Shira Kramer, Elizabeth Ward, Anna Meadows, Kathleen E Malone
A matched case-control study of prenatal risk factors for neuroblastoma was conducted, including 104 cases diagnosed over the period 1970-79 in the Greater Delaware Valley. Significantly elevated odds ratios (OFls) were associated with maternal use of a neurally active drug during pregnancy (OR = 2.83), sex hormone exposure 3 months prior to or during pregnancy (OR = 2.25), frequent alcohol consumption during pregnancy (OR = 9.0), and maternal use of diuretic drugs during pregnancy (OR = 5.75). Significantly more case mothers than control mothers reported use of hair coloring products during pregnancy (OR = 3.0). No association was found between cigarette smoking, coffee consumption, or medical irradiation and case-control status.—JNCI 1987; 78:797-804.
{"title":"Medical and Drug Risk Factors Associated With Neuroblastoma: A Case-Control Study","authors":"Shira Kramer, Elizabeth Ward, Anna Meadows, Kathleen E Malone","doi":"10.1093/jnci/78.5.797","DOIUrl":"https://doi.org/10.1093/jnci/78.5.797","url":null,"abstract":"A matched case-control study of prenatal risk factors for neuroblastoma was conducted, including 104 cases diagnosed over the period 1970-79 in the Greater Delaware Valley. Significantly elevated odds ratios (OFls) were associated with maternal use of a neurally active drug during pregnancy (OR = 2.83), sex hormone exposure 3 months prior to or during pregnancy (OR = 2.25), frequent alcohol consumption during pregnancy (OR = 9.0), and maternal use of diuretic drugs during pregnancy (OR = 5.75). Significantly more case mothers than control mothers reported use of hair coloring products during pregnancy (OR = 3.0). No association was found between cigarette smoking, coffee consumption, or medical irradiation and case-control status.—JNCI 1987; 78:797-804.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In view of the suggested similarity in risk factors for breast cancer and colon cancer in women, an analysis was undertaken to investigate age, period, and cohort influences on the risk of these diseases by use of incidence data for Scotland, Statistical modeling of data for the period 1960-84 revealed that both the age effects and the cohort effects were different for each site. While younger cohorts apparently had signs of reduced risk of both diseases, reduced risk was only apparent among the very youngest cohorts in the case of breast cancer, whereas there has been a gradual reduction in the risk of colon cancer among successive cohorts born since the beginning of the century. Clemmesen’s hook was demonstrated in the age-incidence curve of breast cancer, which was clearly shown to have two different slopes: among premenopausal and among postmenopausal women. The declining risk of breast cancer in younger cohorts appeared contradictory to their apparently “high-risk” profile (in terms of present knowledge of etiologic factors) and suggested the possible existence of a factor that protects against breast cancer, at least at younger ages, but that remains, as yet, unidentified.—JNCI 1987; 79:1175-1179.
{"title":"Breast Cancer and Colon Cancer Incidence in Females in Scotland, 1960-84","authors":"P Boyle, C Robertson","doi":"10.1093/jnci/79.6.1175","DOIUrl":"https://doi.org/10.1093/jnci/79.6.1175","url":null,"abstract":"In view of the suggested similarity in risk factors for breast cancer and colon cancer in women, an analysis was undertaken to investigate age, period, and cohort influences on the risk of these diseases by use of incidence data for Scotland, Statistical modeling of data for the period 1960-84 revealed that both the age effects and the cohort effects were different for each site. While younger cohorts apparently had signs of reduced risk of both diseases, reduced risk was only apparent among the very youngest cohorts in the case of breast cancer, whereas there has been a gradual reduction in the risk of colon cancer among successive cohorts born since the beginning of the century. Clemmesen’s hook was demonstrated in the age-incidence curve of breast cancer, which was clearly shown to have two different slopes: among premenopausal and among postmenopausal women. The declining risk of breast cancer in younger cohorts appeared contradictory to their apparently “high-risk” profile (in terms of present knowledge of etiologic factors) and suggested the possible existence of a factor that protects against breast cancer, at least at younger ages, but that remains, as yet, unidentified.—JNCI 1987; 79:1175-1179.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The effects of both α1- and β-adrenergic blocking agents on the vascular perfusion of tumors were studied with the ultimate goal of improving diagnosis and therapy of solid tumors with the use of monoclonal antibody (MAb) conjugates. With the use of a subcutaneously growing murine thymoma, it was demonstrated that nonselective and cardioselective β-adrenergic blocking agents were capable of increasing threefold tumor-to-blood and tumor-to-liver perfusion of 125I-labeled MAbs. Subsequently, these β-adrenergic blocking agents were found to increase the antitumor efficacy of idarubicin (Ida)-MAb conjugates. Conjugate-treated mice that also received β-adrenergic blocking agents had a smaller mean tumor size and a greater number of regressions than mice receiving Ida-MAb conjugate alone. By contrast, prazosin HCl, an α1-adrenergic blocking agent, and Cyclospasmol, a peripheral vasodilator, did not enhance the tumor perfusion and antitumor efficacy of 125I- or Ida-conjugated MAbs, and no vasoactive agent enhanced the antitumor effect of Ida when used alone. By their selective action on normal blood vessels, vasoactive drugs can change the tumor-to-normal tissue perfusion ratio, thereby enhancing the access of drug-MAb conjugates to tumors and increasing the effectiveness of tumor therapy with the use of drug-MAb conjugates.—JNCI 1987; 79:1367-1373.
