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1.
Laryngoscope ; 134(7): 3406-3411, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38516821

ABSTRACT

OBJECTIVES: Obstructive sleep apnea (OSA) is usually assessed at discrete and infrequent timepoints. Wearable consumer sleep technologies (CST) may allow for more granular and longitudinal assessments of OSA therapy responses and OSA-related symptoms. METHODS: In this case series, we enrolled hypoglossal nerve stimulator (HGNS) patients who had an effective treatment response for an 8-week study using a wearable CST. Participants started with "HGNS-on," were randomized to turn off HGNS therapy during either week 4 or 5 ("HGNS-off"), followed by a return to therapy, "HGNS-resume." Participants completed validated symptom questionnaires assessing sleepiness, insomnia symptoms, functional status, and overall sleep health (Satisfaction, Alertness, Timing, Efficiency, and Duration, SATED) each week. CST metrics and survey scores were compared between HGNS treatment phases. Associations between CST metrics and survey scores were assessed. RESULTS: Seven participants with a total of 304 nights of CST data showed no statistically significant changes in total sleep time (TST), wake time after sleep onset, or sleep efficiency (SE) across the study periods. During HGNS-off, survey scores indicated significantly worsened OSA-related symptom scores. Two participants had significantly higher heart rate variability (HRV) during HGNS-off (by 3.3 and 6.3 ms) when compared to HGNS active therapy periods. Amongst CST metrics, SATED scores correlated with TST (r = 0.434, p < 0.0001), HRV (r = -0.486, p < 0.0001), and SE (r = 0.320, = 0.0014). In addition, FOSQ-10 scores correlated with average HR during sleep (r = -0.489, p < 0.001). CONCLUSION: A 1-week HGNS therapy withdrawal period impacted OSA-related sleep symptoms. Sleep-related metrics measured by a wearable CST correlated with symptom scores indicating potential value in the use of CSTs for longitudinal sleep-tracking in OSA patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3406-3411, 2024.


Subject(s)
Electric Stimulation Therapy , Hypoglossal Nerve , Sleep Apnea, Obstructive , Humans , Sleep Apnea, Obstructive/therapy , Sleep Apnea, Obstructive/physiopathology , Male , Middle Aged , Female , Electric Stimulation Therapy/methods , Electric Stimulation Therapy/instrumentation , Adult , Surveys and Questionnaires , Treatment Outcome , Wearable Electronic Devices , Aged , Polysomnography , Sleep/physiology
2.
Mol Cancer ; 23(1): 40, 2024 02 22.
Article in English | MEDLINE | ID: mdl-38383439

ABSTRACT

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.


Subject(s)
Melanoma , RNA, Long Noncoding , Humans , Mice , Animals , Melanoma/pathology , RNA, Long Noncoding/genetics , Apoptosis/genetics , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/therapeutic use , Cell Line, Tumor , Membrane Proteins/genetics , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism
3.
Laryngoscope ; 134(2): 987-992, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37334840

ABSTRACT

Longitudinal snoring changes can be captured using a mobile phone application. During hypoglossal nerve stimulator (HNS) therapy up-titration, increasing stimulation voltage was associated with reduced snoring frequency and intensity in this case series of six patients. Laryngoscope, 134:987-992, 2024.


Subject(s)
Cell Phone , Electric Stimulation Therapy , Sleep Apnea, Obstructive , Humans , Sleep Apnea, Obstructive/therapy , Snoring/therapy , Hypoglossal Nerve
4.
Res Sq ; 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-38077055

ABSTRACT

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impacton normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

5.
Oncotarget ; 14: 543-560, 2023 05 26.
Article in English | MEDLINE | ID: mdl-37235843

ABSTRACT

The long non-coding RNA (lncRNA) MALAT1 is a regulator of oncogenesis and cancer progression. MAPK-pathway upregulation is the main event in the development and progression of human cancer, including melanoma and recent studies have shown that MALAT1 has a significant impact on the regulation of gene and protein expression in the MAPK pathway. However, the role of MALAT1 in regulation of gene and protein expression of the MAPK-pathway kinases RAS, RAF, MEK and ERK in melanoma is largely unknown. We demonstrate the impacts of antisense oligonucleotide (ASO)-based MALAT1-inhibition on MAPK-pathway gene regulation in melanoma. Our results showed that MALAT1-ASO treatment decreased BRAF RNA expression and protein levels, and MALAT1 had increased correlation with MAPK-pathway associated genes in melanoma patient samples compared to healthy skin. Additionally, drug-induced MAPK inhibition upregulated MALAT1-expression, a finding that resonates with a paradigm of MALAT1-expression presented in this work: MALAT1 is downregulated in melanoma and other cancer types in which MALAT1 seems to be associated with MAPK-signaling, while MALAT1-ASO treatment strongly reduced the growth of melanoma cell lines, even in cases of resistance to MEK inhibition. MALAT1-ASO treatment significantly inhibited colony formation in vitro and reduced tumor growth in an NRAS-mutant melanoma xenograft mouse model in vivo, while showing no aberrant toxic side effects. Our findings demonstrate new insights into MALAT1-mediated MAPK-pathway gene regulation and a paradigm of MALAT1 expression in MAPK-signaling-dependent cancer types. MALAT1 maintains essential oncogenic functions, despite being downregulated.


