Overexpression of TPD52L2 in HNSCC: prognostic significance and correlation with immune infiltrates.

BACKGROUND: Evidence has been presented that the tumor protein D52 (TPD52) family plays a critical role in tumor development and progression. As a member of the TPD52 family, the changes in TPD52L2 gene status are instrumental in kinds of cancer development. However, its effects on patient prognosis and immune infiltration in Head and Neck Squamous Carcinoma (HNSCC) are still poorly understood. METHODS: The Tumor Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and c-BioPortal database was used to explore the expression pattern, prognostic value, and variation of gene status in HNSCC. The LinkedOmics database was used to obtain the co-expression genes of TPD52L2 and identify the diagnostic value of TPD52L2 in HNSCC. The correlations between TPD52L2 expression and six main types of immune cell infiltrations and immune signatures were explored using Tumor Immune Estimation Resource (TIMER). The correlation between TPD52L2 expression and immune checkpoint genes (ICGs) was analyzed by TCGA database. Immunohistochemistry (IHC) was performed to validate the expression of three ICGs (PDL1, PDL2, EGFR) and TPD52L2 using 5 paired HNSCC and normal head and neck tissues. Polymerase Chain Reaction (PCR) and Western Blot (WB) of HNSCC and normal head and neck cell lines were performed to verify the high level of TPD52L2 mRNA and protein expression. protein expression of TPD52L2 in pan-cancer was also validated using UALCAN. RESULTS: TPD52L2 was overexpressed in tumor tissues, and it predicted worse survival status in HNSCC. ROC analysis suggested that TPD52L2 had a diagnostic value. Multivariate Cox analysis identified TPD52L2 as an independent negative prognostic marker of overall survival. Functional network analysis suggested that TPD52L2 was associated with immune-related signaling pathways, cell migration pathways, and cancer-related pathways. High expression of TPD52L2 was associated with a more mutant frequency of TP53. Notably, we found that the expression of TPD52L2 was closely negatively correlated with the infiltration levels of 15 types of immune cells and positively correlated with several immune markers. PCR, WB experiments, and UALCAN database verified the high level of TPD52L2 mRNA and protein expression. CONCLUSION: TPD52L2 is upregulated in HNSCC, which is an independent factor for adverse prognosis prediction. It probably plays a role in the negative regulation of immune cell infiltration. TPD52L2 might be a promising prognostic biomarker and therapeutic target in HNSCC.

Molecular Insights into Gas-Particle Partitioning and Viscosity of Atmospheric Brown Carbon.

Biomass burning organic aerosol (BBOA), containing brown carbon chromophores, plays a critical role in atmospheric chemistry and climate forcing. However, the effects of evaporation on BBOA volatility and viscosity under different environmental conditions remain poorly understood. This study focuses on the molecular characterization of laboratory-generated BBOA proxies from wood pyrolysis emissions. The initial mixture, "pyrolysis oil (PO1)", was progressively evaporated to produce more concentrated mixtures (PO1.33, PO2, and PO3) with volume reduction factors of 1.33, 2, and 3, respectively. Chemical speciation and volatility were investigated using temperature-programmed desorption combined with direct analysis in real-time ionization and high-resolution mass spectrometry (TPD-DART-HRMS). This novel approach quantified saturation vapor pressures and enthalpies of individual species, enabling the construction of volatility basis set distributions and the quantification of gas-particle partitioning. Viscosity estimates, validated by poke-flow experiments, showed a significant increase with evaporation, slowing particle-phase diffusion and extending equilibration times. These findings suggest that highly viscous tar ball particles in aged biomass burning emissions form as semivolatile components evaporate. The study highlights the importance of evaporation processes in shaping BBOA properties, underscoring the need to incorporate these factors into atmospheric models for better predictions of BBOA aging and its environmental impact.

The Tumor Suppressor TPD52-Governed Endoplasmic Reticulum Stress is Modulated by APCCdc20.

Aberrant regulation of unfolded protein response (UPR)/endoplasmic reticulum (ER) stress pathway is associated with cancer development, metastasis, and relapse, and the UPR signal transducer ATF6 has been proposed as a diagnostic and prognostic marker for many cancers. However, a causal molecular link between ATF6 activation and carcinogenesis is not established. Here, it is found that tumor protein D52 (TPD52) integrates ER stress and UPR signaling with the chaperone machinery by promoting S2P-mediated cleavage of ATF6. Although TPD52 has been generally considered as an oncogene, TPD52 is identified as a novel tumor suppressor in bladder cancer. Significantly, attenuation of the ER stress via depletion of TPD52 facilitated tumorigenesis in a subset of human carcinomas. Furthermore, the APCCdc20 E3 ligase is validated as the upstream regulator marking TPD52 for polyubiquitination-mediated proteolysis. In addition, inactivation of Cdc20 sensitized cancer cells to treatment with the ER stress inducer in a TPD52-dependent manner. Thus, the study suggests that TPD52 is a novel Cdc20 substrate that may modulate ER stress to prevent tumorigenesis.