{"title":"Use of Vasoactive Agents To Increase Tumor Perfusion and the Antitumor Efficacy of Drug-Monoclonal Antibody Conjugates","authors":"M J Smyth, G A Pietersz, I F C McKenzie","doi":"10.1093/jnci/79.6.1367","DOIUrl":"https://doi.org/10.1093/jnci/79.6.1367","url":null,"abstract":"The effects of both α1- and β-adrenergic blocking agents on the vascular perfusion of tumors were studied with the ultimate goal of improving diagnosis and therapy of solid tumors with the use of monoclonal antibody (MAb) conjugates. With the use of a subcutaneously growing murine thymoma, it was demonstrated that nonselective and cardioselective β-adrenergic blocking agents were capable of increasing threefold tumor-to-blood and tumor-to-liver perfusion of 125I-labeled MAbs. Subsequently, these β-adrenergic blocking agents were found to increase the antitumor efficacy of idarubicin (Ida)-MAb conjugates. Conjugate-treated mice that also received β-adrenergic blocking agents had a smaller mean tumor size and a greater number of regressions than mice receiving Ida-MAb conjugate alone. By contrast, prazosin HCl, an α1-adrenergic blocking agent, and Cyclospasmol, a peripheral vasodilator, did not enhance the tumor perfusion and antitumor efficacy of 125I- or Ida-conjugated MAbs, and no vasoactive agent enhanced the antitumor effect of Ida when used alone. By their selective action on normal blood vessels, vasoactive drugs can change the tumor-to-normal tissue perfusion ratio, thereby enhancing the access of drug-MAb conjugates to tumors and increasing the effectiveness of tumor therapy with the use of drug-MAb conjugates.—JNCI 1987; 79:1367-1373.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
For the investigation of the possibility of its being a marker enzyme for tumor cells, the activity of dipeptidyl peptidase (DPP) IV (EC 3.4.14.5), a membrane-bound enzyme, in cultured human carcinoma cells was examined. The homogenates of three carcinoma cell lines (HeLa, KB, and K-44) contained lower glycylprolyl methylcoumarinamide (Gly-Pro-MCA) hydrolase activities at pH 8.7 (assumed to be DPP IV) and higher activities of alkaline phosphatase and ɣ-glutamyl transpeptidase, which are also membrane-bound enzymes, than those of normal human fibroblasts (HF). Examination of carcinoma cells for the subcellular localization and pH optimum of Gly-Pro-MCA hydrolase activity revealed that the activity of a lysosomal enzyme that hydrolyzes Gly-Pro-MCA at pH 6.4 was markedly increased in carcinoma cells, but not in normal cells. The separation and characterization of Gly-Pro-MCA hydrolases by gel filtration, affinity chromatography, and substrate specificity demonstrated that HF have three peaks indicating DPP IV, DPP II, and an unknown enzyme, whereas the three carcinoma cell lines gave a prominent peak indicating DPP II and a trace of DPP IV. The DPP II activity was 6- to 24-fold higher in carcinoma cell lines than in HF, and it also was 2.85- to 4.13-fold higher than the DPP IV activity in carcinoma cell lines but was 10-fold lower in HF. These clear enzymatic differences between carcinoma cells and normal HF may be useful as a marker of malignancy.—JNCI 1987; 78:863-868.
