Family Caregivers' Subjective Caregiving Burden,Quality of Life,and Depressive Symptoms Are Associated With Terminally Ill Cancer Patients' Distinct Patterns of Conjoint Symptom Distress and Functional Impairment in Their Last Six Months of Life

Context

Family caregivers constitute a critical component of the end-of-life care system with considerable cost to themselves. However, the joint association of terminally ill cancer patients' symptom distress and functional impairment with caregivers' subjective caregiving burden, quality of life (QOL), and depressive symptoms remains unknown.

INAUGURAL ARTICLE by a Recently Elected Academy Member:Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit skeletal muscle growth (for review, see ref. 1). Mice lacking MSTN exhibit dramatic increases in muscle mass throughout the body, with individual muscles growing to about twice the normal size (2). MSTN appears to play two distinct roles in regulating muscle size, one to regulate the number of muscle fibers that are formed during development and a second to regulate the growth of those fibers postnatally. The sequence of MSTN has been highly conserved through evolution, with the mature MSTN peptide being identical in species as divergent as humans and turkeys (3). The function of MSTN has also been conserved, and targeted or naturally occurring mutations in MSTN have been shown to cause increased muscling in numerous species, including cattle (3–5), sheep (6), dogs (7), rabbits (8), rats (9), swine (10), goats (11), and humans (12). Numerous pharmaceutical and biotechnology companies have developed biologic agents capable of blocking MSTN activity, and these have been tested in clinical trials for a wide range of indications, including Duchenne and facioscapulohumeral muscular dystrophy, inclusion body myositis, muscle atrophy following falls and hip fracture surgery, age-related sarcopenia, Charcot–Marie–Tooth disease, and cachexia due to chronic obstructive pulmonary disease, end-stage kidney disease, and cancer.The finding that certain inhibitors of MSTN signaling can increase muscle mass even in Mstn^−/− mice revealed that the function of MSTN as a negative regulator of muscle mass is partially redundant with at least one other TGF-β family member (13, 14), and subsequent studies have identified activin A as one of these cooperating ligands (15, 16). MSTN and activin A share many key regulatory and signaling components. For example, the activities of both MSTN and activin A can be modulated extracellularly by naturally occurring inhibitory binding proteins, including follistatin (17, 18) and the follistatin-related protein, FSTL-3 or FLRG (19, 20). Moreover, MSTN and activin A also appear to share receptor components. Based on in vitro studies, MSTN is capable of binding initially to the activin type II receptors, ACVR2 and ACVR2B (also called ActRIIA and ActRIIB) (18) followed by engagement of the type I receptors, ALK4 and ALK5 (21). In previous studies, we presented genetic evidence supporting a role for both ACVR2 and ACVR2B in mediating MSTN signaling and regulating muscle mass in vivo. Specifically, we showed that mice expressing a truncated, dominant-negative form of ACVR2B in skeletal muscle (18) or carrying deletion mutations in Acvr2 and/or Acvr2b (13) have significantly increased muscle mass. One limitation of the latter study, however, was that we could not examine the consequence of complete loss of both receptors using the deletion alleles, as double homozygous mutants die early during embryogenesis (22). Moreover, the roles that the two type I receptors, ALK4 and ALK5, play in regulating MSTN and activin A signaling in muscle in vivo have not yet been documented using genetic approaches. Here, we present the results of studies in which we used floxed alleles for each of the type II and type I receptor genes in order to target these receptors alone and in combination in muscle fibers. We show that these receptors are functionally redundant and that signaling through each of these receptors contributes to the overall control of muscle mass.     

Comparison of the Emergency Severity Index (ESI) and the Taiwan Triage System in predicting resource utilization.

