Smad8B, a Smad8 splice variant lacking the SSXS site that inhibits Smad8-mediated signalling

BACKGROUND: Members of the TGF-beta superfamily of ligands bind to and activate surface serine/threonine-kinase receptors. Transduction of these signals requires the Smad proteins, which transiently interact with the activated receptor complex and are phosphorylated on their C terminus, SSXS site, by the type I receptor. Smad8 is a downstream signalling mediator of ALK2/ActRIA. RESULTS: We have cloned a splice variant of Smad8, designated Smad8B. The Smad8 and Smad8B cDNAs are identical in sequence, except that Smad8B lacks a portion encoding 47 amino acids, including the SSXS phosphorylation site, in the C-terminal MH2 region. Both Smad8 and Smad8B were expressed in many of the same cell types. Smad8B was capable of specific complex formation with either Smad8 or Smad4 in mammalian cells. In cells expressing constitutively activated ALK2, Smad8B was localized to the cytoplasmic region, whereas Smad8 was translocated into the nucleus. In mammalian cells, Smad8B acted as a dominant inhibitor of BMP signalling. CONCLUSIONS: Smad8B, a splice variant of Smad8, was isolated and found to specifically associate with both Smad8 and Smad4. Smad8B inhibited BMP signalling. Smad8 and Smad8B thus represent novel signal transduction proteins that may regulate the BMP signalling pathway.     

Comparison of Drug-Eluting Embolics versus Conventional Transarterial Chemoembolization for the Treatment of Patients with Unresectable Hepatocellular Carcinoma: A Cost-Effectiveness Analysis

PurposeTo compare the cost-effectiveness of using doxorubicin-loaded drug-eluting embolic (DEE) transarterial chemoembolization versus that of using conventional transarterial chemoembolization for patients with unresectable hepatocellular carcinoma (HCC).Materials and MethodsA decision-analysis model was constructed over the lifespan of a payer’s perspective. The model simulated the clinical course, including periprocedural complications, additional transarterial chemoembolization or other treatments (ablation, radioembolization, or systemic treatment), palliative care, and death, of patients with unresectable HCC. All clinical parameters were derived from the literature. Base case calculations, probabilistic sensitivity analyses, and multiple two-way sensitivity analyses were performed.ResultsIn the base case calculations for patients with a median age of 67 years (range for conventional transarterial chemoembolization: 28–88 years, range for DEE-transarterial chemoembolization: 16–93 years), conventional transarterial chemoembolization yielded a health benefit of 2.11 quality-adjusted life years (QALY) at a cost of $125,324, whereas DEE-transarterial chemoembolization yielded 1.71 QALY for $144,816. In 10,000 Monte Carlo simulations, conventional transarterial chemoembolization continued to be a more cost-effective strategy. conventional transarterial chemoembolization was cost-effective when the complication risks for both the procedures were simultaneously varied from 0% to 30%. DEE-transarterial chemoembolization became cost-effective if the conventional transarterial chemoembolization mortality exceeded that of DEE-transarterial chemoembolization by 17% in absolute values. The two-way sensitivity analyses demonstrated that conventional transarterial chemoembolization was cost-effective until the risk of disease progression was >0.4% of that for DEE-transarterial chemoembolization in absolute values. Our analysis showed that DEE-transarterial chemoembolization would be more cost-effective if it offered >2.5% higher overall survival benefit than conventional transarterial chemoembolization in absolute values.ConclusionsCompared with DEE-transarterial chemoembolization, conventional transarterial chemoembolization yielded a higher number of QALY at a lower cost, making it the more cost-effective of the 2 modalities.     

Transitioning Residents from Nursing Facilities to Community Living: Who Wants to Leave?

OBJECTIVES: To examine nursing facility residents' or their legal proxies' perspectives on transitioning out of nursing facilities by assessing residents' perceptions of their ability to live more independently, their preferences regarding leaving the facility, and the feasibility of transitioning with community support.
DESIGN: Analysis of survey findings from the California Nursing Facility Transition Screen (CNFTS).
SETTING: Eight nursing facilities in southern California.
PARTICIPANTS: All chronic maintenance, long-stay residents receiving Medi-Cal (California's Medicaid program) were eligible for the study (n=218). Of these, 121 (56%) self-consenting residents or legal proxies were interviewed. No presumptions were made as to which residents were appropriate candidates for transition based on health or functional capacity.
MEASUREMENTS: CNFTS contains 27 open- and closed-ended questions on preference, ability, and feasibility of transitioning.
RESULTS: Twenty-three percent of residents and proxies believed that the resident had the ability to transition; 46% indicated a preference to transition; and after discussing potential living arrangements and services, 33% thought that transitioning would be feasible. Of those who consented to allow access to their Minimum Data Set 2.0 (MDS) information (n=41; 34% of the sample), agreement in the assessment of preference was found in 39% of cases.
CONCLUSION: Transition decisions are complex and include preference, as well as perceptions of the resident's ability to live in a more independent setting and the feasibility of transitioning. Compared with the MDS, the screen identified a higher proportion of residents who want to transition, suggesting that a systematic approach to assessing the complex decision to transition is needed.     

