Objectives/Hypothesis To evaluate the prevalence, characteristics, and associated risk factors of tinnitus in U.S. adolescents. Study Design Cross‐sectional analyses of U.S. representative demographic and audiometric data, the National Health and Nutrition Examination Survey (NHANES) 2005 to 2008. Methods The study population consisted of 3,520 individuals aged 12 to 19 years with complete tinnitus‐related data. Tinnitus was defined as the presence of ringing or buzzing in the ears lasting for at least 5 minutes during the preceding 12 months. In addition, we defined a chronic tinnitus subgroup as being bothered by tinnitus for more than 3 months. Demographic and other data regarding tinnitus, smoking, body mass index (BMI), anemia, hypertension, history of ear infections, tympanostomy tube placement, otoscopy, tympanometry and hearing thresholds, history of firearm use, and recreational and occupational exposure to noise were extracted and analyzed. Results Overall, tinnitus lasting 5 minutes or more in the preceding 12 months was reported by 7.5% of the 12‐ to 19‐year‐old population. This represents about 2.5 million adolescents in the United States. The prevalence of chronic tinnitus was 4.7%, corresponding to about 1.6 million adolescents in the United States. Multivariable‐adjusted analysis revealed that both overall and chronic tinnitus were associated with female gender, low income, exposure to passive smoking, type A tympanogram, and occupational and recreational noise exposure. History of ≥3 ear infections and history of tympanostomy tube placement were associated only with overall tinnitus. Conclusions Tinnitus afflicts a substantial portion of the youth population. Further investigation of the association between tinnitus and the identified risk factors is warranted. Level of Evidence N/A. Laryngoscope, 123:2001–2008, 2013

Obesity increases the risk of distant metastatic recurrence and reduces breast cancer (BC) survival. However, the mechanisms behind this pathology and identification of relevant therapeutic targets are poorly defined. Plasma free fatty acids (FFA) levels are elevated in obese individuals. Here we report that TGF-β transiently activates ERK and subsequently phosphorylates SMAD4 at Thr277, which facilitates a SMAD4-USP9x interaction, SMAD4 nuclear retention, and stimulates TGF-β /SMAD3-mediated transcription of Twist and Snail. USP9x inhibited the E3 ubiquitin-protein ligase TIF1γ from binding and monoubiquitinating SMAD4, hence maintaining SMAD4 nuclear retention. FFA further facilitated TGF-β-induced ERK activation, SMAD4 phosphorylation and nuclear retention, promoting TGF-β-dependent cancer progression. Inhibition of ERK and USP9x suppressed obesity-induced metastasis. Additionally, clinical data indicated that phospho-ERK and -SMAD4 levels correlate with activated TGF-β signaling and metastasis in overweight/obese patient BC specimens. Altogether, we demonstrate the vital interaction of USP9x and SMAD4 for governing TGF-β signaling and dyslipidemia-induced, aberrant TGF-β activation during BC metastasis.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. The malignant CRC that undergoes metastasis in the advanced stage is usually refractory to existing chemotherapy and shows a poor prognosis. However, to date, efficient targeted-therapy for metastatic CRC is ill-defined. We tested the hypothesis that combined treatment of flavonoid morin and telomerase inhibitor MST-312 may reduce the cancer stem cell (CSC) traits. To characterize CSC phenotype, we performed the CD133/CD44 subpopulation profiling, tumorsphere formation assay, cell invasion assay and wound healing assay. We have examined the augmenting effects of the combined treatment of morin and MST-312 for 5-FU (5-fluorouracil) efficacy in human colorectal cancer. Morin and MST-312 combined treatment reduced CD133 (+) and CD44 (+) subpopulations in human colorectal and breast cancer cells, respectively. Tumorsphere formation and cell invasiveness were decreased with the morin and MST-312 combination treatment. Consistent with these data, morin and MST-312 treatment decreased the wound healing capacity of human breast cancer cells. Stress and apoptosis antibody arrays revealed that there were specific upregulated and downregulated proteins resulting from different treatments. Phosphorylation levels of BAD, p53 and Chk1 were enhanced upon morin/MST-312 treatments in HT-29 cells, whereas caspase-3 cleavage level and expression of IκBα were down-regulated by combined morin/MST-312 treatment in SW620 cells. Finally, morin and MST-312 co-treatment further augmented the 5-FU efficacy, chemosensitizing the 5-FU resistant human colorectal cancer cells. Taken together, our study suggests that novel targeted-therapy can be implemented by using flavonoid morin and telomerase inhibitor MST-312 for improved cancer prognosis.

PurposeThe aim of this study is to investigate the mechanisms of interactions between TGF-β and Wnt/β-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment.MethodsThe effect of TGF-β on Wnt/β-catenin signaling pathway was examined by using a human Wnt/β-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay.ResultsHER2-overexpressing breast cancer cells treated with TGF-β have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF-β-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and β-catenin pathways. The TGF-β-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-β regulating Wnt3 during EMT. Subsequently, TGF-β-induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/β-catenin signaling were repressed by the shRNA treatment. TGF-βR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-β-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-β-induced cell invasion significantly in both trastuzumab responsive and resistant cells.ConclusionsOur data demonstrated an important interdependence between TGF-β and Wnt/β-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-β-induced EMT. A83-01 could inhibit the TGF-β-initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4211-y) contains supplementary material, which is available to authorized users.

Hearing loss (HL) is the most common sensory impairment and is caused by a broad range of inherited to environmental causes. Inherited HL consists 50-60% of all HL cases. The inherited form of HL is further classified to different categories. More than 300 syndromes and 40 genes have been identified to result in different levels of HL. Although several diagnostic or screening tests have been developed, yet there are controversies around their use.