BACKGROUND/PURPOSE: The importance of accurate triage in Taiwan is becoming more apparent with the increasing number of emergency department (ED) patients, and resources for the National Health Insurance becoming constrained. This study compared the ability of the Taiwan triage system (TTS) and the standardized 5-level Emergency Severity Index (ESI) triage system to predict ED resource utilization. METHODS: Patients arriving at the ED were triaged by both TTS and by using a two-page checklist of ESI criteria during the 3-month study period. The ESI triage level was calculated independently to avoid bias. Disease category (trauma vs. nontrauma), length of stay (LOS) and hospitalization data were evaluated. RESULTS: A total of 3172 patients with both ESI and TWN evaluation were included. The distributions of ESI ratings within TTS level 1 were: ESI 1, 21.1%; ESI 2, 68.1%; ESI 3, 7.4%; ESI 4, 3.4%; ESI 5, 0%. For TTS level 3, they were: ESI 1, 0.1%; ESI 2, 26.2%; ESI 3, 39.5%; ESI 4, 27.5%; ESI 5, 6.8%. Hospitalization rates were 74.5%, 40.9% and 22.2% in TTS levels 1, 2 and 3, respectively; and were 96.2%, 47.0%, 30.9%, 6.7%and 6.6% in ESI levels 1, 2, 3, 4 and 5, respectively. TTS triaged more trauma patients as life-threatening/emergent condition than nontrauma patients (68.8% vs. 48.4%, p < 0.001). Triage by ESI, however, showed no significant difference in the percentage of trauma and nontrauma patients with highly acute conditions (44.2% vs. 46.6%, p = 0.230). Patients with ESI level 4 or 5 have significantly shorter ED LOS than those with ESI level 3. CONCLUSION: ESI produces more accurate discriminating patient acuity, ED LOS and hospitalization rate than TTS. Adopting a standardized 5-level triage tool might improve resource utilization planning of ED practice.     

Gene expression patterns and profile changes pre- and post-erlotinib treatment in patients with metastatic breast cancer.

PURPOSE: To delineate gene expression patterns and profile changes in metastatic tumor biopsies at baseline and 1 month after treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib in patients with metastatic breast cancer. EXPERIMENTAL DESIGN: Patients were treated with 150 mg of oral erlotinib daily. Gene expression profiles were measured with Affymetrix U133A GeneChip and immunohistochemistry was used to validate microarray findings. RESULTS: Estrogen receptor (ER) status by immunohistochemistry is nearly coincided with the two major expression clusters determined by expression of genes using unsupervised hierarchical clustering analysis. One of 10 patients had an EGFR-positive tumor detected by both microarray and immunohistochemistry. In this tumor, tissue inhibitor of metalloproteinases-3 and collagen type 1 alpha 2, which are the EGF-down-regulated growth repressors, were significantly increased by erlotinib. Gene changes in EGFR-negative tumors are those of G-protein-linked and cell surface receptor-linked signaling. Gene ontology comparison analysis pretreatment and posttreatment in EGFR-negative tumors revealed biological process categories that have more genes differentially expressed than expected by chance. Among 495 gene ontology categories, the significant differed gene ontology groups include G-protein-coupled receptor protein signaling (34 genes, P = 0.002) and cell surface receptor-linked signal transduction (74 genes, P = 0.007). CONCLUSIONS: ER status reflects the major difference in gene expression pattern in metastatic breast cancer. Erlotinib had effects on genes of EGFR signaling pathway in the EGFR-positive tumor and on gene ontology biological process categories or genes that have function in signal transduction in EGFR-negative tumors.     

腮腺舍格伦综合征与非霍奇金淋巴瘤相关性分析

目的:了解腮腺非霍奇金淋巴瘤与舍格伦综合征的临床及发病机制的相关性，正确诊断和治疗舍格伦综合征，尽早明确有无恶性变。方法：对142例口腔颌面部的非霍奇金淋巴瘤中21例发生在腮腺的非霍奇金淋巴瘤，及3例从合格伦综合征演变成淋巴瘤的病例进行分析。结果：21例腮腺区非霍奇金淋巴瘤的局部表现主要为肿块、反复肿胀，与类肿瘤型舍格伦综合征的一般特征和腮腺表现有相关性，其中3例腮腺淋巴瘤患者有明确的舍格伦综合征病史。结论：舍格伦综合征与腮腺非霍奇金淋巴瘤的发生发展，以及临床表现有相关性，部分类肿瘤型舍格伦综合征可演变为淋巴瘤，临床表现和免疫学改变可早期判断舍格伦综合征有无恶性变。