymphoma Incidence

IntroductionExposure to lymphomagens vary by geography. The extent to which these contribute to racial and ethnic disparities in non-Hodgkin lymphoma (NHL) incidence is not well understood. We sought to evaluate the association between urban–rural status and racial and ethnic disparities in the 3 major NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL).Patients and MethodsWe used data on NHL incidence from 21 Surveillance, Epidemiology, and End Results (SEER) population-based registries for the period 2000 to 2016. Population characteristics were compared by NHL subtype and urban–rural status, using rural-urban continuum codes from the US Department of Agriculture. Incidence rate ratios were calculated, and Poisson regression was used to assess the association between incidence and rurality.ResultsA total of 136,197 DLBCL, 70,882 FL, and 120,319 CLL incident cases aged ≥ 20 years were reported. The majority of DLBCL patients were non-Hispanic white (73.5%), with 11.9% Hispanic and 7.3% non-Hispanic black, with a similar distribution observed in FL and CLL. Adjusting for age, sex, and family poverty, we found increased DLBCL incidence among Hispanics in increasingly urban areas compared to rural areas (rural incidence rate ratio [IRR] = 1.00; nonmetropolitan urban IRR = 1.32, 95% CI 1.16, 1.51; metropolitan urban IRR = 1.55, 95% CI 1.36, 1.76). Among non-Hispanic blacks, urban areas, relative to rural areas, were associated with increased CLL incidence (IRR = 1.48; 95% CI 1.27, 1.72).ConclusionUrban–rural incidence patterns suggest that environmental exposures in urban areas associated with DLBCL and CLL pathogenesis may disproportionately affect Hispanics and non-Hispanic blacks.     

Cancers, precancers, and pseudocancers on the male genitalia. A review of clinical appearances, histopathology, and management

Leukoplakia penis and balanitis xerotica obliterans are precancerous lesions. Bowen's disease, erythroplasia (Queyrat), and extramammary Paget's disease are carcinomas in situ. Lesions of both types may closely mimic benign skin conditions that may occur in the genital region. Histologic examination is usually the only certain means of diagnosis. The same considerations apply to pseudomalignancies, e.g., giant condyloma acuminatum (Buschke-Loewenstein), which clinically behaves as a carcinoma but histologically appears benign, and Bowenoid papulosis, a new entity that is believed to be benign although it has histologic features of a carcinoma in situ.     

肥胖脂肪因子与食管腺癌的研究进展

肥胖与肿瘤是全球两大影响健康的重要问题,肥胖增加食管腺癌的发病及死亡风险。脂肪组织能够分泌多种生物学活性的脂肪因子,如瘦素、脂联素、抵抗素等。近年研究发现脂肪因子在胃食管返流病、Barrett食管及癌变中发挥重要作用。本文就肥胖及脂肪因子与食管腺癌的研究进展进行综述。     

Comparative effects of aplysiatoxin, debromoaplysiatoxin, and teleocidin on receptor binding and phospholipid metabolism

We have compared the activities of aplysiatoxin and debromoaplysiatoxin, two polyacetate marine algae toxins, with teleocidin, a tumor-promoting indole alkaloid from Streptomyces, with respect to inhibition of specific binding of epidermal growth factor, and phorbol-12,13-dibutyrate to their respective receptors and ability to stimulate the release of radioactivity from cells prelabeled with choline or arachidonic acid. Although these compounds have chemical structures that are quite different from the phorbol esters, both aplysiatoxin and teleocidin are essentially equipotent with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate in all four assays. The fact that aplysiatoxin and teleocidin inhibit phorbol-12,13-dibutyrate-receptor binding suggests that their biological activities are mediated by binding to the same receptors utilized by the phorbol esters. Debromoaplysiatoxin, a debrominated form of aplysiatoxin, is about 10-fold weaker than aplysiatoxin in inhibiting epidermal growth factor and phorbol-12,13-dibutyrate-receptor binding, but is equipotent with aplysiatoxin in stimulating the release of lipid metabolites from the prelabeled cells. The results are discussed in terms of possible heterogeneity of cellular receptors for this group of compounds.     

A randomized,placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep,mood, and hot flashes

The purpose is to examine the effects of melatonin supplementation on sleep, mood, and hot flashes in postmenopausal breast cancer survivors. In a randomized, double-blind, placebo-controlled study, 95 postmenopausal women with a prior history of stage 0–III breast cancer, who had completed active cancer treatment (including hormonal therapy) were randomly assigned 1:1 to either 3 mg oral melatonin (n = 48) or placebo daily (n = 47) for 4 months. Sleep, mood, and hot flashes were assessed at baseline and 4 months via self-administered questionnaire using the Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiologic Studies—Depression (CES-D), and the North Central Cancer Treatment Group (NCCTG) hot flash diary, respectively. Eighty-six women (91 %) completed the study and provided pre- and post-questionnaires. At baseline, 52 % of participants reported poor sleep in the month prior to enrollment. Compared to subjects on placebo, subjects randomized to melatonin experienced significantly greater improvements in subjective sleep quality as measured by the PSQI, including domains on sleep quality, daytime dysfunction and total score. For example, the mean change in PSQI score was ?0.1 in the placebo group compared to ?1.9 in the melatonin group (p < 0.001). There were no significant differences in measures of depression or hot flashes. Sleep disturbances are common among breast cancer survivors, even after completion of active cancer treatment. This is the first randomized placebo-controlled study among breast cancer survivors to demonstrate that melatonin was associated with an improvement in subjective sleep quality, without any significant adverse effects.