Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in CTNNB1 or APC: A Multi-institutional Retrospective Study.

PURPOSE: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments. EXPERIMENTAL DESIGN: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen. RESULTS: A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First- and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APC-mutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or "other" therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations. CONCLUSIONS: Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated. See related commentary by Greene and Van Tine, p. 3911.

Genome Sequence of the Siphoviridae Staphylococcus aureus Phage vB_SauS_BaqSau1.

Here, we report the genome sequence of a Siphoviridae phage named vB_SauS_BaqSau1 (BaqSau1), infecting Staphylococcus aureus Phage BaqSau1 was isolated from a sewage water treatment plant in Sahagún, Córdoba, Colombia. It has a double-stranded DNA (dsDNA) genome of 44,384 bp with 67 predicted genes, including a lysin containing a CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) domain.

The burden of lung cancer in Latin-America and challenges in the access to genomic profiling, immunotherapy and targeted treatments.

Lung cancer is a public health problem worldwide and Latin America (LATAM) cannot escape this reality. This malignant disease has not only a high prevalence in the region, but is also the main cause of cancer related deaths, and in other emerging countries, the incidence rates are still on the rise. Interestingly in most LATAM countries, lung cancer mortality has been decreasing in men but not in women, reflecting smoking patterns in countries such as Chile, Bolivia, and Brazil. Despite the fact that these issues are well known to government agencies, physicians and patients in the region, current efforts still fall behind those needed in order to face this problem of epidemic proportions. Tobacco control and smoking cessation are the most important interventions against lung cancer, but even with their optimal implementation (which is far from reality at this time) the number of cases in the foreseeable future would still be significant. Beyond tobacco control, advances in our understanding of the molecular component of lung cancer have resulted in new targeted therapies and immune check point inhibitors, which have improved clinical outcomes but at a considerably higher financial cost. LATAM has not widely and speedily adopted these strategies, including new technology and approved novel drugs, due to a number of facts, and therefore only a dismal proportion of LATAMs patient population have benefited from these new advances. A keen focus on a heterogeneous education system for caregivers in lung cancer treatment would likely help standardize care and improve future potential gains from domestic research. In this review we discuss the challenges of treatment implementation, focusing on new technologies.

E6-AP facilitates efficient transcription at estrogen responsive promoters through recruitment of chromatin modifiers.

E6-AP is a known coactivator of the estrogen receptor alpha (ERα), however the coactivation mechanism of E6-AP is not clear. This work was undertaken to elucidate the coactivation mechanism of E6-AP. In order to examine the role of E6-AP in ERα signaling, we knocked-down the expression of E6-AP and examined the transactivation functions of ERα. Knockdown of E6-AP showed reduced mRNA production of the ERα target genes pS2 and GREB1 suggesting that E6-AP is required for their proper transcription facilitated by ERα. In order to study the mechanism(s) by which E6-AP regulates the transcriptional functions of ERα, we performed chromatin immunoprecipitation (ChIP) assays under E6-AP knockdown conditions. Our ChIP data suggest that knockdown of E6-AP leads to decreased recruitment of the histone acetylase p300 to the ERα target gene pS2 promoter as well as reduced histone modifications at the promoter. Although there was reduced p300 recruitment to the pS2 promoter, loss of p300 did not account fully for the loss of histone acetylation. Taken together our data suggest that E6-AP regulates the transactivation functions of ERα in part by complexing with p300 and other chromatin modifying enzymes at target gene promoters to create a transcriptionally active promoter environment.

MIR-206 regulates connexin43 expression during skeletal muscle development.

Skeletal myoblast fusion in vitro requires the expression of connexin43 (Cx43) gap junction channels. However, gap junctions are rapidly downregulated after the initiation of myoblast fusion in vitro and in vivo. In this study we show that this downregulation is accomplished by two related microRNAs, miR-206 and miR-1, that inhibit the expression of Cx43 protein during myoblast differentiation without altering Cx43 mRNA levels. Cx43 mRNA contains two binding sites for miR-206/miR-1 in its 3'-untranslated region, both of which are required for efficient downregulation. While it has been demonstrated before that miR-1 is involved in myogenesis, in this work we show that miR-206 is also upregulated during perinatal skeletal muscle development in mice in vivo and that both miR-1 and miR-206 downregulate Cx43 expression during myoblast fusion in vitro. Proper development of singly innervated muscle fibers requires muscle contraction and NMJ terminal selection and it is hypothesized that prolonged electrical coupling via gap junctions may be detrimental to this process. This work details the mechanism by which initial downregulation of Cx43 occurs during myogenesis and highlights the tight control mechanisms that are utilized for the regulation of gap junctions during differentiation and development.

Cross-sectional and longitudinal association between antihypertensive medications and cognitive impairment in an elderly population.

BACKGROUND: The effect of antihypertensive medications on cognitive function has not been well studied. The authors' objectives were to investigate the cross-sectional and longitudinal association between the use of antihypertensive medications and cognitive function and to compare different antihypertensive medication classes with regard to this association in an elderly population. METHODS: The medical records of a convenience sample of patients (n = 993 cross-sectional and 350 longitudinal; mean age, 76.8 +/- 0.3 years; 74% women; 87% White) followed at a geriatric practice were reviewed. Data abstracted included demographics, medical history (Alzheimer's disease [AD] or vascular dementia [VaD]), use of antihypertensive medications, and results of cognitive assessments (the Mini-Mental Status Examination [MMSE] and the Clock Draw Test [CDT]). RESULTS: In the cross-sectional analysis, antihypertensive use was not associated with MMSE (p >.05), CDT (p >.05), or dementia diagnosis (odds ratio for AD, 0.8; 95% confidence interval [CI], 0.6 to 1.2; odds ratio for VaD, 1.6; 95% CI, 0.6 to 4.0). In the longitudinal analysis, antihypertensive use was associated with a lower rate of cognitive decline on the MMSE (-0.8 +/- 2 points in users vs -5.8 +/- 2.5 points in nonusers; p =.007) and on the CDT (-0.3 +/- 0.8 points in users vs -2.2 +/- 0.8 points in nonusers; p =.002), and with a lower risk for the development of cognitive impairment (odds ratio, 0.56; 95% CI, 0.38 to 0.83; p =.004). The trend was similar in patients with baseline AD (p =.02). Patients taking diuretics (p =.007), angiotensin-converting enzyme inhibitors (p =.016), and beta-blockers (p =.014) had a lower rate of cognitive decline, and patients taking angiotensin receptor blockers (p =.016) had improved cognitive scores. CONCLUSIONS: Antihypertensive use, particularly diuretics, angiotensin-converting enzymes inhibitors, beta-blockers, and angiotensin receptor blockers, may be associated with a lower rate of cognitive decline in older adults, including those with AD. Until a randomized clinical trial confirms our results, findings of this observational study should be interpreted with caution.