为了探讨其作为肿瘤细胞标记酶的可能性，我们检测了培养的人癌细胞中膜结合酶二肽基肽酶（DPP） IV （EC 3.4.14.5）的活性。三种癌细胞系（HeLa， KB和K-44）的匀浆在pH 8.7（假设为DPP IV）下具有较低的甘酰丙氨酸甲基香豆素酰胺（gy - pro - mca）水解酶活性，而碱性磷酸酶和-谷氨酰转肽酶（也是膜结合酶）的活性高于正常人成纤维细胞（HF）。对癌细胞的亚细胞定位和Gly-Pro-MCA水解酶活性的最适pH检查显示，在pH 6.4时，癌细胞中水解Gly-Pro-MCA的溶酶体酶活性显著增加，而在正常细胞中则没有。通过凝胶过滤、亲和层析和底物特异性对gy - pro - mca水解酶的分离和表征表明，HF有三个峰，分别表示DPP IV、DPP II和一种未知酶，而三个癌细胞系有一个突出的峰，表示DPP II和微量的DPP IV。DPP - IV在肝癌细胞系中的活性比肝癌细胞系高2.85 ~ 4.13倍，而在HF细胞系中的活性比肝癌细胞系低10倍。癌细胞和正常心衰细胞之间这些明显的酶促差异可能有助于作为恶性肿瘤的标志物。-JNCI 1987;78:863 - 868。
{"title":"Alteration in Dipeptidyl Peptidase Activities in Cultured Human Carcinoma Cells","authors":"Masatalta Komatsu, Masahlro Urade, Minoru Yamaoka, Katsuhiko Fukasawa, Minoru Harada","doi":"10.1093/jnci/78.5.863","DOIUrl":"https://doi.org/10.1093/jnci/78.5.863","url":null,"abstract":"For the investigation of the possibility of its being a marker enzyme for tumor cells, the activity of dipeptidyl peptidase (DPP) IV (EC 3.4.14.5), a membrane-bound enzyme, in cultured human carcinoma cells was examined. The homogenates of three carcinoma cell lines (HeLa, KB, and K-44) contained lower glycylprolyl methylcoumarinamide (Gly-Pro-MCA) hydrolase activities at pH 8.7 (assumed to be DPP IV) and higher activities of alkaline phosphatase and ɣ-glutamyl transpeptidase, which are also membrane-bound enzymes, than those of normal human fibroblasts (HF). Examination of carcinoma cells for the subcellular localization and pH optimum of Gly-Pro-MCA hydrolase activity revealed that the activity of a lysosomal enzyme that hydrolyzes Gly-Pro-MCA at pH 6.4 was markedly increased in carcinoma cells, but not in normal cells. The separation and characterization of Gly-Pro-MCA hydrolases by gel filtration, affinity chromatography, and substrate specificity demonstrated that HF have three peaks indicating DPP IV, DPP II, and an unknown enzyme, whereas the three carcinoma cell lines gave a prominent peak indicating DPP II and a trace of DPP IV. The DPP II activity was 6- to 24-fold higher in carcinoma cell lines than in HF, and it also was 2.85- to 4.13-fold higher than the DPP IV activity in carcinoma cell lines but was 10-fold lower in HF. These clear enzymatic differences between carcinoma cells and normal HF may be useful as a marker of malignancy.—JNCI 1987; 78:863-868.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
George S Bailey, Jerry D Hendricks, Dennis W Shelton, Joseph E Nixon, Norman E Pawlowski
Indole-3-carbinol (I3C), a natural constituent of cruciferous vegetables, is an inhibitor in several experimental animal models of carcinogenesis by polynuclear aromatic hydrocarbons or aflatoxin B1 (AFB1) when administered prior to or during carcinogen exposure. For assessment of the postinitiation effects of I3C, rainbow trout were exposed to dietary I3C in two different protocols—before and during AFB1 exposure or after AFB1 exposure only. Preinitiation exposure to I3C reduced AFB1-initiated hepatocellular carcinomas in trout as previously reported, but postinitiation I3C exposure strongly enhanced the tumor incidence above the positive AFB, control. These results reveal the need for additional research to elucidate the overall effect of I3C on chemical carcinogenesis—JNCI 1987; 78:931-934.
