Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: Subanalysis of the PREMIER study

<p>Abstract</p> <p>Background</p> <p>Anti-TNF therapy has been shown to reduce radiographic joint damage in rheumatoid arthritis (RA) independent of clinical response. This has previously not been examined for periarticular bone loss, the other characteristic feature of bone involvement in RA.</p> <p>The objective of this study was to examine if treatment with the TNF-α inhibitor adalimumab also could reduce periarticular bone loss in RA patients independent of disease activity.</p> <p>Methods</p> <p>RA patients were recruited from the PREMIER study and included 214 patients treated with methotrexate (MTX) plus adalimumab and 188 patients treated with MTX monotherapy. Periarticular bone loss was assessed by digital X-ray radiogrammetry metacarpal cortical index (DXR-MCI). Change in DXR-MCI was evaluated in patients with different levels of clinical response, as assessed by changes in DAS28 score at 52 weeks and in mean C-reactive protein (CRP) levels during follow-up.</p> <p>Results</p> <p>In the MTX group, there was a greater median DXR-MCI loss among patients with moderate and high disease activity compared to those in remission or with low disease activity (-3.3% vs. -2.2%, p = 0.01). In contrast, periarticular bone loss was independent of disease activity (-1.9% vs. -2.4%, p = 0.99) in the combination group. In the MTX group patients with a mean CRP of ≥ 10 mg/l lost significantly more DXR-MCI than patients with low CRP (-3.1% vs. -1.9%, p <0.01) whereas in the combination group no significant differences between the two CRP groups was seen (-2.4% vs. -2.0%, p = 0.48).</p> <p>Conclusion</p> <p>Adalimumab in combination with MTX reduces periarticular bone loss independently of clinical response. These results support the hypothesis that TNF-α stimulates the osteoclast not only by the inflammatory pathway but do also have a direct effect on the osteoclast.</p> <p>Trial Registration</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT001195663">NCT001195663</a></p

Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan

INTRODUCTION: Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases. METHOD: This is a retrospective study conducted in the Department of Pathology at Jordan University of Science and Technology. A confirmed 91 cases of BC diagnosed in the period 1995 to 1998 were reviewed and graded. We used immunohistochemistry to evaluate the expression of ER, PR, and Her-2. Immunohistochemical findings were correlated with age, tumor size, grade and axillary lymph node status. RESULTS: Her-2 was overexpressed in 24% of the cases. The mean age of Her-2 positive cases was 42 years as opposed to 53 years among Her-2 negative cases (p = 0.0001). Her-2 expression was inversely related to ER and PR expression. Her-2 positive tumors tended to be larger than Her-2 negative tumors with 35% overexpression among T3 tumors as opposed to 22% among T2 tumors (p = 0.13). Her-2 positive cases tended to have higher rates of axillary metastases, but this did not reach statistical significance. ER and PR positive cases were seen in older patients with smaller tumor sizes. CONCLUSION: Her-2 overexpression was seen in 24% of BC affecting Jordanian females. Her-2 overexpression was associated with young age at presentation, larger tumor size, and was inversely related to ER and PR expression. One-fifth of the carcinomas were Her-2 positive and ER negative. This group appears to represent an aggressive form of BC presenting at a young age with large primary tumors and a high rate of four or more axillary lymph node metastases

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

Greatly increased occurrence of breast cancers in areas of mammographically dense tissue

