Published on Web 12/03/2008 A Robust Platform for the Synthesis of New Tetracycline Cuixiang Sun, Qiu Wang, Jason D. Brubaker, Peter M. Wright, Christian D. Lerner, Kevin Noson, Mark Charest, Dionicio R. Siegel, Yi-Ming Wang, and Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138 Received August 21, 2008; E-mail: [email protected]
Medonline.huCancer Causes Control (2014) 25:1131–1140 Serum levels of vitamin D, parathyroid hormone and calciumin relation to survival following breast cancer Linnea Huss • Salma Butt • Signe Borgquist •Martin Almquist • Johan Malm • Jonas Manjer Received: 3 January 2014 / Accepted: 5 June 2014 / Published online: 22 June 2014Ó The Author(s) 2014. This article is published with open access at Springerlink.com 2006. Serum samples collected at baseline were analyzed for Vitamin D, parathyroid hormone (PTH) and cal- 25OHD, PTH and calcium. All patients were followed until 31 cium in blood are correlated with each other. Previous December 2010 using the Swedish Cause of Death Registry.
studies have suggested vitamin D to have anti-proliferative The analytes were divided into tertiles and the risk of death effects on tumor cells, whereas PTH may have carcinogenic from breast cancer was analyzed using an adjusted Cox pro- effects. A cancer disease may influence calcium levels in portional hazards analysis, yielding hazard ratios with 95 % blood, but less is known about calcium and its potential effect on cancer risk and survival. The aim of this study was to Levels of 25OHD and breast cancer mortality examine pre-diagnostic levels of vitamin D (25OHD), PTH were associated in a u-shaped manner with the highest and calcium in relation to survival after breast cancer.
mortality among patients in the first (2.46: 1.38–4.37) and The Malmo¨ Diet and Cancer Study enrolled third tertiles (1.99: 1.14–3.49), as compared to the second.
17,035 women between 1991 and 1996. 672 patients devel- An inverse relation was found between calcium levels and oped incident invasive breast cancer up until 31 December breast cancer mortality, with the lowest mortality in thethird tertile, (0.53: 0.30–0.92) as compared to the first.
There was no clear association between PTH and breast L. Huss (&) S. Butt J. Manjer cancer mortality.
Department of Surgery, Ska˚ne University Hospital, Lund This study shows that pre-diagnostic 25OHD University, 205 02 Malmo¨, Sweden and calcium may affect survival following breast cancer.
Breast cancer Calcium Mortality PTH Department of Oncology, Ska˚ne University Hospital, Lund, Survival Vitamin D S. BorgquistDivision of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden Vitamin D has been suggested to have anti-proliferative M. AlmquistDepartment of Surgery, Ska˚ne University Hospital, Lund effects on breast tumor cells in animal and in vitro studies University, Lund, Sweden Ecological studies have shown a difference in breast cancerincidence and survival related to geography, suggesting a beneficial effect of vitamin D levels due to solar exposure Section for Clinical Chemistry, Department of LaboratoryMedicine, Ska˚ne University Hospital, Lund University, Malmo¨, and others have shown a better survival in patients diag- nosed with breast cancer during summer and autumn investigated the relationship between vitamin D and breast Department of Plastic Surgery, Ska˚ne University Hospital, LundUniversity, Malmo¨, Sweden cancer incidence, but with conflicting results [, A Cancer Causes Control (2014) 25:1131–1140 recent meta-analysis of studies which had measured vita- A total of 41 % of eligible subjects participated and 17,035 min D levels (25OHD in serum or plasma) close to diag- women completed the baseline examination ]. Written nosis in early stage breast cancer, found an association informed consent was obtained from all participants.
between low levels of vitamin D and a high mortality, i.e., Baseline examination included a dietary assessment and a a poor survival [Only one study has previously self-administered questionnaire on different life-style fac- investigated pre-diagnostic serum levels of vitamin D in tors. Moreover, a trained nurse performed anthropometric relation to breast cancer mortality among breast cancer measurements and blood samples were drawn. Subjects patients. Freedman et al. [found an inverse relationship were included, and had their blood samples drawn, evenly between low pre-diagnostic levels of vitamin D (25OHD) over the calendar year, except for less recruitment in and high breast cancer mortality.