Fragment-based approaches to discover ligands for tumor-specific E3 ligases.

INTRODUCTION: Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy through selective degradation of specific proteins by harnessing the cellular ubiquitin-proteasome system (UPS), which involves over 600 E3 ubiquitin ligases. Recent proteome profiling reported tumor-specific E3 ligases in human. Development of those tumor-specific E3 ligase ligands would provide a solution for tumor-specific TPD for effective cancer treatment. AREAS COVERED: This review provides a comprehensive list of E3 ligases found only in specific types of tumor from public databases and highlights examples of their ligands discovered through fragment-based approaches. It details their discovery process and potential applications for precise TPD and effective cancer treatments. EXPERT OPINION: Current TPD strategies using proteolysis-targeting chimeras (PROTACs) primarily utilize general E3 ligases, such as CRBN and VHL. Since these E3 ligases demonstrate effective protein degradation activity in most human cell types, CRBN and VHL-based PROTACs can exhibit undesired TPD in off-target tissues, which often leads to the side effects. Therefore, developing tumor-specific E3 ligase ligands can be crucial for effective cancer treatments. Fragment-based ligand discovery (FBLD) approaches would accelerate the identification of these tumor-specific E3 ligase ligands and associated PROTACs, thereby advancing the field of targeted cancer therapies.

Probing class I histone deacetylases (HDAC) with proteolysis targeting chimera (PROTAC) for the development of highly potent and selective degraders.

Class I HDACs are considered promising targets for cancer due to their role in epigenetic modifications. The main challenges in developing a new, potent and non-toxic class I HDAC inhibitor are selectivity and appropriate pharmacokinetics. The PROTAC technique (Proteolysis Targeting Chimera) is a new method in drug development for the production of active substances that can degrade a protein of interest (POI) instead of inhibiting it. This technique will open the era to produce selective and potent drugs with a high margin of safety. Previously, we reported different inhibitors targeting class I HDACs functionalized with aminobenzamide or hydroxamate groups. In the current research work, we will employ PROTAC technique to develop class I HDAC degraders based on our previously reported inhibitors. We synthesized two series of aminobenzamide-based PROTACs and hydroxamate-based PROTACs and tested them in vitro against class I HDACs. To ensure their degradation, all of them were screened against HDAC2 as representative example of class I. The best candidates were evaluated at different concentrations at various HDAC subtypes. This resulted in the PROTAC (32a) (HI31.1) that degrades HDAC8 with a DC50 of 8.9 nM with a proper margin of selectivity against other isozymes. Moreover, PROTAC 32a is able to degrade HDAC6 with DC50 = 14.3 nM. Apoptotic study on leukemic cells (MV-4-11) displayed more than 50 % apoptosis took place at 100 nM. PROTAC 32a (HI31.1) showed a good margin of safety against normal cell line and proper chemical stability.

Tidal Versus Intermittent Peritoneal Dialysis in Chronic Peritoneal Dialysis Patients: Randomized, Open-Label, Prospective Control Study.

BACKGROUND: Tidal peritoneal dialysis (TPD) provides better fluid flow mechanics and is more comfortable for the patient, owing to fewer alarms and less pain during inflow and outflow. The long-term characteristics of patients with TPD were not evident. In this randomized controlled follow-up study, we aimed to explore the characteristics of patients with TPD, compared to IPD. METHODS: A total of 85 patients were randomized to either IPD or 70% TPD between January 2019 and December 2020, and all patients were followed up on December 2021. The characteristics of patients between the two groups were analyzed using a t-test or chi-square as appropriate. The overall survival and technical survival were analyzed using Kaplan-Meier analysis. RESULTS: Forty-two patients were assigned to IPD, and 43 patients were assigned to TPD. The basal characteristics of patients were not different between the two groups. In an average of 16 months of follow-up, 19 patients died, and 25 patients dropped out of peritoneal dialysis. The two groups had no difference in overall survival and technical survival. TPD was associated with high urine volume (p = 0.001), lower blood urea nitrogen (p = 0.002), lower phosphorus (p = 0.004), and fewer cycler alarms (p < 0.001). The chance of patients reporting abdominal fullness was higher in patients with TPD (p = 0.001). CONCLUSION: In the randomized, controlled, follow-up study, TPD may preserve residual renal function and is associated with lower urea nitrogen and phosphorus in chronic peritoneal dialysis patients. TPD is associated with fewer cycler alarms but may increase the chance of patients reporting abdominal distension.