{"title":"Enhancement of Carcinogenesis by the Natural Anticarcinogen Indole-3-carbinol","authors":"George S Bailey, Jerry D Hendricks, Dennis W Shelton, Joseph E Nixon, Norman E Pawlowski","doi":"10.1093/jnci/78.5.931","DOIUrl":"https://doi.org/10.1093/jnci/78.5.931","url":null,"abstract":"Indole-3-carbinol (I3C), a natural constituent of cruciferous vegetables, is an inhibitor in several experimental animal models of carcinogenesis by polynuclear aromatic hydrocarbons or aflatoxin B1 (AFB1) when administered prior to or during carcinogen exposure. For assessment of the postinitiation effects of I3C, rainbow trout were exposed to dietary I3C in two different protocols—before and during AFB1 exposure or after AFB1 exposure only. Preinitiation exposure to I3C reduced AFB1-initiated hepatocellular carcinomas in trout as previously reported, but postinitiation I3C exposure strongly enhanced the tumor incidence above the positive AFB, control. These results reveal the need for additional research to elucidate the overall effect of I3C on chemical carcinogenesis—JNCI 1987; 78:931-934.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regional differences in goblet cell glycoproteins have been demonstrated qualitatively and, to a limited extent, quantitatively in the normal adult colon. In disease states, alterations in these glycoproteins, particularly the sialoglycoproteins (SGs), have been reported. The present study defined parallel qualitative and quantitative changes in SGs in three colon regions during 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]-induced carcinogenesis. SGs were assessed histochemically by use of high iron diamine-Alcian blue (pH 2.5) staining, and tissue sialic acid levels were measured by a modified Warren assay. Two groups of inbred SD rats (n = 28) were pair-fed nutritionally complete liquid diets with 36% of calories supplied as ethanol or isocaloric carbohydrates. The dietary alcohol was added to selectively enhance rectal tumors, a region of prevalent tumors in humans. Both groups received 4 weeks of liquid diet followed by 4 weeks of standard laboratory chow with weekly sc injections of DMH. This 8-week cycle was repeated four times (32 wk). Animals from each group were sacrificed at 8, 16, 24, and 32 weeks, and adjacent tissues from proximal and distal colon and rectum were prepared for histology and biochemical assay. The results showed a progressive increase in sialomucin staining in normal-appearing mucosa in distal colon and rectum in both groups but not in the proximal colon. In contrast, tissue sialic acid increased in all three regions as early as 8 weeks, and significant increases were consistently present by 32 weeks. A different pattern was observed in tissue from frank tumors. Compared with normal-appearing mucosa, both sialomucin staining and tissue sialic acid levels were reduced in tumor tissue by 32 weeks. These studies indicated that tissue sialic acid levels may provide a simple and reliable screening technique in the early diagnosis of premalignant change in all regions of the colon.—JNCI 1987; 79:1375-1382.
{"title":"Qualitative and Quantitative Changes in Sialomucins During 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in the Rat","authors":"Thomas J McGarrity, Emily A Via, Pamela C Colony","doi":"10.1093/jnci/79.6.1375","DOIUrl":"https://doi.org/10.1093/jnci/79.6.1375","url":null,"abstract":"Regional differences in goblet cell glycoproteins have been demonstrated qualitatively and, to a limited extent, quantitatively in the normal adult colon. In disease states, alterations in these glycoproteins, particularly the sialoglycoproteins (SGs), have been reported. The present study defined parallel qualitative and quantitative changes in SGs in three colon regions during 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]-induced carcinogenesis. SGs were assessed histochemically by use of high iron diamine-Alcian blue (pH 2.5) staining, and tissue sialic acid levels were measured by a modified Warren assay. Two groups of inbred SD rats (n = 28) were pair-fed nutritionally complete liquid diets with 36% of calories supplied as ethanol or isocaloric carbohydrates. The dietary alcohol was added to selectively enhance rectal tumors, a region of prevalent tumors in humans. Both groups received 4 weeks of liquid diet followed by 4 weeks of standard laboratory chow with weekly sc injections of DMH. This 8-week cycle was repeated four times (32 wk). Animals from each group were sacrificed at 8, 16, 24, and 32 weeks, and adjacent tissues from proximal and distal colon and rectum were prepared for histology and biochemical assay. The results showed a progressive increase in sialomucin staining in normal-appearing mucosa in distal colon and rectum in both groups but not in the proximal colon. In contrast, tissue sialic acid increased in all three regions as early as 8 weeks, and significant increases were consistently present by 32 weeks. A different pattern was observed in tissue from frank tumors. Compared with normal-appearing mucosa, both sialomucin staining and tissue sialic acid levels were reduced in tumor tissue by 32 weeks. These studies indicated that tissue sialic acid levels may provide a simple and reliable screening technique in the early diagnosis of premalignant change in all regions of the colon.—JNCI 1987; 79:1375-1382.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"126 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular epidemiology is a promising new tool in the study of environmental carcinogenesis and, particularly, in cancer prevention. Genetic damage and mutation are believed to play a critical role in chemical carcinogenesis. By incorporating biologic markers of dose or response to carcinogens (such as mutagenicity of body fluids, carcinogen-DNA adducts, chromosomal abnormalities, and somatic cell mutation) into human biomonitoring or molecular epidemiologic studies, one can detect potential hazards early and increase the power of studies to determine causal relationships. Such markers can also improve extrapolation of risks from experimental animals to humans or from one human population to another. During the past 5 years, there has been considerable progress in developing markers and applying them in human (largely pilot) studies. A review of this experience-with particular emphasis on carcinogen-DNA adducts-affords a better awareness both of the significance of biologic markers and the research needed to fill gaps in understanding. Criteria for marker validation and sound study design are presented that should greatly enhance future research.—JNCI 1987; 78:887-898.
