Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies

Poor oral health has been reported as a risk factor in the etiology of head and neck cancer. Data on oral health were ascertained as part of two multicenter case-control studies comprising 924 cases and 928 controls in central Europe and 2,286 cases and 1,824 controls in Latin America. Incident cases of squamous cell carcinoma of the head and neck (oral cavity, pharynx, larynx) and esophagus, as well as age (in quinquennia)- and sex frequency-matched controls, were enrolled from 1998 to 2003. Poor condition of the mouth (central Europe: odds ratio (OR) = 2.89, 95% confidence interval (CI): 1.74, 4.81; Latin America: OR = 1.89, 95% CI: 1.47, 2.42), lack of toothbrush use (Latin America: OR = 2.36, 95% CI: 1.28, 4.36), and daily mouthwash use (Latin America: OR = 3.40, 95% CI: 1.96, 5.89) emerged as risk factors for head and neck cancer, independent of tobacco use and alcohol consumption. Missing between six and 15 teeth was an independent risk factor for esophageal cancer (central Europe: OR = 2.84, 95% CI: 1.26, 6.41; Latin America: OR = 2.18, 95% CI: 1.04, 4.59). These results indicate that periodontal disease (as indicated by poor condition of the mouth and missing teeth) and daily mouthwash use may be independent causes of cancers of the head, neck, and esophagus.     

A prospective study of urinary electrolytes and bone turnover in adolescent males

BACKGROUND & AIMS: The role of excessive salt on bone metabolism in children is uncertain. The aim of this 6-week prospective study was to describe the association between urinary electrolytes and bone turnover markers in a convenience sample of adolescent boys (N = 136, mean age 16 yr). METHODS: Urinary electrolytes (sodium, potassium, calcium and magnesium) were assessed on spot overnight urines on three occasions to minimise regression dilution bias. Bone turnover was assessed by bone specific alkaline phosphatase (BAP) and urinary pyridinoline (PYR) at baseline and follow up. RESULTS: In multivariate analysis, urinary sodium (but not other electrolytes) was positively associated with both PYR and BAP both before and after taking short-term growth into account (both p < 0.05) and explained 3-6% of the variation in bone turnover markers. Urinary sodium was associated with urinary magnesium (r = +0.26, p < 0.05) but only weakly with calcium (r = +0.18, p = 0.08). Urinary potassium was significantly associated with urinary magnesium (r = -0.24, p < 0.05). CONCLUSION: High urinary sodium (which largely reflects dietary sodium intake in our location) results in a high bone turnover state in adolescent boys which is most likely detrimental for bone. Other urinary electrolytes are not related to bone turnover but may influence bone via other pathways.     

Can homeopathic arsenic remedy combat arsenic poisoning in humans exposed to groundwater arsenic contamination?: a preliminary report on first human trial

Groundwater arsenic (As) has affected millions of people globally distributed over 20 countries. In parts of West Bengal (India) and Bangladesh alone, over 100 million people are at risk, but supply of As-free water is grossly inadequate. Attempts to remove As by using orthodox medicines have mostly been unsuccessful. A potentized homeopathic remedy, Arsenicum Album-30, was administered to a group of As affected people and thereafter the As contents in their urine and blood were periodically determined. The activities of various toxicity marker enzymes and compounds in the blood, namely aspartate amino transferase, alanine amino transferase, acid phosphatase, alkaline phosphatase, lipid peroxidation and reduced glutathione, were also periodically monitored up to 3 months. The results are highly encouraging and suggest that the drug can alleviate As poisoning in humans.     

Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model

In septic shock, tissue factor (TF) activates blood coagulation, and cytokines and chemokines orchestrate an inflammatory response. In this study, the role of Egr-1 in lipopolysaccharide (LPS) induction of TF and inflammatory mediators in vivo was evaluated using Egr-1(+/+) and Egr-1(-/-) mice. Administration of LPS transiently increased the steady-state levels of Egr-1 mRNA in the kidneys and lungs of Egr-1(+/+) mice with maximal induction at one hour. Egr-1 was expressed in epithelial cells in the kidneys and lungs in untreated and LPS-treated mice. LPS induction of monocyte chemoattractant protein mRNA in the kidneys and lungs of Egr-1(-/-) mice was not affected at 3 hours, but its expression was significantly reduced at 8 hours compared with the expression observed in Egr-1(+/+) mice. Similarly, LPS induction of TF mRNA expression in the kidneys and lungs at 8 hours was reduced in Egr-1(-/-) mice. However, Egr-1 deficiency did not affect plasma levels of tumor necrosis factor alpha in endotoxemic mice. Moreover, Egr-1(+/+) and Egr-1(-/-) mice exhibited similar survival times in a model of acute endotoxemia. These data indicate that Egr-1 does not contribute to the early inflammatory response in the kidneys and lungs or the early systemic inflammatory response in endotoxemic mice. However, Egr-1 does contribute to the sustained expression of inflammatory mediators and to the maximal expression of TF at 8 hours in the kidneys and lungs.     