Bioinformatic and Phenotypic Analysis of AtPCP-Ba Crucial for Silique Development in Arabidopsis.

Silique development exerts significant impacts on crop yield. CRPs (Cysteine-rich peptides) can mediate cell-cell communication during plant reproduction and development. However, the functional characterization and regulatory mechanisms of CRPs in silique development remain unclear. In this study, we identified many CRP genes downstream of the CRP gene TPD1 (TAPETUM DETERMINANT1) during silique development using a microarray assay. The novel Arabidopsis thaliana pollen-borne CRPs, the PCP-Bs (for pollen coat protein B-class) gene AtPCP-Ba, along with TPD1, are essential for silique development. The AtPCP-Ba was significantly down-regulated in tpd1 flower buds but up-regulated in OE-TPD1 flower buds and siliques. The silencing of AtPCP-Ba compromised the wider silique of OE-TPD1 plants and inhibited the morphology of OE-TPD1 siliques to the size observed in the wild type. A total of 258 CRPs were identified with the bioinformatic analysis in Arabidopsis, Brassica napus, Glycine max, Oryza sativa, Sorghum bicolor, and Zea mays. Based on the evolutionary tree classification, all CRP members can be categorized into five subgroups. Notably, 107 CRP genes were predicted to exhibit abundant expression in flowers and fruits. Most cysteine-rich peptides exhibited high expression levels in Arabidopsis and Brassica napus. These findings suggested the involvement of the CRP AtPCP-Ba in the TPD1 signaling pathway, thereby regulating silique development in Arabidopsis.

Personality interferences in the pathology of breast cancer: a cross-sectional single-center study.

Individual personality refers to the Ego and the interpersonal sector. The Ego corresponds to consciousness and self-esteem, including the capacities for emotional self-regulation, self-control, self-evaluation, and self-direction in relation to personal goals. When neoplastic and psychiatric diseases coexist, a patient's quality of life is significantly impacted. While there are somatic differences in disease progression, how the illness is perceived and mainly experienced depends on personality traits. In this study, we administered the DECAS Personality Inventory (a Romanian-validated instrument based on the Five-Factor model of personality) to a group of 121 patients diagnosed with breast cancer to explore the relationships among their personality traits. Descriptive statistics revealed that the mean T scores for openness, extroversion, and emotional stability were low, while the scores for conscientiousness and agreeableness were at an average level. Our findings suggest that, in the studied group, low levels of emotional stability, extroversion, and openness were unfavorable personality dimensions that should be a primary focus of therapeutic strategies, as they significantly affect the quality of life in patients with breast cancer.

Medial temporal lobe atrophy patterns in early-versus late-onset amnestic Alzheimer's disease.

BACKGROUND: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. METHODS: BioFINDER-2 participants with memory impairment, abnormal amyloid-ß and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-ß-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. RESULTS: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. CONCLUSIONS: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.

Targeting eukaryotic elongation factor 2 kinase (eEF2K) with small-molecule inhibitors for cancer therapy.

Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the α-kinase family that is activated by calcium/calmodulin. Of note, eEF2K is crucial for regulating translation and is often highly overexpressed in malignant cells. Therefore in this review, we summarize the molecular structure of eEF2K and its oncogenic roles in cancer. Moreover, we further discuss the inhibition of eEF2K with small-molecule inhibitors and other new emerging therapeutic strategies in cancer therapy. Taken together, these inspiring findings provide new insights into a promising strategy for inhibiting eEF2K to greatly improve future cancer therapy.

Evaluating teacher competencies in Pakistan's public schools: Enhancing the impact of professional development programs.