INTRODUCTION: Mammographic density is a strong, independent risk factor for breast cancer. A critical unanswered question is whether cancers tend to arise in mammographically dense tissue (i.e. are densities directly related to risk or are they simply a marker of risk). This question cannot be addressed by studying invasive tumors because they manifest as densities and cannot be confidently differentiated from the densities representing fibrous and glandular tissue. We addressed this question by studying ductal carcinoma in situ (DCIS), as revealed by microcalcifications. METHOD: We studied the cranio-caudal and the mediolateral-oblique mammograms of 28 breasts with a solitary DCIS lesion. Two experienced radiologists independently judged whether the DCIS occurred in a mammographically dense area, and determined the density of different areas of the mammograms. RESULTS: It was not possible to determine whether the DCIS was or was not in a dense area for six of the tumors. Of the remaining 22 lesions, 21 occurred in dense tissue (test for difference from expected taken as the percentage of density of the 'mammographic quadrant' containing DCIS; P < 0.0001). A preponderance of DCIS (17 out of 28) occurred in the mammographic quadrant with the highest percentage density. CONCLUSION: DCIS occurs overwhelmingly in the mammographically dense areas of the breast, and pre-DCIS mammograms showed that this relationship was not brought about by the presence of the DCIS. This strongly suggests that some aspect of stromal tissue comprising the mammographically dense tissue directly influences the carcinogenic process in the local breast glandular tissue

Paradoxes in carcinogenesis: New opportunities for research directions

<p>Abstract</p> <p>Background</p> <p>The prevailing paradigm in cancer research is the somatic mutation theory that posits that cancer begins with a single mutation in a somatic cell followed by successive mutations. Much cancer research involves refining the somatic mutation theory with an ever increasing catalog of genetic changes. The problem is that such research may miss paradoxical aspects of carcinogenesis for which there is no likely explanation under the somatic mutation theory. These paradoxical aspects offer opportunities for new research directions that should not be ignored.</p> <p>Discussion</p> <p>Various paradoxes related to the somatic mutation theory of carcinogenesis are discussed: (1) the presence of large numbers of spatially distinct precancerous lesions at the onset of promotion, (2) the large number of genetic instabilities found in hyperplastic polyps not considered cancer, (3) spontaneous regression, (4) higher incidence of cancer in patients with xeroderma pigmentosa but not in patients with other comparable defects in DNA repair, (5) lower incidence of many cancers except leukemia and testicular cancer in patients with Down's syndrome, (6) cancer developing after normal tissue is transplanted to other parts of the body or next to stroma previously exposed to carcinogens, (7) the lack of tumors when epithelial cells exposed to a carcinogen were transplanted next to normal stroma, (8) the development of cancers when Millipore filters of various pore sizes were was inserted under the skin of rats, but only if the holes were sufficiently small. For the latter paradox, a microarray experiment is proposed to try to better understand the phenomena.</p> <p>Summary</p> <p>The famous physicist Niels Bohr said "How wonderful that we have met with a paradox. Now we have some hope of making progress." The same viewpoint should apply to cancer research. It is easy to ignore this piece of wisdom about the means to advance knowledge, but we do so at our peril.</p

Skeletal carbonate mineralogy of Scottish bryozoans

This paper describes the skeletal carbonate mineralogy of 156 bryozoan species collected from Scotland (sourced both from museum collections and from waters around Scotland) and collated from literature. This collection represents 79% of the species which inhabit Scottish waters and is a greater number and proportion of extant species than any previous regional study. The study is also of significance globally where the data augment the growing database of mineralogical analyses and offers first analyses for 26 genera and four families. Specimens were collated through a combination of field sampling and existing collections and were analysed by X-ray diffraction (XRD) and micro-XRD to determine wt% MgCO3 in calcite and wt% aragonite. Species distribution data and phylogenetic organisation were applied to understand distributional, taxonomic and phylo-mineralogical patterns. Analysis of the skeletal composition of Scottish bryozoans shows that the group is statistically different from neighbouring Arctic fauna but features a range of mineralogy comparable to other temperate regions. As has been previously reported, cyclostomes feature low Mg in calcite and very little aragonite, whereas cheilostomes show much more variability, including bimineralic species. Scotland is a highly variable region, open to biological and environmental influx from all directions, and bryozoans exhibit this in the wide range of within-species mineralogical variability they present. This plasticity in skeletal composition may be driven by a combination of environmentally-induced phenotypic variation, or physiological factors. A flexible response to environment, as manifested in a wide range of skeletal mineralogy within a species, may be one characteristic of successful invasive bryozoans