Clinical features of pulmonary arterial hypertension in patients receiving dasatinib

The prognosis of most leukemia patients treated with BCR‐ABL tyrosine kinase inhibitors (TKIs) is favorable, and a more precise understanding of serious and potentially irreversible treatment‐related toxicities is essential to properly inform treatment choice. Few cases of pulmonary arterial hypertension (PAH) have been reported in patients with leukemia treated with dasatinib, a second‐generation BCR‐ABL TKI. To better understand characteristics and outcomes of dasatinib‐treated patients with PAH, all clinical cases of PAH confirmed by right‐heart catheterization in the Bristol‐Myers Squibb pharmacovigilance database (N = 41), including 22 previously unpublished cases, were examined for previous treatments for leukemia, patient characteristics, time to PAH onset, and outcomes. Our analysis shows that compared with PAH due to other etiologies, dasatinib‐related PAH is atypical, in that it is associated with partial to complete reversibility upon treatment discontinuation. The incidence of dasatinib‐related PAH appears to be low. Most PAH cases were observed in patients who had received prior treatments for leukemia. No specific patient attributes appear to be associated with an increased risk of developing PAH while receiving dasatinib. Symptoms of PAH in dasatinib‐treated leukemia patients should prompt a thorough workup, including consideration of confirmatory right‐heart catheterization. In cases of confirmed PAH, dasatinib should be discontinued. Am. J. Hematol. 90:1060–1064, 2015. © 2015 Wiley Periodicals, Inc.     

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.First developed as anticancer agents in the 1950s, microtubule targeting agents (MTAs) are used in the treatment of a wide variety of malignancies and until now have been thought to kill cells by arresting them in mitosis (1, 2). Although this explanation applies to rapidly dividing cells in preclinical models, it cannot explain the activity of these agents in tumors in humans because these cells divide much more slowly. For the latter situtation, a different paradigm must explain the activity of MTAs, and we have proposed that interfering with microtubule (MT) trafficking in interphase cells is the principal mechanism of MTA action (3–5). In breast, ovarian, lung, and head and neck cancers, as well as in most lymphomas, combination regimens that include a MTA and a DNA-damaging agent (DDA) are preferred (Table S1). Although the frequency with which these combinations are used might be fortuitous, it is likely there is a mechanistic basis for this outcome. We hypothesized that by hampering the trafficking of essential DNA repair proteins, MTAs synergize with DDAs, augmenting their toxicity. To explore this theory further we studied the effects of combining a MTA and a DDA in a number of cell models and examined the distribution and biology of nine different proteins involved in DNA repair. We have confirmed the hypothesis and report our findings.     

Long-term adverse outcomes in survivors of childhood bone sarcoma: the British Childhood Cancer Survivor Study

Background:

With improved survival, more bone sarcoma survivors are approaching middle age making it crucial to investigate the late effects of their cancer and its treatment. We investigated the long-term risks of adverse outcomes among 5-year bone sarcoma survivors within the British Childhood Cancer Survivor Study.

Methods:

Cause-specific mortality and risk of subsequent primary neoplasms (SPNs) were investigated for 664 bone sarcoma survivors. Use of health services, health and marital status, alcohol and smoking habits, and educational qualifications were investigated for survivors who completed a questionnaire.

Results:

Survivors were seven times more likely to experience all-cause mortality than expected, and there were substantial differences in risk depending on tumour type. Beyond 25 years follow-up the risk of dying from all-causes was comparable to the general population. This is in contrast to dying before 25 years where the risk was 12.7-fold that expected. Survivors were also four times more likely to develop a SPN than expected, where the excess was restricted to 5–24 years post diagnosis. Increased health-care usage and poor health status were also found. Nonetheless, for some psychosocial outcomes survivors were better off than expected.

Conclusions:

Up to 25 years after 5-year survival, bone sarcoma survivors are at substantial risk of death and SPNs, but this is greatly reduced thereafter. As 95% of all excess deaths before 25 years follow-up were due to recurrences and SPNs, increased monitoring of survivors could prevent mortality. Furthermore, bone and breast SPNs should be a particular concern. Since there are variations in the magnitude of excess risk depending on the specific adverse outcome under investigation and whether the survivors were initially diagnosed with osteosarcoma or Ewing sarcoma, risks need to be assessed in relation to these factors. These findings should provide useful evidence for risk stratification and updating clinical follow-up guidelines.