Professional Development (PD) programs in Pakistan typically follow a standardized approach, often overlooking the diverse strengths and weaknesses of various teacher groups, which may not adequately address their specific needs. This study aims to evaluate teacher competencies among different groups from the perspective of school principals in Pakistan's public schools, with the goal of enhancing the effectiveness of PD programs. Initially, the study identifies three key themes of 21st-century teacher competencies through an extensive review of recent literature. An interview guide, based on these competencies, was used to gather data from seven public school principals via structured interviews. The data were analyzed using a deductive content analysis approach, with MAXQDA software employed for theme coding. The findings revealed notable differences in teacher competencies from the principals' perspectives. Female and younger teachers exhibited more competencies compared to their male and senior counterparts. These insights provide crucial information for planning and customizing Teacher Professional Development (TPD) programs, emphasizing an objective evaluation of teachers rather than self-assessment. Tailored PD programs based on these findings can more effectively enhance teachers' professional growth and competence."

Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies.

Histone deacetylase 6 (HDAC6) plays a crucial role in the initiation and progression of various cancers, as its overexpression is linked to tumor growth, invasion, migration, survival, apoptosis, and angiogenesis. Therefore, HDAC6 has emerged as an attractive target for anticancer drug discovery in the past decade. However, the development of conventional HDAC6 inhibitors has been hampered by their limited clinical efficacy, acquired resistance, and inability to inhibit non-enzymatic functions of HDAC6. To overcome these challenges, new strategies, such as dual-acting inhibitors, targeted protein degradation (TPD) technologies (including PROTACs, HyT), are essential to enhance the anticancer activity of HDAC6 inhibitors. In this review, we focus on the recent advances in the design and development of HDAC6 modulators, including isoform-selective HDAC6 inhibitors, HDAC6-based dual-target inhibitors, and targeted protein degraders (PROTACs, HyT), from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and clinical status. Finally, we discuss the challenges and future directions for HDAC6-based drug discovery for cancer therapy.

Conditional PROTAC: Recent Strategies for Modulating Targeted Protein Degradation.

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising technology for inducing targeted protein degradation by leveraging the intrinsic ubiquitin-proteasome system (UPS). While the potential druggability of PROTACs toward undruggable proteins has accelerated their rapid development and the wide-range of applications across diverse disease contexts, off-tissue effects and side-effects of PROTACs have recently received attentions to improve their efficacy. To address these issues, spatial or temporal target protein degradation by PROTACs has been spotlighted. In this review, we explore chemical strategies for modulating protein degradation in a cell type-specific (spatio-) and time-specific (temporal-) manner, thereby offering insights for expanding PROTAC applications to overcome the current limitations of target protein degradation strategy.

Endoscopic Combined Drainage of One Giant and Multiple Small Pancreatic Pseudocysts: A Case Report.

A pancreatic pseudocyst (PPC) is a frequent complication of pancreatitis, often stemming from alcohol, gallstones, or hyperlipidemia. Endoscopic treatment of PPC has become the mainstream treatment. A case of one giant and multiple small PPCs was observed, manifesting as repeated abdominal bloating, abdominal pain, nausea, and vomiting after meals. Initial computed tomography scans revealed the presence of multiple PPCs. Despite ineffective medical treatment, the pseudocysts progressively increased. In response, we conducted a combined endoscopic intervention, involving Hot AXIOS (Boston Scientific, Marlborough, MA) stenting through endoscopic ultrasound-guided transmural drainage (EUS-TMD) and the placement of the endoscopic nasopancreatic drainage (ENPD) mimic stent through endoscopic retrograde pancreatography (ERP). Remarkably, after nine months of postoperative follow-up, the patient had no discomfort symptoms and the cyst disappeared. We conducted a literature review on endoscopic combined drainage for PPCs, which is still controversial. Our presented case serves as a demonstration that endoscopic combined drainage can effectively and successfully manage giant and multiple PPCs.

Hydrophobic tagging of small molecules: an overview of the literature and future outlook.

INTRODUCTION: Hydrophobic tagging (HyT) technology presents a distinct therapeutic strategy diverging from conventional small molecule drugs, providing an innovative approach to drug design. This review aims to provide an overview of the HyT literature and future outlook to offer guidance for drug design. AREAS COVERED: In this review, the authors introduce the composition, mechanisms and advantages of HyT technology, as well as summarize the detailed applications of HyT technology in anti-cancer, neurodegenerative diseases (NDs), autoimmune disorders, cardiovascular diseases (CVDs), and other fields. Furthermore, this review discusses key aspects of the future development of HyT molecules. EXPERT OPINION: HyT emerges as a highly promising targeted protein degradation (TPD) strategy, following the successful development of proteolysis targeting chimeras (PROTAC) and molecular glue. Based on exploring new avenues, modification of the HyT molecule itself potentially enhances the technology. Improved synthetic pathways and emphasis on pharmacokinetic (PK) properties will facilitate the development of HyT. Furthermore, elucidating the biochemical basis by which the compound's hydrophobic moiety recruits the protein homeostasis network will enable the development of more precise assays that can guide the optimization of the linker and hydrophobic moiety.