Achieving Speaker Gender Equity at the SIR Annual Scientific Meeting: The Effect of Female Session Coordinators

PurposeTo examine the impact of targeted efforts to increase the number of female speakers at the Society of Interventional Radiology (SIR) Annual Scientific Meeting (ASM) by reporting gender trends for invited faculty in 2017/2018 vs 2016.Materials and MethodsFaculty rosters for the 2016, 2017, and 2018 SIR ASMs were stratified by gender to quantify female representation at plenary sessions, categorical courses, symposia, self-assessment modules, and “meet-the-expert” sessions. Keynote events, scientific abstract presentations, and award ceremonies were excluded. In 2017, the SIR Annual Meeting Committee issued requirements for coordinators to invite selected women as speakers. Session coordinators are responsible for issuing speaker invitations, and invited speakers have the option to decline.ResultsYears 2017 and 2018 showed increases in female speaker representation, with women delivering 13% (89 of 687) and 14% (85 of 605) of all assigned presentations, compared with 9% in 2016 (46 of 514; P = .03 and P = .01, respectively). Gender diversity correlated with the gender of the session coordinator(s). When averaged over a 3-year period, female speakers constituted 7% of the speaker roster (112 of 1,504 presentations) for sessions led by an all-male coordinator team, compared with 36% (108 of 302) for sessions led by at least 1 female coordinator (P < .0001). Results of the linear regression model confirmed the effect of coordinator team gender composition (P < .0001).ConclusionsHaving a woman as a session coordinator increased female speaker participation, which suggests that the inclusion of more women as coordinators is one mechanism for achieving gender balance at scientific meetings.     

CT‐Guided Wire Localization for Involved Axillary Lymph Nodes After Neo‐adjuvant Chemotherapy in Patients With Initially Node‐Positive Breast Cancer

Resection of biopsy‐proven involved axillary lymph nodes (iALNs) is important to reduce the false‐negative rates of sentinel lymph node (SLN) biopsy after neo‐adjuvant chemotherapy (NAC) in patients with initially node‐positive breast cancer. Preoperative wire localization for iALNs marked with clips placed during biopsy is a technique that may help the removal of iALNs after NAC. However, ultrasound (US)‐guided localization is often difficult because the clips cannot always be reliably visible on US. Computed tomography (CT)‐guided wire localization can be used; however, to date there have been no reports on CT‐guided wire localization for iALNs. The aim of this study was to describe a series of patients who received CT‐guided wire localization for iALN removal after NAC and to evaluate the feasibility of this technique. We retrospectively analyzed five women with initially node‐positive breast cancer (age, 41–52 years) who were scheduled for SLN biopsy after NAC and received preoperative CT‐guided wire localization for iALNs. CT visualized all the clips that were not identified on post‐NAC US. The wire tip was deployed beyond or at the target, with the shortest distance between the wire and the index clip ranging from 0 to 2.5 mm. The total procedure time was 21–38 minutes with good patient tolerance and no complications. In four of five cases, CT wire localization aided in identification and resection of iALNs that were not identified with lymphatic mapping. Residual nodal disease was confirmed in two cases: both had residual disease in wire‐localized lymph nodes in addition to SLNs. Although further studies with more cases are required, our results suggest that CT‐guided wire localization for iALNs is a feasible technique that facilitates identification and removal of the iALNs as part of SLN biopsy after NAC in situations where US localization is unsuccessful.     

Critical role of Frizzled1 in age‐related alterations of Wnt/β‐catenin signal in myogenic cells during differentiation

Activation of Wnt/β‐catenin signal in muscle satellite cells (mSCs) of aged mice during myogenic differentiation has been appreciated as an important age‐related feature of the skeletal muscles, resulting in impairment of their regenerative ability following muscle injury. However, it remains elusive about molecules involved in this age‐related alteration of Wnt/β‐catenin signal in myogenic cells. To clarify this issue, we carried out expression analyses of Wnt receptor genes using real‐time RT‐PCR in mSCs isolated from the skeletal muscles of young and aged mice. Here, we show that expression of Frizzled1 (Fzd1) was detected at high levels in mSCs of aged mice. Higher expression levels of Fzd1 were also detected in mSC‐derived myogenic cells from aged mice and associated with activation of Wnt/β‐catenin signal during their myogenic differentiation in vitro. We also provide evidence that suppressed expression of Fzd1 in myogenic cells from aged mice results in a significant increase in myogenic differentiation, and its forced expression in those from young mice results in its drastic inhibition. These findings indicate the critical role of Fzd1 in altered myogenic differentiation associated with aging.     

Phase II study of concurrent chemoradiotherapy with use of uneven fractionation for the treatment of glioblastoma

Background A phase II one-arm study was performed to evaluate the efficacy and safety of concurrent chemoradiotherapy with the use of uneven fractionation in glioblastoma patients. Methods A total of 19 glioblastoma patients underwent concurrent chemoradiotherapy with the use of uneven fractionation. Vincristine (VCR) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) were administered on day 1 and day 2, respectively. Irradiation at a dose of 3 Gy was administered on days 3 and 4, and at a dose of 1.5 Gy from day 5 on. The treatment was repeated at 10 day intervals. The total radiation dose was 57 Gy. Results All 19 patients received full dose irradiation. However, 8 patients required treatment interruption, and 2 patients required decreases in drug dosages due to the effects of acute toxicity such as, myelosuppression, liver function disorder and skin toxicity. The treatment responses were recorded as CR in 5, PR in 1, and NC in 10 patients. The remaining three patients received total removal of the enhancing area on CT or MRI. The 1 year and 2 year survival rates were 73% and 23%, respectively. The median survival times of this study and the historical controls were 16 months and 15 months, respectively. Conclusion The concurrent chemoradiotherapy failed to prolong the survival of glioblastoma patients.