Subject(s)
Melanoma , RNA, Long Noncoding , Humans , Animals , Mice , RNA, Long Noncoding/metabolism , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/metabolism , Cell Line, Tumor , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mitogen-Activated Protein Kinase Kinases/metabolism , Proto-Oncogene Proteins B-raf/genetics , MAP Kinase Signaling System
6.
Melanoma Res ; 32(6): 411-418, 2022 12 01.
Article in English | MEDLINE | ID: mdl-35993892

ABSTRACT

Immunosuppressive therapy is standard for the treatment of inflammatory diseases and for minimizing rejection in transplant patients. However, immunosuppressant drugs are associated with an increased risk of certain cancers. In particular, melanoma is an immunogenic tumor and as such, is strongly influenced by the immune system. We performed this literature review to summarize the effects of commonly used immunomodulating agents on melanoma development, recurrence and progression. We outline the mechanism of action of each drug and discuss the available evidence on its influence on melanoma. Based on existing literature, we recommend avoiding the following agents in patients with a history of invasive melanoma: cyclosporine, sirolimus, natalizumab, IL-6 inhibitors, cyclophosphamide, methotrexate and the tumor necrosis factor-alpha inhibitors infliximab and etanercept. If there are no viable alternative agents, we recommend for these patients to see a dermatologist every 6 months for a thorough skin examination.


Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Skin Neoplasms/diagnosis , Tumor Necrosis Factor-alpha , Etanercept , Infliximab
7.
JAMA Otolaryngol Head Neck Surg ; 147(4): 336-342, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33475683

ABSTRACT

Importance: During the novel coronavirus disease 2019 pandemic, telehealth has become a vital component of health care delivery. For otolaryngology evaluations, examination of the ear and oropharynx is important but difficult to achieve remotely. Objective: To assess the feasibility of patient use of low-cost digital videoscopes and smartphones for examination of the ear and oropharynx. Design, Setting, and Participants: A prospective quality improvement study was conducted in an academic adult otolaryngology clinic including 23 patients who presented for an in-person appointment and owned a smartphone device. The study was conducted from July 1 to 15, 2020. Interventions: Participants were asked to capture pictures and videos of their ear canals and oropharynx with digital videoscopes and their smartphones under real-time guidance over a telehealth platform. They were then surveyed about their experience. Main Outcomes and Measures: The primary outcomes were ratings by health care clinicians and a blinded otolaryngologist reviewer of image acceptability. Secondary outcomes included participant time to image acquisition and willingness to purchase digital videoscopes for telehealth use. Results: Of the 23 participants included, 14 were women (61%); mean age was 50 years (range, 21 to 80 years). Of the images obtained using the digital otoscope ear examination, 95% were considered acceptable by the health care clinicians and 91% were considered acceptable by the blinded reviewer; 16 participants (70%) reported that the otoscope was easy to use. The mean time to acquire images for both ears was 114 seconds (95% CI, 84-145 seconds). Twenty-one participants (91%) were willing to pay for a digital otoscope for telehealth use. For the oropharyngeal examination, a greater proportion of smartphone video examinations were considered acceptable by clinicians (63% acceptability) and the blinded reviewer (55%) compared with the digital endoscope (clinicians, 40%; blinded reviewer, 14%). The mean time required for the oropharyngeal examination smartphone video capture was shorter at 35 seconds compared with both the digital endoscope (difference, -27 seconds; 95% CI, -7 to -47 seconds) and smartphone photo capture (difference, -53 seconds; 95% CI, -20 to -87 seconds). Conclusions and Relevance: Digital otoscopes and smartphones apparently can facilitate remote head and neck physical examination in telehealth. Digital otoscopes were useful for ear examinations, and smartphone videos appeared to be the most useful for oropharyngeal examinations. Further studies are required to determine specific diagnostic capabilities in various telehealth practice settings.


Subject(s)
Otolaryngology/economics , Otolaryngology/instrumentation , Remote Consultation/methods , Smartphone , Video Recording , Adult , Aged , Aged, 80 and over , Ear Canal/pathology , Feasibility Studies , Female , Humans , Male , Middle Aged , Office Visits , Oropharynx/pathology , Otolaryngology/methods , Otoscopes/economics , Patient Acceptance of Health Care , Patient Satisfaction , Pilot Projects , Prospective Studies , Young Adult
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