December and June, and none in July. The ethical com- Levels of vitamin D and parathyroid hormone (PTH) are mittee in Lund, Sweden, approved the MDCS (LU 51-90), inversely correlated with each other ], and both influ- and the present study (Dnr 652/2005 and Dnr 23/2007).
ence the level of calcium in blood. PTH is secreted fromthe parathyroid gland when calcium levels are low and stimulates release of calcium from bone into blood andsynthesis of active vitamin D (1,25(OH)2D) from its stor- For identification of breast cancer cases within the MDCS age form (25OHD). It has been suggested in experimental cohort, The Swedish Cancer Registry was used. Prior to studies that PTH has a carcinogenic and tumor promoting baseline examination, 576 out of the 17,035 women were effect , and it has also been indicated that primary diagnosed with breast cancer. These women were catego- hyperparathyroidism may increase the risk of breast cancer rized as prevalent breast cancer cases and therefore [To our knowledge, no previous study has inves- excluded from the current analysis. In all, 766 women were tigated the relationship between levels of PTH and breast diagnosed with breast cancer up until December 31, 2006, cancer survival.
but two incident cases had not donated blood at baseline It is well known that calcium levels may be increased We found that 77 tumors were cases of ductal cancer following different cancer forms. One previous study has in situ, and these cases were excluded as the present study shown an increased incidence of breast cancer with high intended to examine survival, i.e., there is a very low pre-diagnostic calcium levels ]. It is, however, unknown mortality, if any, associated with in situ breast cancer.
what impact pre-diagnostic calcium levels may have on Another 15 cases were excluded due to bilateral cancer, as breast cancer survival. Since calcium has been shown to be it was difficult to interpret information about tumor char- an important intracellular messenger, involved in prolifer- acteristics in these cases. Finally, a total of 672 women ation, apoptosis and cell signaling [it is possible to with invasive unilateral breast cancer were included in the hypothesize that calcium may affect survival following present analysis. Mean time from baseline examinations to breast cancer.
diagnosis was 7.12 years with a standard deviation (SD) of In 1991, inclusion in a population-based prospective cohort study began in Malmo¨, creating The Malmo¨ Dietand Cancer Study (MDCS), including 17,035 women.
Clinical information Blood samples taken at baseline are now available foranalysis.
Information on type of surgery and planned adjuvant therapy, Our main hypothesis is that low vitamin D (25OHD) is recommended by a treatment conference immediately fol- associated with a poor survival following breast cancer, i.e., lowing surgery, was retrieved from clinical notes. Some 41 % a high mortality among cases. Our secondary hypothesis is (n = 272) underwent mastectomy, and 57 % (n = 382) had a that high pre-diagnostic PTH is also associated with a poor partial mastectomy. Lymph nodes were examined after sen- survival. As a third explorative analysis, we investigated if tinel node biopsy in 26 % (n = 173) and after axillary dis- calcium also had an effect on survival.
section in 62 % (n = 416). Adjuvant treatment withradiotherapy was planned for 54 % (n = 361) of patients,endocrine treatment in 46 % (n = 312), and 14 % (n = 92) Materials and methods were planned for chemotherapy, Table The Malmo¨ Diet and Cancer Study (MDCS) Between 1991 and 1996, all residents in the Southern Information on laterality, tumor size and lymph node Swedish city of Malmo¨, born 1923–1950, were invited to metastasis was retrieved from medical records and histo- participate in a population-based prospective cohort study.
pathological reports. All invasive tumors, diagnosed Cancer Causes Control (2014) 25:1131–1140 Table 1 Vital status in relation to age at baseline between 1991 and 2004, were pathologically re-evaluatedby one senior pathologist. The re-evaluation concerned tumor invasiveness, tumor type according to WHO and grading according to Elston–Ellis , ]. Tumors diag- nosed between 2005 and 2006 were classified according to WHO type and Elston–Ellis grade at diagnosis, thus Number (column percent) information was readily available from clinical notes and Mean (SD) in italics pathology reports. Estrogen receptor status (ER) and pro-gesterone receptor status (PgR) on all tumors were evalu- ated with tissue microarray technique (TMA), using immunohistochemical (IHC) analysis with specific anti- bodies as described in detail previously [In line with Swedish clinical practice, the cutoff points for dichoto- mizing tumors, as being negative or positive, were 0–10 and 11–100 % positive nuclei, respectively.
