Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers

Background Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin–proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis.Methods Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancer cell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays.Results Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients.Conclusion We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers.Subject terms: Oral cancer detection, Oral cancer detection     

Extensive and Progressing Congenital Dermal Melanocytosis Leading to Diagnosis of GM1 Gangliosidosis

Congenital dermal melanocytosis (CDM) is a birthmark composed of macular blue‐grey hyperpigmentation commonly observed in the lumbosacral region of infants. Generally resolving by childhood, it is traditionally considered a benign condition, but it may be a sign of underlying lysosomal storage disease. We report a case of biopsy‐confirmed CDM in a 2‐month‐old girl of Brazilian descent later diagnosed with infantile GM1 gangliosidosis.     

Longitudinal utilization of systemic immunomodulators before and after dupilumab approval in children with atopic dermatitis

In our cohort study, we sought to describe the utilization patterns of systemic immunomodulators in children with atopic dermatitis (AD) and how utilization changed after approval of dupilumab, the first systemic drug approved for the treatment of AD. Using US nationwide claims data, we identified children with AD who initiated a systemic therapy (dupilumab, cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil) from March 2015 to February 2021 and used Sankey plots to describe patterns of starting, switching, and discontinuing these drugs. Dupilumab use among children increased from 19.4% before approval in children to 88.3% after approval in 2019–20. Adherence to dupilumab may suggest better tolerance and improved outcomes in children with AD.     

An artificial intelligence platform provides an accurate interpretation of esophageal motility from Functional Lumen Imaging Probe Panometry studies

Background

Functional lumen imaging probe (FLIP) Panometry is performed at the time of sedated endoscopy and evaluates esophageal motility in response to distension. This study aimed to develop and test an automated artificial intelligence (AI) platform that could interpret FLIP Panometry studies.

Methods

The study cohort included 678 consecutive patients and 35 asymptomatic controls that completed FLIP Panometry during endoscopy and high-resolution manometry (HRM). “True” study labels for model training and testing were assigned by experienced esophagologists per a hierarchical classification scheme. The supervised, deep learning, AI model generated FLIP Panometry heatmaps from raw FLIP data and based on convolutional neural networks assigned esophageal motility labels using a two-stage prediction model. Model performance was tested on a 15% held-out test set (n = 103); the remainder of the studies were utilized for model training (n = 610).

Key Results

“True” FLIP labels across the entire cohort included 190 (27%) “normal,” 265 (37%) “not normal/not achalasia,” and 258 (36%) “achalasia.” On the test set, both the Normal/Not normal and the achalasia/not achalasia models achieved an accuracy of 89% (with 89%/88% recall, 90%/89% precision, respectively). Of 28 patients with achalasia (per HRM) in the test set, 0 were predicted as “normal” and 93% as “achalasia” by the AI model.

Conclusions

An AI platform provided accurate interpretation of FLIP Panometry esophageal motility studies from a single center compared with the impression of experienced FLIP Panometry interpreters. This platform may provide useful clinical decision support for esophageal motility diagnosis from FLIP Panometry studies performed at the time of endoscopy.     

Complementary and Alternative Medicine in Cancer Pain Management: A Systematic Review

Quality of life (QoL) encompasses the physical, psychosocial, social and spiritual dimensions of life lived by a person. Cancer pain is one of the physical component has tremendous impact on the QoL of the patient. Cancer pain is multifaceted and complex to understand and managing cancer pain involves a tool box full of pharmacological and non pharmacological interventions but still there are 50-70% of cancer patients who suffer from uncontrolled pain and they fear pain more than death. Aggressive surgeries, radiotherapy and chemotherapy focus more on prolonging the survival of the patient failing to realize that the QoL lived also matters equally. This paper reviews complementary and alternative therapy approaches for cancer pain and its impact in improving the QoL of cancer patients.     

Chest MRI Using Multivane-XD,a Novel T2-Weighted Free Breathing MR Sequence

ObjectiveTo compare image quality of free-breathing T2-weighted MultiVane-XD (MVXD) sequence (non-Cartesian k-space filling using radial rectangular blades) with conventional MR sequences (short tau inversion recovery [STIR],balanced true field echo [BTFE], T1 in phase fast field echo [T1 FFE], and T1-fat saturated postgadolinium [T1PG]) in MR imaging of chest.Materials and MethodsTwenty-one patients (10 men and 11 women) underwent chest MRI including T2W MVXD, STIR, BTFE (18/21), T1 FFE, T1PG (10/21) sequences at 1.5 T. Two reviewers (A.S.B and M.J. with 20 and 10 years of experience in pulmonary imaging, respectively) evaluated each sequence with respect to overall image quality, image sharpness, definition of mediastinal vessels including the aorta, pulmonary arteries, superior vena cava, intrapulmonary vessels; trachea, main bronchi, intrapulmonary airways; lung-mediastinal interface, pulmonary lesion detection, and artefacts in the upper, middle, and lower third of chest using 5-point scales. No sedation was given. Pairwise comparisons between T2W MVXD and the 4 conventional sequences were made using unpaired student's t test.ResultsMean age of patients was 30.67 years (range: 6-60 years). T2 MVXD showed significantly better overall image quality and sharpness than STIR, T1 FFE, and T1PG (P < 0.01) while it was comparable to BTFE. Mediastinal vessels were significantly better visualized on T2 MVXD as compared to STIR and T1 (P < 0.003). However, BTFE and T1PG were superior to T2 MVXD for visualization of great vessels, SVC, and intrapulmonary vessels (P < 0.01). Visualization of trachea, major bronchi, intrapulmonary airways as well as intrapulmonary lesion detection was significantly better on T2 MVXD images in comparison to any of the other 4 sequences (P < 0.03). Intrapulmonary artifacts were significantly lesser in BTFE images as compared to T2 MVXD (P < 0.01). No significant difference was found between the severity of intrapulmonary artifacts in other MR sequences as compared to T2 MVXD.ConclusionsBy virtue of its better overall image quality, sharpness, superior visualization of mediastinal airways, and lesion detection, T2 MultiVane-XD promises to be a robust addition in the armamentarium of thoracic radiologists.