Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence.
In this population-based case-control study, we included women diagnosed with stage I-III breast cancer between 1985 and 2001, aged 35-69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER-/TAM-). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence.
HIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER-/TAM- stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER-/TAM- OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER-/TAM- stratum.
In this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER- breast cancer.

To evaluate Cu and Zn levels in bladder cancer (BC) patients and their relationship with expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1). Plasma levels of Cu and Zn were determined in 66 transitional bladder cell carcinoma patients (BC group) and 60 matched controls. The concentration of Cu and Zn as well as the expressions of both VEGF and HIF-1 were also estimated in cancerous and non-cancerous bladder tissues in the BC group. The results showed that plasma Cu and Cu/Zn ratio were significantly higher in BC group when compared with the control group. In contrast, the plasma Zn in BC group was significantly lower than in the controls. Comparing levels of Cu and Zn in cancerous and non-cancerous bladder tissues among the BC group indicated a significantly higher Cu levels in the cancerous tissues, while Zn levels was significantly lower. There were higher expressions of both VEGF and HIF-1 in the cancerous samples. Moreover, the Cu concentration in cancerous tissues was significantly correlated with expressions of VEGF and HIF-1. Logistic regression analysis revealed that the increase in plasma Cu/Zn ratio and plasma Cu and the decrease in plasma Zn may be risk factors for development of bladder cancer. We concluded that alteration of plasma and bladder tissue levels of both Cu and Zn is correlated with pathogenesis of bladder cancer. The increase in Cu level in cancerous tissues of BC group has an important role in angiogenesis in bladder cancer cells.

Despite the fact that external cervical resorption (ECR) is a well-known and rather frequently met condition, the driving force of this phenomenon still remains unclear. Recently, hypoxia has been linked to ECR. Thus, the aim of this work was to investigate the existence of hypoxia in ECR and hypothesize on its role at the time of extraction. This work is a case study of a tooth with ECR. ECR diagnosis was based on clinical and radiographic examination with cone-beam computed tomographic imaging. The extracted tooth was further analyzed by using nanofocus computed tomographic imaging and immunohistology. To investigate the 3-dimensional extent and pattern of ECR, in vivo cone-beam computed tomographic imaging and ex vivo nanofocus computed tomographic imaging were used. Different histologic stains were used to investigate the presence of a hypoxic environment and to gain a better insight into the involved cells, neuronal structures, and remodeling process during ECR. A higher distribution of hypoxia-inducible factor 1a-positive cells was found in the apical part of the resorption area when compared with the coronal area of the resorption. In addition, a similar distribution of hypoxia-inducible factor 1a-positive odontoblasts was observed in the pulp. Three-dimensional analysis of the calcification of the pulp revealed the formation of pulp stones in areas with higher hypoxia. Histology showed that remodeling during ECR can occur according to a layered pattern. This investigation confirms the presence of hypoxia in ECR and shows that there is a gradient of hypoxia within the ECR lesion and surrounding tooth structure. The hypoxic environment within the pulp is also indicated by the formation of pulp stones.

Stabilizing the labile factor HIF (hypoxia inducible factor) for therapeutic use has led to the development of various molecules by pharmaceutical companies. These HIF stabilizers show promising erythropoiesis stimulating capacities and are of great interest for patients with chronical kidney disease and anemia. Amongst them FG-4592 from FibroGen is now under phase 3 of clinical studies. While this drug is still under investigation, a parallel market already allows to buy this product, which could be tempting for some athletes willing to increase their performances. To avoid such a use for doping purpose, WADA has listed HIF stabilizers and FG-4592 in particular as prohibited substances since 2011 and some anti-doping laboratories have developed a technique of identification of FG-4592 in urine. Here, we described the first case ever identified by an anti-doping laboratory of an athlete using FG-4592. Detection and confirmation in urinary samples was performed by LC-MS/MS. In addition, potential indirect markers erythropoietin (EPO) and hematological parameters followed in the Athlete Biological Passport (ABP) were analyzed during and after the period of use but showed no profound alterations. Only ABPS (abnormal blood profile score) reached (but did not exceed) the upper limit proposed by the ABP adaptive model just after the period of use of FG-4592. Altogether this case sends a warning for anti-doping laboratories which now must strengthen surveillance on HIF stabilizers and develop sensitive methods of detection for this new class of drugs.