Laboratory analysis At baseline examination, serum was extracted within 1 h from venipuncture and samples were thereafter stored at -80 °C ]. Serum from identified cases of breast cancer was retrieved from the MDCS bio bank and analyzed for 25OHD, PTH and calcium. The samples had not been previously thawed. High-pressure liquid chromatography (HPLC) was used to analyze 25OHD3, and laboratory analysis was successful in 655 out of 672 cases in the present study population. PTH was analyzed with the Im- munoliteÒ 2000 Intact PTH immunoassay (Diagnostic Products corporation, Los Angeles, CA), 664 successful analyses. Total calcium was successfully analyzed in 661 cases by neutral carrier ion-selective electrode [ Unsuccessful analyses were due to inadequate volume or quality of sera. The analysis of blood samples was per- formed during 2007 as part of a previous case–control study and has previously been described in detail .
Endpoint retrieval The Swedish Cause of Death Registry was used to identify cases that had deceased as well as their cause and date of death. End of follow-up was the date of death, date of emigration or December 31, 2010. Mean time from diag- nosis until end of follow-up was 8.7 years (SD: 4.0).
Subsequently, the women were divided into three different groups: (1) women still alive at end of follow-up; (2) women with breast cancer as cause of death or with breast cancer as a contributing cause of death which were clas- sified as ‘‘dead from breast cancer,'' i.e., ‘‘breast cancer- specific mortality''; and (3) women deceased from causes Age at diagnosis and prognostic factors for breast cancer unrelated to breast cancer (‘‘dead from other cause'').
Cancer Causes Control (2014) 25:1131–1140 Table 2 Vital status in relation Surgical treatment Partial mastectomy Local excision or surgical biopsy No axillary dissection Axillary dissection Sentinel node biopsy Singular node biopsy Planned adjuvant radiotherapy Planned adjuvant endocrine therapy Aromatase inhibitor Other/unknown drug Planned adjuvant chemotherapy Statistical methods status and PgR status. All confounders were tested one at atime in the model in order to see which factor affected Levels of 25OHD, PTH and calcium were divided into ter- hazard ratio (HR) the most.
tiles. Survival was assessed as mortality from breast cancer As a sensitivity analysis, we adjusted our exposures for per 100,000 person-years. In order to test differences in each other. As an example, 25OHD was adjusted for the mortality between tertiles, a Cox's proportional hazards other exposures, PTH and calcium, individually and analysis, yielding hazard ratios (HR) and 95 % confidence intervals (CI), was used. The assumption of proportional To assess the risk of reverse causality, we performed hazards was met as tested by log—minus log plots.
sensitivity analyses, repeating all analyses, excluding The model was subsequently adjusted for factors known women diagnosed with breast cancer within 2 years from the to influence levels of 25OHD, PTH and calcium, such as baseline examination (n = 82). Another sensitivity analysis, season of blood draw and age at baseline. In order to adjust in which the Cox analyses were also adjusted for different for storage time, year of baseline examination was included types of adjuvant therapy, was also performed.
in the model.
Moreover, we made sensitivity analyses in which we The Cox analysis was further adjusted for factors known stratified the analyses for premenopausal, respectively, to affect survival following breast cancer such as age at postmenopausal women at the time of diagnosis, and for diagnosis, tumor size, lymph node status, the presence of body mass index (BMI) 25 (considered normal weight) distant metastases, Nottingham grade, histological type, ER versus BMI C25 (overweight).
Cancer Causes Control (2014) 25:1131–1140 Table 3 Tertiles of 25OHD3, PTH and Ca in relation to breast cancer mortality a Crude analysisb Adjusted for season and year of blood sample, and age at baselinec Adjusted for same factors as b but also for age at diagnosis, size of tumor, Elston–Ellis grade, histological type, ER status, PGR status, lymphnode status and distant metastasis at diagnosis This association was not statistically significant in thecrude analysis, but it was stronger and turned statistically Out of 672 women, 101 had died due to breast cancer, significant 0.53 (0.30–0.92) when the analysis was adjusted which gives a breast cancer-specific mortality of 1,738/ for known prognostic factors (Table ). Factors adding 100,000 person-years. A comparison between different most to the stronger association were lymph node status outcomes and factors possibly affecting survival is pre- and distant metastasis.
sented in Table Table shows the distribution of treat- In the adjusted analyses, where our studied exposures ment in different groups defined the outcome.
were adjusted for the other exposures, all results remained There was a statistically significantly higher breast cancer- the same (data not shown).
specific mortality (HR) among patients in the first 1.84 In order to exclude women with subclinical breast cancer at (1.08–3.13) as well as the third 1.81 (1.06–3.07) tertile of the time of baseline blood donation, we repeated analyses 25OHD as compared to the second tertile (Table In the excluding women diagnosed with breast cancer within 2 years adjusted analysis, these associations were strengthened, fac- as a sensitivity analysis. We found similar associations tors that affected the results most were lymph node status and regarding 25OHD in the first tertile (2.22: 1.20–4.11), but sta- distant metastasis, and remained statistically significant.