{"title":"Molecular Cancer Epidemiology: A New Tool in Cancer Prevention","authors":"Frederica P Perera","doi":"10.1093/jnci/78.5.887","DOIUrl":"https://doi.org/10.1093/jnci/78.5.887","url":null,"abstract":"Molecular epidemiology is a promising new tool in the study of environmental carcinogenesis and, particularly, in cancer prevention. Genetic damage and mutation are believed to play a critical role in chemical carcinogenesis. By incorporating biologic markers of dose or response to carcinogens (such as mutagenicity of body fluids, carcinogen-DNA adducts, chromosomal abnormalities, and somatic cell mutation) into human biomonitoring or molecular epidemiologic studies, one can detect potential hazards early and increase the power of studies to determine causal relationships. Such markers can also improve extrapolation of risks from experimental animals to humans or from one human population to another. During the past 5 years, there has been considerable progress in developing markers and applying them in human (largely pilot) studies. A review of this experience-with particular emphasis on carcinogen-DNA adducts-affords a better awareness both of the significance of biologic markers and the research needed to fill gaps in understanding. Criteria for marker validation and sound study design are presented that should greatly enhance future research.—JNCI 1987; 78:887-898.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study evaluated whether altered insulin metabolism is a key factor behind weight loss during sarcoma growth in nongrowing mice (C57BL/6J). Fasted sarcoma-bearing mice had decreased blood glucose concentrations but unchanged levels of insulin, compared with those in pair-weighed and freely fed controls. During refeeding, insulin levels were inappropriately low for the degree of glycemia in sarcoma-bearing mice compared with those of pair-weighed and freely fed controls. Injections ip of glucose to tumor-bearing animals resulted in insulin levels comparable to postabsorptive values in healthy control animals, indicating that hypoinsulinemia in freely eating tumor-bearing animals was due to a reduced glycemic sensitivity for pancreatic insulin release. Insulin supplementation at doses [4 IU/100 g (body wt)] that increase body fat in normal animals could not protect the tumor-bearing host from progressive loss of body fat or lean tissues. Exogenous insulin in excess of endogenous insulin production did not stimulate tumor growth. Nitrogen and RNA-DNA content were significantly decreased in the quadriceps muscle of tumor-bearing mice. This reduction was independent of altered insulin levels and could not be prevented by exogenous insulin. The depressed capacity of protein synthesis in extensor digitorum longus (EDL) muscle could be entirely attributed to the state of malnutrition in tumor-bearing animals. The sensitivity and responsiveness of protein synthesis in EDL muscles to insulin were normal in tumor-bearing mice, regardless of whether exogenous insulin exerted its effect in vivo or in vitro. This study confirms insulin resistance for glucose metabolism in an experimental sarcoma animal model. Such changes are concluded to be secondary to anorexia and necessary to counteract hypoglycemia. In nongrowing sarcoma-bearing mice, malnutrition and anorexia account entirely for depressed muscle protein synthesis, which is not explained by insulin resistance at the translational level. Insulin metabolism is not a key factor behind progression of wasting in sarcoma-bearing mice, but anorexia is.—JNCI 1987; 78:943-950.
