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Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities.

The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl-protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP-deficient cells, lower sDMA modification prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post-translational regulation.

KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.

Simple Summary: Imiquimod (IMQ) is clinically used in the treatment of various skin malignancies. We previously showed that IMQ-induced apoptosis and autophagic cell death in skin cancer cells are ROS-dependent. Additionally, IMQ-induced apoptosis is associated with a decrease in Mcl-1 levels. However, the exact role of Mcl-1 in IMQ-induced apoptosis, including its protective mechanisms and physiological function in cancer cells, remains unclear. This study demonstrated that the overexpression of Mcl-1 or IL-6-induced Mcl-1 upregulation reversed mitochondrial dysfunction, mitochondrial fission, and mitophagy in IMQ-treated cancer cells and protected them from IMQ-induced apoptosis. These results provide significant insights supporting the role of Mcl-1 in mitochondria and suggest that it may be a potential target for cancer research and therapy. Mitochondria, vital organelles that generate ATP, determine cell fate. Dysfunctional and damaged mitochondria are fragmented and removed through mitophagy, a mitochondrial quality control mechanism. The FDA-approved drug IMQ, a synthetic agonist of Toll-like receptor 7, exhibits antitumor activity against various skin malignancies. We previously reported that IMQ promptly reduced the level of the antiapoptotic Mcl-1 protein and that Mcl-1 overexpression attenuated IMQ-triggered apoptosis in skin cancer cells. Furthermore, IMQ profoundly disrupted mitochondrial function, promoted mitochondrial fragmentation, induced mitophagy, and caused cell death by generating high levels of ROS. However, whether Mcl-1 protects mitochondria from IMQ treatment is still unknown. In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development. [ABSTRACT FROM AUTHOR]

Background and Objectives: As the global aging population grows, the incidence of thyroidectomy in elderly patients is increasing. This study aimed to evaluate the surgical outcomes of thyroidectomy in patients aged 80 years and older. Materials and Methods: All patients aged 80 years and older who underwent thyroidectomies at our hospital between January 2015 and December 2022 were reviewed in this retrospective cohort study. Collected data consisted of patients' clinical characteristics, functional status, compression symptoms, preoperative assessments, perioperative outcomes, postoperative complications (such as bleeding events, recurrent laryngeal nerve injury, hypocalcemia), pathological findings, readmission, and follow-up outcomes. Results: Seventeen patients were included in this study, with female predominance (82.4%). The mean age was 85.6 ± 4.8 years. Fourteen patients (82.4%) exhibited compression-related symptoms as surgical indications. Based on pathological reports, patients were categorized into benign (12/17, 70.6%) and malignancy (5/17, 29.4%) groups. The benign group had a shorter operation time compared with the malignancy group (164.3 ± 32.0 min vs. 231.0 ± 79.1 min, p = 0.048). No major postoperative complications developed. The median postoperative follow-up duration was 28 months (range: 2–91 months). Thirteen patients (76.5%) were alive at the end of the study period. Conclusions: Despite potential age-related risks, thyroidectomy is feasible for carefully selected patients aged 80 years and older. It provides benefits not only in terms of oncological curative treatment but also in improving the quality of life, such as compressive symptoms and wound condition. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphorylation plays a critical role in initiating upstream cellular signaling transduction. However, the challenge in biological samples is the variability in relative concentrations (0.1%) of site‐specific tyrosine phosphorylation on proteins. To navigate these fluctuations and accurately quantify the absolute levels of tyrosine phosphosites among different samples, we reported a hybrid data‐independent acquisition‐parallel reaction monitoring (DIA‐PRM) MS technique for the robust identification and quantification of the phosphoproteome, the establishment of a comprehensive library of tyrosine phosphosites, and the specific assessment of changes in tyrosine phosphorylation. In our model study on non‐small cell lung cancer cells, our PRM strategy accomplished by a spiked‐in synthetic heavy phosphopeptide demonstrated reliable targeted quantification of the pY1197 on EGFR, revealing levels of 2.5, 4.9, and 5.3 fmol in pervanadate (PV)‐treated cells at 0, 15, and 30 min, respectively. Additionally, DIA‐extensive phosphoproteomic analysis provided 2765 tyrosine phosphosites within 14,961 global phosphosites corresponding to 1536 phosphoproteins, contributing to the phospho‐library establishment and relative quantification of phosphorylation level, especially in the PV‐treated time‐dependent increase of ErbB signaling pathway. This hybrid DIA‐PRM approach will advance the application of precise measurement of changes in multiple phosphotyrosine residues and enhance our understanding of phosphoproteomic dynamics in drug‐resistant cascades. [ABSTRACT FROM AUTHOR]

Glossogyne tenuifolia (Labill.) Cass. ex Cass (Compositae) is a herbaceous plant that is endemic to Taiwan. Traditional Chinese Medicine has utilized it as a treatment for fever, inflammation, and liver preservation. Recent research has unveiled its bioactivities, including anti-inflammation, anti-cancer, antiviral, antioxidant, anti-fatigue, hepatoprotection, and immune modulation elements. Nevertheless, its effect on skin health remains to be investigated. Thus, we investigated the impact of G. tenuifolia essential oil (GTEO) on forskolin (FRK)-induced melanin biosynthesis and its mechanisms in B16-F10 murine melanoma in vitro. Treatment of GTEO resulted in a substantial decrease in FRK-induced melanin production, accompanied by a significant decrease in tyrosinase mRNA and protein expression levels. Additionally, our data demonstrated that the decrease in tyrosinase expression resulted from the suppression of MITF, as indicated by the reduced movement of MITF into the cell nucleus. Moreover, GTEO prompted a prolonged ERK1/2 activation, leading to the decline of MITF through proteasomal degradation, and it was verified that GTEO had no inhibitory impact on MITF activity in ERK1/2 inhibitor-treated cells. Additional studies demonstrated that α-pinene and D-limonene, which are the primary components in GTEO, showed strong melanin and tyrosinase inhibitory effects, indicating that α-pinene and D-limonene may contribute to its anti-melanogenic effects. Collectively, these data presented compelling proof that GTEO, along with its primary components α-pinene and D-limonene, show great potential as natural sources for developing innovative skin-whitening agents in the field of cosmetics. [ABSTRACT FROM AUTHOR]

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