tistical significance was lost for the third tertile (1.65: When studying pre-diagnostic levels of PTH, there was 0.89–3.06). No association could be seen between PTH levels also a higher breast cancer-specific mortality among sub- and breast cancer mortality in this analysis. There was still a low jects in the first 1.31 (0.81–2.12) as well as in the third 1.20 mortality from breast cancer among patients with calcium levels (0.73–1.96) tertile (Table however, the results were not within the third tertile in the adjusted analysis, but this associ- statistically significant. Several factors coincided to make ation did not reach statistical significance (0.69: 0.37–1.30).
the associations disappear in the adjusted analysis, but The sensitivity analysis adjusting also for adjuvant when adjusting for size of tumor and lymph node status, the therapy showed similar associations in all analyses (data reduction was strongest (data not shown).
An inverse relationship was seen between calcium levels Due to statistical instability in the premenopausal group and breast cancer-specific mortality, with lower mortality (n = 65), the stratified analyses on menopausal status among subjects within the third tertile 0.88 (0.54–1.44).
showed inconclusive results. In the postmenopausal group Cancer Causes Control (2014) 25:1131–1140 (n = 587), results were similar in all analyses, though con- To this date, there are no available guidelines regarding fidence intervals were somewhat widened (data not shown).
adequate 25OHD levels, though the Committee of the Insti- In the analyses, where we stratified for BMI, we noticed tute of Medicine has recommended 40–50 nmol/liter as a that results were attenuated in the group with BMI C25 lower acceptable level and that levels above 125 nmol/L (n = 326), compared to the group with BMI 25 should raise concern among clinicians in North America (n = 346), though this observation is inconclusive due to These recommended clinical cut points are within the first, low statistical power in the analysis (data not shown).
respectively, third of our tertiles, and 5.9 % (n = 39) of oursubjects had levels underneath 50 nmol/L, 9.3 % (n = 62)above 125 nmol/L.
In addition to the findings that women with low levels of 25OHD had a high mortality, i.e., a poorer survival, we found We found a statistically significant u-shaped relationship, that patients within the third tertile were also at a higher risk for between pre-diagnostic levels of 25OHD and breast cancer- a breast cancer-related death. To date, this has not been shown specific mortality, with higher mortality, i.e., poor survival, previously and the findings do not support our primary among patients with 25OHD levels within the first and hypothesis. However, a similar pattern, with a u-shaped rela- third tertiles as compared to the second. There was no tionship, between levels of 25OHD and risk of subsequent association between PTH and breast cancer-specific mor- prostate cancer has been found in our cohort Also, one tality. Regarding levels of calcium and breast cancer-spe- previous study on 25OHD levels measured at diagnosis and cific mortality, we saw that patients within the highest overall mortality in postmenopausal breast cancer patients, tertile had a lower mortality, i.e., a better survival.
showed the lowest mortality among patients within the secondtertile Since most of the anti-carcinogenic effects of Vitamin D and breast cancer vitamin D seem to be mediated by the vitamin D receptor(VDR) , individual- or tumor-specific differences in VDR The finding that low 25OHD levels were associated with a high may be of importance.
breast cancer-specific mortality is in line with our hypothesis. Itis now well known that vitamin D inhibits growth of tumor- PTH and breast cancer derived cells from breast [and promote apoptosis in breastcancer cells On a molecular level, active vitamin D We did not find any association between levels of PTH and (1,25(OH)2D) has been shown to act as a cancer inhibitor in breast cancer-specific mortality. Previous experimental many other ways, such as enhanced DNA repair, immuno- studies have suggested that PTH may be associated with poor modulation and protection against antioxidants, although there breast cancer survival due to carcinogenic and tumor pro- are areas not yet understood , . These mechanisms may moting effects [–], such as regulating angiogenesis and indeed explain the results seen in the present study.
osteoclastogenesis in bone metastasis by breast cancer cells One previous study has shown a better survival for breast-, Therefore, our hypothesis was that there would be an colon- and prostate cancer patients diagnosed during summer association. Due to intra-individual variation of PTH levels or early fall, which would indicate advantages of adequate ], there is a risk of misclassification, which might have vitamin D levels during treatment ]. It has also been sug- affected our results. There are no previous results reported gested that less favorable outcome for African–American from epidemiological studies on PTH and breast cancer sur- women with breast cancer in the USA is due to lower habitual vival, and our explorative analysis is the first within the area.