{"title":"Role of Insulin in Development of Cancer Cachexia in Nongrowing Sarcoma-Bearing Mice: Special Reference to Muscle Wasting","authors":"Gösta Svaninger, Christer Drott, Kent Lundholm","doi":"10.1093/jnci/78.5.943","DOIUrl":"https://doi.org/10.1093/jnci/78.5.943","url":null,"abstract":"This study evaluated whether altered insulin metabolism is a key factor behind weight loss during sarcoma growth in nongrowing mice (C57BL/6J). Fasted sarcoma-bearing mice had decreased blood glucose concentrations but unchanged levels of insulin, compared with those in pair-weighed and freely fed controls. During refeeding, insulin levels were inappropriately low for the degree of glycemia in sarcoma-bearing mice compared with those of pair-weighed and freely fed controls. Injections ip of glucose to tumor-bearing animals resulted in insulin levels comparable to postabsorptive values in healthy control animals, indicating that hypoinsulinemia in freely eating tumor-bearing animals was due to a reduced glycemic sensitivity for pancreatic insulin release. Insulin supplementation at doses [4 IU/100 g (body wt)] that increase body fat in normal animals could not protect the tumor-bearing host from progressive loss of body fat or lean tissues. Exogenous insulin in excess of endogenous insulin production did not stimulate tumor growth. Nitrogen and RNA-DNA content were significantly decreased in the quadriceps muscle of tumor-bearing mice. This reduction was independent of altered insulin levels and could not be prevented by exogenous insulin. The depressed capacity of protein synthesis in extensor digitorum longus (EDL) muscle could be entirely attributed to the state of malnutrition in tumor-bearing animals. The sensitivity and responsiveness of protein synthesis in EDL muscles to insulin were normal in tumor-bearing mice, regardless of whether exogenous insulin exerted its effect in vivo or in vitro. This study confirms insulin resistance for glucose metabolism in an experimental sarcoma animal model. Such changes are concluded to be secondary to anorexia and necessary to counteract hypoglycemia. In nongrowing sarcoma-bearing mice, malnutrition and anorexia account entirely for depressed muscle protein synthesis, which is not explained by insulin resistance at the translational level. Insulin metabolism is not a key factor behind progression of wasting in sarcoma-bearing mice, but anorexia is.—JNCI 1987; 78:943-950.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Siddhartha Yadav,Sonya Reid,Binyam Yilma,Stamatina Fragkogianni,Jennifer G Whisenant,Anne Weidner,Padma Sheila Rajagopal,Minxuan Huang,Elizabeth Mauer,Ali T Arafa,Calvin Chao,Emily A Teslow,Emmanuel S Antonarakis,Allison Kurian,Fergus J Couch,Tuya Pal
BACKGROUNDThe association of germline pathogenic and likely pathogenic variants (GPVs) in hereditary breast cancer genes with underlying tumor biology and clinical outcomes remain incompletely understood. This study characterized differences in somatic alterations and intrinsic subtypes between sporadic and hereditary breast cancers associated with GPVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2.METHODSThis retrospective cohort study included women with breast cancer and an ATM, BRCA1, BRCA2, CHEK2, or PALB2 GPV who underwent tumor sequencing and whole transcriptome RNA expression analysis. Clinicopathologic features, intrinsic subtypes, somatic alterations, and survival were compared by GPV status and immunohistochemistry-defined subtype, and to sporadic cases. All significance tests were 2-sided.RESULTS4,988 women with breast cancer included 98 BRCA1, 126 BRCA2, 74 PALB2, 54 ATM, and 83 CHEK2 GPVs. Compared to sporadic cases, HR+/HER2- tumors in BRCA1 GPVs were significantly enriched for basal subtype (45.5% vs 11.4%, p < 0.001), while CHEK2 carriers had a higher prevalence of luminal A subtype (80.4% vs 60.3%, p = 0.006). In HR+/HER2- breast cancers, BRCA1 GPVs were enriched for TP53 alterations (84.6% vs 29.8%, q < 0.001), ATM GPVs with FGFR1 alterations (35.4% vs 12.7%, q = 0.04), and BRCA2 GPVs with APC alterations (10.1% vs 1.5%, q = 0.004). Conversely, BRCA2 GPVs were inversely associated with PIK3CA alterations (13.0% vs 34.1%, q = 0.005), and CHEK2 GPVs with TP53 alterations (8.0% vs 29.8%, q = 0.02).CONCLUSIONSGPVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2 are associated with distinct intrinsic breast cancer subtypes and somatic genomic alterations. These findings may enhance precision in risk stratification and guide personalized treatment strategies.