TPD52 is a prognostic biomarker and potential therapeutic target for ER+/PR+/HER2+ breast cancer.

BACKGROUND: Breast cancer (BRCA) represents a significant health challenge for women globally, with refractory cases showing resistance to current therapeutic strategies. The discovery of novel molecular markers and therapeutic targets is critical for improving outcomes in these patients. The primary aim of this study is to elucidate the role of tumor protein D52 (TPD52) as a novel molecular marker and potential therapeutic target to improve outcomes for BRCA patients. METHODS: Using bioinformatics methods, we screened and evaluated the expression, prognosis, and associated mechanisms of TPD52 in BRCA. Two hundred and thirty-eight BRCA cases and 19 control cases were collected from Shanghai First Maternity and Infant Hospital, and the protein expression of TPD52 was detected by immunohistochemistry, and the correlation between TPD52 and the prognosis of BRCA was analyzed. RESULTS: The expression of TPD52 in BRCA tissues was significantly higher than that in the control (P<0.001), displaying a strong association with key clinical variables, concurrently indicating an unfavorable prognostic implication. The survival analysis revealed high TPD52 expression was an independent adverse prognostic factor for overall (P=0.008) and disease-specific survival (P=0.005). Gene set enrichment analysis showed that TPD52 negatively correlated with estradiol, AMP-activated protein kinase, and other responses. Immune infiltration analysis showed that TPD52 was associated with immune cell infiltration, Th-1/Th-2 cell balance, and immune defense cells such as dendritic and plasmacytoid dendritic cells. It is further found that high TPD52 expression is associated with progression-free and disease-free survival from the analysis of immunohistochemical data of the patients at our hospital. CONCLUSIONS: In summary, TPD52 may serve as an independent prognostic biomarker for BRCA, which may represent a promising novel therapeutic target, particularly for the refractory estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+)/human epidermal growth factor receptor 2-positive (HER2+) BRCA cases that have failed endocrine therapy and targeted treatment.

The surface chemistry of the atomic layer deposition of metal thin films.

In this perspective we discuss the progress made in the mechanistic studies of the surface chemistry associated with the atomic layer deposition (ALD) of metal films and the usefulness of that knowledge for the optimization of existing film growth processes and for the design of new ones. Our focus is on the deposition of late transition metals. We start by introducing some of the main surface-sensitive techniques and approaches used in this research. We comment on the general nature of the metallorganic complexes used as precursors for these depositions, and the uniqueness that solid surfaces and the absence of liquid solvents bring to the ALD chemistry and differentiate it from what is known from metalorganic chemistry in solution. We then delve into the adsorption and thermal chemistry of those precursors, highlighting the complex and stepwise nature of the decomposition of the organic ligands that usually ensued upon their thermal activation. We discuss the criteria relevant for the selection of co-reactants to be used on the second half of the ALD cycle, with emphasis on the redox chemistry often associated with the growth of metallic films starting from complexes with metal cations. Additional considerations include the nature of the substrate and the final structural and chemical properties of the growing films, which we indicate rarely retain the homogeneous 2D structure often aimed for. We end with some general conclusions and personal thoughts about the future of this field.

Medial temporal lobe atrophy patterns in early- versus late-onset amnestic Alzheimer's disease.

Background: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfield volumes and drivers of atrophy in amnestic EOAD is lacking. Methods: BioFINDER-2 participants with memory impairment, abnormal amyloid-ß status and tau-PET were included. Forty-one EOAD individuals aged ≤65 years and, as comparison, late-onset AD (LOAD, ≥70 years, n=154) and Aß-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. Results: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups, although LOAD showed thinner entorhinal cortices compared to EOAD. EOAD showed lower WMH compared to LOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity was found. Conclusions: We found in vivo evidence for MTL atrophy in amnestic EOAD and overall similar levels to LOAD of MTL tau pathology and co-pathologies.

Synthetic lethality: targeting the SMARCA2 bromodomain for degradation in SMARCA4-deficient tumors - a review of patent literature from 2019-June 2023.

INTRODUCTION: SMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer. AREAS COVERED: The current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated. EXPERT OPINION: SMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.