vitamin D status among these women Directly measuredsufficient levels at diagnosis in early breast cancer have in otherstudies been shown to improve survival , ]. Experi- Calcium and breast cancer mental and epidemiological studies taken together; they areconsistent with our finding that lower pre-diagnostic levels of High levels of calcium at diagnosis of breast cancer have 25OHD are related to poor survival. One study measuring previously been associated with large tumors, and this may vitamin D before diagnosis found an inverse relationship well be an effect of the tumor per se Previous findings between pre-diagnostic levels of vitamin D (25OHD) and suggest an increased incidence and more aggressive breast breast cancer mortality ]. When analyzing breast cancer cancer tumor characteristics, associated with higher pre- mortality, they choose to stratify 25OHD in two categories with diagnostic calcium levels , ]. In contrast, our levels [62.5 and B62.5 nmol/L hence they differ only explorative analysis found an association between high pre- between high and low 25OHD. This cut point is within our first diagnostic levels of calcium and a lower breast cancer-specific tertile and is therefore also in line with our results.
mortality. This finding needs further scientific attention, and Cancer Causes Control (2014) 25:1131–1140 the expression or activity of the calcium receptor may mod- As it has been previously shown that women within the ulate the effect of calcium on breast tumors.
MDCS cohort have a higher incidence of breast cancer, butlower breast cancer mortality, than non-participants, there Methodological issues is a risk of a selection bias. The mortality risk betweenparticipants in this study group and general population of This study was performed using blood samples taken Malmo¨, hence, may differ. However, as there was a broad before diagnosis. Therefore, the tumor itself cannot have distribution of 25OHD, and to some extent PTH in our influenced the analyzed levels. The sensitivity analysis material, we consider that relative risks were less likely to excluding women diagnosed within 2 years from baseline have been affected by a potential selection bias.
showed similar results regarding 25OHD and mortality Primarily, we chose not to adjust for BMI in this study, from breast cancer, but statistical significance was lost in since previous studies have shown that a high BMI is asso- the upper tertile, assumingly due to loss of statistical power ciated with low levels of vitamin D and high BMI is also with a decreasing number of outcomes, more precisely 94 associated with a poor prognosis hence, it may be part of deaths from breast cancer instead of 113.
the casual pathway. A previous study has suggested the pos- It must be considered that there is only one blood sibility of trapping vitamin D in subcutaneous fat sample available for analysis, sometimes taken many years Therefore, an adjustment for BMI could possibly have before diagnosis, and it is possible that this sample does not masked an association between vitamin D levels and breast reflect the individuals' habitual vitamin D, PTH and cal- cancer prognosis. When we stratified the analyses for normal cium status. Previous studies have shown, though, that versus overweight, we noted that associations were stronger in 25OHD measured at two times, several years apart have a the overweight group compared to normal weight, which high correlation , ].
could be explained by the above reasoning.
Regarding PTH, it has been shown that there is a short-term Since the analysis was adjusted for prognostic factors (up to 6 weeks) intra-individual variation of about 25 % [ that are used when deciding on adjuvant treatment, we PTH also shows a relatively large circadian fluctuation chose to present the analyses not adjusting for treatment as ], and the time of the day for blood donation in the present this may have lead to an over-adjustment. Moreover, the study has not been recorded ]. Therefore, there is a risk of sensitivity analysis that included treatment showed similar misclassification of PTH levels that may have attenuated a results as the main analysis.
potential possibly obscure true association between pre-diag- Apart from the variables adjusted for in the present nostic levels of PTH and mortality from breast cancer. Contrary analyses, there may have been other factors of interest, to PTH, total serum calcium has been shown to have a low intra- such as information on human epidermal growth factor individual variation over short as well as long time , ].
receptor 2 (HER-2), which is a known prognostic factor Vitamin D levels tend to decrease with increasing age, that influences both choice of treatment as well as prog- whereas PTH and calcium increases , Therefore, nosis of a diagnosed breast cancer. Unfortunately many we adjusted our analyses for age. We decided not to adjust tumors in our material were diagnosed before HER-2 was for menopause in our analysis, as menopause is heavily recognized and used in clinical practice.