背景：遗传性乳腺癌基因中生殖系致病性和可能致病性变异（GPVs）与潜在肿瘤生物学和临床结果的关系尚不完全清楚。本研究表征了与gpv相关的散发性和遗传性乳腺癌在ATM、BRCA1、BRCA2、CHEK2或PALB2基因中的体细胞改变和内在亚型的差异。方法本回顾性队列研究纳入了患有ATM、BRCA1、BRCA2、CHEK2或PALB2 GPV的女性乳腺癌患者，并进行了肿瘤测序和全转录组RNA表达分析。通过GPV状态、免疫组织化学定义的亚型和散发性病例，比较临床病理特征、内在亚型、体细胞改变和生存率。所有显著性检验均为双侧检验。结果4988例乳腺癌患者包括98例BRCA1、126例BRCA2、74例PALB2、54例ATM和83例CHEK2 gpv。与散发病例相比，BRCA1 gpv中HR+/HER2-肿瘤的基础亚型显著富集（45.5% vs 11.4%, p < 0.001），而CHEK2携带者的腔a亚型患病率更高（80.4% vs 60.3%, p = 0.006）。在HR+/HER2-乳腺癌中，BRCA1 gpv富集于TP53改变（84.6% vs 29.8%, q < 0.001）， ATM gpv富集于FGFR1改变（35.4% vs 12.7%, q = 0.04）， BRCA2 gpv富集于APC改变（10.1% vs 1.5%, q = 0.004）。相反，BRCA2 gpv与PIK3CA改变呈负相关（13.0%对34.1%,q = 0.005）， CHEK2 gpv与TP53改变呈负相关（8.0%对29.8%,q = 0.02）。结论BRCA1、BRCA2、ATM、CHEK2和PALB2中的sgpv与不同的内在乳腺癌亚型和体细胞基因组改变相关。这些发现可以提高风险分层的准确性，并指导个性化的治疗策略。
{"title":"Landscape of somatic genetic alterations and PAM50 intrinsic subtypes in breast cancer associated with germline pathogenic variants in DNA-repair genes.","authors":"Siddhartha Yadav,Sonya Reid,Binyam Yilma,Stamatina Fragkogianni,Jennifer G Whisenant,Anne Weidner,Padma Sheila Rajagopal,Minxuan Huang,Elizabeth Mauer,Ali T Arafa,Calvin Chao,Emily A Teslow,Emmanuel S Antonarakis,Allison Kurian,Fergus J Couch,Tuya Pal","doi":"10.1093/jnci/djag070","DOIUrl":"https://doi.org/10.1093/jnci/djag070","url":null,"abstract":"BACKGROUNDThe association of germline pathogenic and likely pathogenic variants (GPVs) in hereditary breast cancer genes with underlying tumor biology and clinical outcomes remain incompletely understood. This study characterized differences in somatic alterations and intrinsic subtypes between sporadic and hereditary breast cancers associated with GPVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2.METHODSThis retrospective cohort study included women with breast cancer and an ATM, BRCA1, BRCA2, CHEK2, or PALB2 GPV who underwent tumor sequencing and whole transcriptome RNA expression analysis. Clinicopathologic features, intrinsic subtypes, somatic alterations, and survival were compared by GPV status and immunohistochemistry-defined subtype, and to sporadic cases. All significance tests were 2-sided.RESULTS4,988 women with breast cancer included 98 BRCA1, 126 BRCA2, 74 PALB2, 54 ATM, and 83 CHEK2 GPVs. Compared to sporadic cases, HR+/HER2- tumors in BRCA1 GPVs were significantly enriched for basal subtype (45.5% vs 11.4%, p < 0.001), while CHEK2 carriers had a higher prevalence of luminal A subtype (80.4% vs 60.3%, p = 0.006). In HR+/HER2- breast cancers, BRCA1 GPVs were enriched for TP53 alterations (84.6% vs 29.8%, q < 0.001), ATM GPVs with FGFR1 alterations (35.4% vs 12.7%, q = 0.04), and BRCA2 GPVs with APC alterations (10.1% vs 1.5%, q = 0.004). Conversely, BRCA2 GPVs were inversely associated with PIK3CA alterations (13.0% vs 34.1%, q = 0.005), and CHEK2 GPVs with TP53 alterations (8.0% vs 29.8%, q = 0.02).CONCLUSIONSGPVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2 are associated with distinct intrinsic breast cancer subtypes and somatic genomic alterations. These findings may enhance precision in risk stratification and guide personalized treatment strategies.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Channing J Paller,Shuanzeng Wei,Megan Schumacher,Daniel Rabizadeh,Yu-Ching Hsu,Changxue Lu,Yidong Chen,Yuezhou Jing,Bruce J Trock,Mayuko Kanayama,Stefan Ambs,Diana M Stafforini,William B Isaacs,George J Netto,Tamara L Lotan,Angelo M De Marzo,Elizabeth A Platz,Jun Luo
