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Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes.

Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATCderived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4 + T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting *10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET–rearranged thyroid cancer.

Background and Aims: Breast cancer is the prime cause of mortality among women of both developing and developed world. Out of 34.6% of female cancer patients, malignant breast cancer being the most common cancer found in Pakistan. The current study aims to evaluate the diagnostic accuracy of magnetic resonance spectroscopy in diagnosing malignant breast lesions taking histopathology as a gold standard. Materials and Methods: This cross-sectional study was carried out on 135 female patients with suspicious palpable lesions for malignancy referred from surgical OPD of Liaquat University of Medical and Health Sciences, Jamshoro during the period from October 2020 to March 2021. Magnetic resonance spectroscopy (MRS) dynamic enhanced images taken with contrast on 1.5 Tesla MRI machines were assessed based on kinetic and morphology. Malignancy biomarker was assessed with choline peak (Cho) allowed by MRS. The Single-voxel technique was utilized in order to evaluate the diagnostic performance of MRS in breast lesions malignancy. A comparison was made between MRS and biopsy findings. Results: Out of 135 female patients, 118 (87.40%) were malignant lesions patients assessed by MRS while histopathologically proven patients were 104 (77.33%). The calculated mean age of all the malignant patients was 48.3 ± 14.5 years with a range of 40-79 years. The diagnostic parameters of MRS such as specificity, accuracy, sensitivity, negative predictive value (NPV), and positive predictive value (PPV) was 74%, 88.2%, 93%, 77.8%, and 93.1% respectively while taking histopathology as a gold standard. Conclusion: MRS must be utilized as a primary imaging technique for the diagnosis of breast lesions malignancy due to its higher specificity, sensitivity, and accuracy in breast lumps characterization. MRS was found to be specific 74%, sensitive 88.2%, and accurate 93% in malignant breast cancer diagnosis. Keywords: MRS, Malignant breast lesions, Histopathology

From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher 1-3 . Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy 4 . For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the wellestablished role of diet, exercise and small molecules that target the pace of metabolic aging [5][6][7][8] . Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.It has long been known that age is one of the main risk factors for cancer incidence [9][10][11] . How it contributes to cancer progression, however, is not well understood 2,3,12 . Considering the growing body of evidence demonstrating that cancer cell-extrinsic factors are key in modulating tumor progression, we hypothesized that aging produces a systemic environment that supports tumor progression and development of aggressive properties. To test this hypothesis, we cultured A549 non-small cell lung cancer (NSCLC) and HCC1806 triple negative breast cancer (TNBC) cells in 10% human serum from 30 young (age ≤ 30) and 30 old (age ≥ 60) individuals with no diagnosed disease ( Fig. 1a; Extended Data Table 1). While the majority of cells treated with young donor sera maintained their epithelial morphology (25 out of 30), cells treated with 25 out of the 30 old donor sera became mesenchymal, losing polarity and displaying a spindle-shaped morphology (Extended Data Fig. 1-3). These phenotypes were independent of donor ethnicity, and resembled epithelial-to-mesenchymal transition (EMT), a developmental process that during cancer pathogenesis can confer cells the cellular plasticity necessary to acquire proaggressive and pro-metastatic properties 13 . Cells cultured in the presence of sera from aged donors displayed a pronounced loss of the epithelial marker E-cadherin and gain of the mesenchymal markers fibronectin and vimentin 13 , in addition to increased expression of SERPINE1 and MMP2 14,15 -proteins highly associated with aggressive phenotypes (Fig. 1b, Extended Data Fig. 4a, b). Moreover, the aged sera promoted resistance to two distinct and widely used chemotherapeutic drugs, carboplatin and paclitaxel (Fig. 1c, Extended Data Fig. 4c). Compelled by these observations, we questioned if the cells treated with the old donor sera would also display heightened metastatic potential. We treated MDA-MB-2...

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