Colorectal cancer (CRC) is one of the three leading causes for cancer mortality. CRC kills over 600,000 people annually worldwide. The most common cause of death from CRC is the metastasis to distant organs. However, biomarkers for CRC metastasis remain ill-defined. We compared primary and metastatic CRC cell lines for their angiogenesis-protein profiles and intracellular signaling profiles to identify novel biomarkers for CRC metastasis. To this end, we used primary and metastatic CRC cell lines as a model system and normal human colon cell line as a control. The angiogenesis profiles two isogenic CRC cell lines, SW480 and SW620, and HT-29 and T84 revealed that VEGF was upregulated in both SW620 and T84 whereas coagulation factor III, IGFBP-3, DPP IV, PDGF AA/AB, endothelin I and CXCL16 were downregulated specifically in metastatic cell lines. Furthermore, we found that TIMP-1, amphiregulin, endostatin, angiogenin were upregulated in SW620 whereas downregulated in T84. Angiogenin was downregulated in T84 and GM-CSF was also downregulated in SW620. To induce CRC cell metastasis, we treated cells with pro-inflammatory cytokine IL-6. Upon IL-6 treatment, epithelial-mesenchymal transition was induced in CRC cells. When DLD-1 and HT-29 cells were treated with IL-6; Akt, STAT3, AMPKα and Bad phosphorylation levels were increased. Interestingly, SW620 showed the same signal activation pattern with IL-6 treatment of HT-29 and DLD-1. Our data suggest that Akt, STAT3, AMPKα and Bad activation can be biomarkers for metastatic colorectal cancer. IL-6 treatment specifically reduced phosphorylation levels of EGFR, HER2 receptor, Insulin R and IGF-1R in receptor tyrosine kinase array study with HT-29. Taken together, we have identified novel biomarkers for metastatic CRC through the angiogenesis-antibody array and intracellular signaling array studies. Present study suggests that those novel biomarkers can be used as CRC prognosis biomarkers, and as potential targets for the metastatic CRC therapy.

Intro: Hematopoietic stem-cell transplant (HSCT) recipients are considered to be at high risk for poor outcomes following COVID-19 infection given their co-morbidities and immunosuppression. Sharma et al published the CIBMTR observational report data that showed that recipients of allogeneic HSCT who contract COVID-19 have poor overall survival with a 30-day mortality of 32%. That being said, there have been relatively few studies that look into the effect of COVID-19 on HSCT recipients in the setting of in vivo T cell depletion protocols. With the increased use of post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis regimens for our match related and match unrelated HSCT recipients since 2018 at our institution, we are interested to see if our COVID-19 outcomes differ from those published in the CIBMTR report. Methods: This is a single institution retrospective analysis evaluating outcomes of HSCT recipients who were diagnosed with COVID-19 between March 2020 and April 2021. Patients 18 years or older who underwent HSCT and subsequently contracted COVID-19 were included in the data collection. Demographic data including age, type of hematologic malignancy, conditioning regimen, GVHD prophylaxis, date of COVID-19 infection, with pre- and post-COVID-19 infection labs were obtained. Our primary endpoint in this retrospective analysis was non-relapse mortality within 30 days of COVID-19 diagnosis. Results: There were 21 patients at our institution who had undergone HSCT and subsequently contracted COVID-19. The most common primary disease types were acute lymphoblastic leukemia (33.3%), acute myeloid leukemia (23.8%), and myelodysplastic syndrome (19.0%). The median age of our patient population was 53 years (range, 24-66). 6 of the patients received match related allografts. 7 received cells from match unrelated donors. 7 received cells from haploidentical donors. 1 patient had received an autologous stem cell transplant. Of the remaining 20 allo-HSCT recipients, 14 of them (70.0%) received myeloablative conditioning regimens, whereas 6 (30.0%) received reduced intensity or non-myeloablative regimens. Our GVHD prophylaxis regimens were PTCy/Tacro/MMF (12 pts, 60.0%) and Tacro/MTX (8 pts, 40.0%). Patient demographics and outcomes are found on Tables 1 and 2. Our patients were diagnosed with COVID-19 a median 469 days post-transplant, with 8 patients (38.1%) diagnosed with COVID-19 within 1 year of transplant. 11 of the patients (52.4%) received steroids following their diagnosis with COVID-19. Of the 20 allo-HSCT recipients with confirmed COVID-19 infection, 1 passed away 20 days after the diagnosis was made. This gives us a 5.0% case fatality rate attributable to COVID-19 in our population in our allo-HSCT population. 16 of the 20 patients were symptomatic at the time of diagnosis (80.0%). 7 of the 20 patients (35.0%) were hospitalized for a median of 7 days (range, 5-17 days), with 2 requiring ICU level of care. The one patient who passed away tested positive for COVID-19 177 days post-transplant and was hospitalized approximately 7 days after diagnosis, where he was intubated on hospital day 4 and ultimately passed away on hospital day 13. The patient had received Tacro/MTX for GVHD prophylaxis. Discussion: Although this is a small sample size, our data suggests that our allo-HSCT recipients who contracted COVID-19 have had generally good short-term outcomes. Our study is limited by the small number of patients who got infected with COVID-19, particularly those within 1-year post-transplant. Furthermore, we acknowledge it is difficult to claim that the PTCy based GVHD prophylaxis regimens for our HSCT recipients were solely responsible for their improved outcomes since 40% of allo-HSCT recipients did not get PTCy for GVHD prophylaxis. However, we believe it would be valuable to evaluate in a prospective analysis. We are currently evaluating if a COVID-19 diagnosis has any effect on long term transplant related complications and outcomes in this population. Figure 1 Figure 1. Disclosures Chaudhary: Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company. Yaghmour: Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau.

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