BACKGROUNDIdentification and characterization of prostate tumor markers differentially expressed in European American (EA) men vs. African American (AA) men has been one of the focus areas positioned to understand and address prostate cancer disparity in the US. While some genes are differentially expressed, validation studies are limited, and the impact of these expression differences on recurrence risk remains unclear.METHODSThis study focused on phospholipase A2 group 7 (PLA2G7) in prostate cancer surgical specimens from EA and AA patients. A nested case-control study was conducted to evaluate the prognostic value of the PLA2G7 protein while controlling for age, stage, and Gleason, followed by re-analysis of a published dataset of 556 EA and 596 AA prostate cancer patients. Expression signatures correlated with PLA2G7 were investigated in both patient populations.RESULTSPLA2G7 was more frequently overexpressed in EA tumors than AA tumors, and higher tumor-specific PLA2G7 expression was associated with divergent outcomes lower biochemical recurrence risk in EA men but elevated risk in AA men. Expression in non-cancer tissues showed no prognostic value. While androgen response signatures were consistently enriched in high-PLA2G7 tumors across both groups, immune and inflammatory response gene sets showed opposite enrichment trends between AA and EA men.CONCLUSIONThis study represents the first identification and validation of a tumor-specific marker that is both differentially expressed between prostate cancers in AA and EA men and demonstrates opposite prognostic effects based on self-reported race/ethnicity. The findings emphasize the importance of evaluating prostate tumor markers across diverse geographic ancestries.
{"title":"Divergent effects of PLA2G7 on prostate cancer biochemical recurrence in european American and african American men.","authors":"Channing J Paller,Shuanzeng Wei,Megan Schumacher,Daniel Rabizadeh,Yu-Ching Hsu,Changxue Lu,Yidong Chen,Yuezhou Jing,Bruce J Trock,Mayuko Kanayama,Stefan Ambs,Diana M Stafforini,William B Isaacs,George J Netto,Tamara L Lotan,Angelo M De Marzo,Elizabeth A Platz,Jun Luo","doi":"10.1093/jnci/djag036","DOIUrl":"https://doi.org/10.1093/jnci/djag036","url":null,"abstract":"BACKGROUNDIdentification and characterization of prostate tumor markers differentially expressed in European American (EA) men vs. African American (AA) men has been one of the focus areas positioned to understand and address prostate cancer disparity in the US. While some genes are differentially expressed, validation studies are limited, and the impact of these expression differences on recurrence risk remains unclear.METHODSThis study focused on phospholipase A2 group 7 (PLA2G7) in prostate cancer surgical specimens from EA and AA patients. A nested case-control study was conducted to evaluate the prognostic value of the PLA2G7 protein while controlling for age, stage, and Gleason, followed by re-analysis of a published dataset of 556 EA and 596 AA prostate cancer patients. Expression signatures correlated with PLA2G7 were investigated in both patient populations.RESULTSPLA2G7 was more frequently overexpressed in EA tumors than AA tumors, and higher tumor-specific PLA2G7 expression was associated with divergent outcomes lower biochemical recurrence risk in EA men but elevated risk in AA men. Expression in non-cancer tissues showed no prognostic value. While androgen response signatures were consistently enriched in high-PLA2G7 tumors across both groups, immune and inflammatory response gene sets showed opposite enrichment trends between AA and EA men.CONCLUSIONThis study represents the first identification and validation of a tumor-specific marker that is both differentially expressed between prostate cancers in AA and EA men and demonstrates opposite prognostic effects based on self-reported race/ethnicity. The findings emphasize the importance of evaluating prostate tumor markers across diverse geographic ancestries.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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