dependent on age. In a sensitivity analysis, where we Fortunately, breast cancer-specific mortality is relatively stratified for menopause, the analysis showed similar low, but this means few deaths from breast cancer in the associations for postmenopausal women, but the analysis present study. Nonetheless, we were able to find statistically was unstable regarding premenopausal women, due to significant data to support that pre-diagnostic 25OHD levels small numbers (n = 65) in this group.
influence mortality from breast cancer. In this analysis, we Another factor that is known to affect serum levels of could not find statistically significant associations between 25(OH)D is season but as this factor was included in the pre-diagnostic levels of PTH and breast cancer survival and multivariate analysis, we consider that such variation ought to also the association between levels of calcium and breast have affected our results only to a minor extent.
cancer mortality was weak. Since outcome, i.e., deaths from Since all Swedish residents are given a unique civil breast cancer are sparse, there is a possibility of type II error registration number, it is possible to link all women to and true associations could have been missed.
different registries. The Swedish Cause of Death Registrythat was used to retrieve information on cause of death, hada coverage of 97.3 % in 2008 [and it has been shown to be correct in 90 % of cases where malignant tumors isthe cause of death [Therefore, it is expected that data Women with pre-diagnostic 25OHD levels within the first concerning cause of death is complete and correct to a and third tertiles as compared to the second have a higher great extent.
breast cancer-specific mortality, i.e., a poor survival. There Cancer Causes Control (2014) 25:1131–1140 was no association between pre-diagnostic levels of PTH (BCLU), and The Region Ska˚ne (ALF). The authors want to thank Dr and breast cancer mortality. A weak association was seen Lola Anagnostaki, for pathologically examining all tumors diagnosedbetween 1991–2004, and RN Anna Hwasser for data management.
between high levels of pre-diagnostic calcium and lowbreast cancer mortality. Our analysis suggests that vitamin This article is distributed under the terms of the D levels may affect breast cancer survival, but that both Creative Commons Attribution License which permits any use, dis- low and relatively high levels may have an adverse effect.
tribution, and reproduction in any medium, provided the originalauthor(s) and the source are credited.
This work was supported by The Swedish Cancer Society, The Gunnar Nilsson Cancer Foundation, The ErnholdLundstro¨m Foundation, The Henning and Ida Persson Foundation, The Einar and Inga Nilsson Foundation, The Malmo¨ UniversityHospital Cancer Research Fund, The Ska˚ne University Hospital Funds and Donations, The Breast Cancer network at Lund University Table 4 Tertiles of vitamin D3 in relation to age and breastcancer characteristics Column percent (mean and SD in italics) Age at diagnosis (years) Lymph node status Distant metastasis Histological type Cancer Causes Control (2014) 25:1131–1140 17. Palmer M, Adami HO, Krusemo UB, Ljunghall S (1988) Increased risk of malignant diseases after surgery for primary 1. Colston KW (2008) Vitamin D and breast cancer risk. Best Pract hyperparathyroidism. A nationwide cohort study. Am J Epi- Res Clin Endocrinol Metab 22(4):587–599. 18. Michels KB, Xue F, Brandt L, Ekbom A (2004) Hyperparathy- 2. Rohan T (2007) Epidemiological studies of vitamin D and breast roidism and subsequent incidence of breast cancer. Int J Cancer cancer. Nutr Rev 65(Supplement 1):80. doi: 110(3):449–451. 19. Nilsson IL, Zedenius J, Yin L, Ekbom A (2007) The association 3. Grant WB (2010) An ecological study of cancer incidence and between primary hyperparathyroidism and malignancy: nation- mortality rates in France with respect to latitude, an index for wide cohort analysis on cancer incidence after parathyroidec- vitamin D production. Dermatoendocrinol 2(2):62–67. doi: tomy. Endocr Relat Cancer 14(1):135–140. 4. Chen W, Armstrong BK, Rahman B, Zheng R, Zhang S, Cle- 20. Pickard AL, Gridley G, Mellemkjae L, Johansen C, Kofoed- ments M (2013) Relationship between cancer survival and Enevoldsen A, Cantor KP, Brinton LA (2002) Hyperparathy- ambient ultraviolet B irradiance in China. Cancer Causes Control.
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Seguridad e Higiene Industrial SEGURIDAD INDUSTRIAL [Guía del participante] Técnico Nivel Operativo Senati [email protected] Seguridad e Higiene Industrial Tabla de Contenido Seguridad e Higiene Industrial Seguridad e Higiene Industrial La promulgación del Reglamento de la Ley Nº 29783, Ley de Seguridad y Salud en el Trabajo, en