SummaryDNA methylation profiling of TAFs reveals global demethylation and a selective impact on the TGF-β pathway. Moreover, it suggests the fibrocyte origin of a fraction of TAFs, and identifies a novel prognostic biomarker in non-small cell lung cancer.

The biomechanics of the glenohumeral joint depend on the interaction of both static and dynamic-stabilizing structures. Static stabilizers include the bony anatomy, negative intra-articular pressure, the glenoid labrum, and the glenohumeral ligaments along with the joint capsule. The dynamic-stabilizing structures include the rotator cuff muscles and the other muscular structures surrounding the shoulder joint. The combined effect of these stabilizers is to support the multiple degrees of motion within the glenohumeral joint. The goal of this article is to review how these structures interact to provide optimal stability and how failure of some of these mechanisms can lead to shoulder joint pathology.

The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal-or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by b1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in b1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), b1 expression, and ERK1/2 (pT202/Y204) than ADCTAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or b1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs.Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.

Myofibroblasts are key effector cells in tissue stiffening and fibrosis progression, but the contribution of cells undergoing epithelial–mesenchymal transition (EMT) is unclear. Unlike EMT, myofibroblasts contribute to tissue stiffening through their contractility and expression of fibrillar collagens, which is associated with aberrant FAK (Y397) hyperactivation.

Study about the relation between aspirin use and the risk of colorectal cancer (Sept. 7 issue), 1 a key question was whether the investigation inadvertently identified women who were resistant to colorectal cancer. A number of potentially confounding factors, including family history of colorectal cancer, smoking history, alcohol consumption, diet, and level of physical activity, were considered in the data analysis. Unaddressed was the effect of hormone-replacement therapy on the risk of colorectal cancer in the study population. Data from the Nurses' Health Study on hormone-replacement therapy and its relation to colorectal cancer have suggested a protective effect of this therapy against colon cancer. 2 Evidence linking hormone-replacement therapy and a reduced risk of colon cancer is also available from other studies. 3,4 Could the authors comment on whether women in their study who used aspirin two or more times a week were also more likely to be receiving hormone-replacement therapy?It was reported previously that the relation between the risk of colorectal cancer and the use of nonsteroidal antiinflammatory drugs (NSAIDs) -almost entirely aspirin -depended more on current use of NSAIDs than on previous use discontinued for at least a year. 5 It would be interesting to know more about this aspect of the data from the Nurses' Health Study. 1. Giovannucci E, Egan KM, Hunter DJ, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995;333:609-14. 2. Chute CG, Willett WC, Colditz GA, Stampfer MJ, Rosner B, Speizer FE. A prospective study of reproductive history and exogenous estrogens on the risk of colorectal cancer in women. Epidemiology 1991;2:201-7. 3. Newcomb PA, Storer BE. Postmenopausal hormone use and risk of largebowel cancer. J Natl Cancer Inst 1995;87:1067-71. 4. Calle EE, Miracle-McMahill HL, Thun MJ, Heath CW Jr. Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women.Letters to the Editor are considered for publication (subject to editing and abridgment) provided they do not contain material that has been submitted or published elsewhere. Please note the following:• Your letter must be typewritten and triple-spaced. • Its text, not including references, must not exceed 400 words (please include a word count). • It must have no more than five references and one figure or table.• It should not be signed by more than three authors. • Letters referring to a recent Journal article must be received within four weeks of its publication. • Please include your full address, telephone number, and fax number (if you have one). Our fax numbers: 617-739-9864 and 617-734-4457Our Internet address: letters@edit.nejm.orgWe cannot acknowledge receipt of your letter, but we will notify you when we have made a decision about publication. We are unable to provide prepublication proofs. Please enclose a stamped, self-addressed envelope if you want unpublished material returned to you.Financial associations or other possible conflicts of interest mu...