Comparative proteomic and clinicopathological analysis of breast adenoid cystic carcinoma and basal-like triple-negative breast cancer

BackgroundAdenoid cystic carcinoma (ACC) is a rare type of triple-negative breast cancer that has an indolent clinical behavior. Given the substantial overlapping morphological, immunohistochemical, and molecular features with other basal-like triple-negative breast cancer (BL-TNBC), accurate diagnosis of ACC is crucial for effective clinical treatment. The integrative analysis of the proteome and clinicopathological characteristics may help to distinguish these two neoplasms and provide a deep understanding on biological behaviors and potential target therapy of ACC.MethodsWe applied mass spectrometry-based quantitative proteomics to analyze the protein expression in paired tumor and adjacent normal breast tissue of five ACC and five BL-TNBC. Bioinformatic analyses and the clinicopathological characteristics, including histological features, immunohistochemistry, and FISH results, were also collected to get comprehensive information.ResultsA total of 307 differentially expressed proteins (DEPs) were identified between ACC and BL-TNBC. Clustering analysis of DEPs clearly separated ACC from BL-TNBC. GSEA found downregulation of the immune response of ACC compared with BL-TNBC, which is consistent with the negative PD-L1 expression of ACC. Vesicle-mediated transport was also inhibited, while ECM organization was enriched in ACC. The top upregulated proteins in DEPs were ITGB4, VCAN, and DPT. Moreover, in comparison with normal breast tissue, ACC showed elevated ribosome biogenesis and RNA splicing activity.ConclusionThis study provides evidence that ACC presents a substantially different proteomic profile compared with BL-TNBC and promotes our understanding on the molecular mechanisms and biological processes of ACC, which might be useful for differential diagnosis and anticancer strategy

A Histone Acetylation Modulator Gene Signature for Classification and Prognosis of Breast Cancer

Regulators of histone acetylation are promising epigenetic targets for therapy in breast cancer. In this study, we comprehensively analyzed the expression of histone acetylation modulator genes in breast cancer using TCGA data sources. A gene signature composed of eight histone acetylation modulators (HAMs) was found to be effective for the classification and prognosis of breast cancers, especially in the HER2-enriched and basal-like molecular subtypes. The eight genes consist of two histone acetylation writers (GTF3C4 and CLOCK), two erasers (HDAC2 and SIRT7) and four readers (BRD4, BRD7, SP100, and BRWD3). Both histone acetylation writer genes and eraser genes were found to be differentially expressed between the two groups indicating a close relationship exists between overall histone acetylation level and prognosis of breast cancer in HER2-enriched and basal-like breast cancer

Tripartite genome of all species [version 1; referees: 1 approved, 2 approved with reservations]

Neutral theory has dominated the molecular evolution field for more than half a century, but it has been severely challenged by the recently emerged Maximum Genetic Diversity (MGD) theory. However, based on our recent work of tripartite human genome architecture, we found that MGD theory may have overlooked the regulatory but variable genomic regions that increase with species complexity. Here we propose a new molecular evolution theory named Increasing Functional Variation (IFV) hypothesis. According to the IFV hypothesis, the genome of all species is divided into three regions that are ‘functional and invariable’, ‘functional and variable’ and ‘non-functional and variable’. While the ‘non-functional and variable’ region decreases as species become more complex, the other two regions increase

Influence of strata-specific forest structural features on the regeneration of the evergreen broad-leaved forest in Tianmu Mountain.

The vertical stratification of the stand may lead to a high heterogeneity of microenvironment in the forest, which further influences the understory regeneration and succession of the forest. Most relevant previous studies emphasized the overall effects of the Whole-stand structural characteristics on understory regeneration, while the strata-specific impacts of the overstory should be explored especially for those forests with a complicated combination of overstory species and heights. In this study, a subtropical evergreen broad-leaved forest in Tianmu Mountain of China was intensively investigated within 25 plots of 20 m × 20 m, aiming to find out how significant the stratified overstory (trees with diameter at breast height (DBH) ≥ 5 cm) structure and non-structure characteristics impact the understory (trees with DBH < 5 cm) regeneration. Regardless of species composition, the studied overstory was evenly divided into three strata (i.e. upper, middle and lower strata) according to their heights. Redundancy analysis was applied to explore both overall and strata-specific forest structure on characteristics (height, DBH, species diversity, and density) of tree regeneration. We found that the overall effect of the whole overstory on the forest regeneration depended mostly on diameter at breast height (DBH), tree species richness index and crown width. However, when analyzing with the strata-specific characteristics, the most pronounced impact factors for the regeneration were tree height of the upper and lower forest strata, tree species richness index and crown width of the middle and lower forest strata, and the competition index impact of the lower forest stratum. Among the three strata, the lower forest stratum showed the most significant impact with three characteristics on the understory regeneration, which may be attributed to their direct competition within the overlapping near-ground niches. Among the new generations, seedlings and saplings were more sensitive to the overstory structural characteristics than young trees. Our results suggest that the overstory showed strata-specific effects on the understory regeneration of evergreen broad-leaved forests in subtropical China, which provides theoretical basis for strata-specific forest management in similar forests

Adverse Events of PD-1 or PD-L1 Inhibitors in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis

(1) Background: This study aimed to develop a comprehensive understanding of the treatment-related adverse events when using PD-1 or PD-L1 inhibitors in triple-negative breast cancer (TNBC). (2) Methods: We conducted a meta-analysis of Phase II/III randomized clinical trials. Studies were searched for using PubMed, Embase, and Cochrane Library from 1 March 1980 till 30 June 2022. Data on adverse events were mainly extracted from ClinicalTrials.gov and published articles. A generalized linear mixed model with the logit transformation was employed to obtain the overall incidence of adverse events across all studies. For serious adverse events with low incidences, the Peto method was used to calculate the odds ratio (OR) and 95% confidence interval (95%CI) in the PD-1 or PD-L1 inhibitors groups compared to the control groups. (3) Results: Nine studies were included in the meta-analysis, including a total of 2941 TNBC patients treated with PD-1 or PD-L1 inhibitors (including atezolizumab, pembrolizumab and durvalumab) and 2339 patients in the control groups. Chemotherapy alone was the control group in all studies. The average incidences of all serious immune-related adverse events of interest (hypothyroidism, hyperthyroidism, pneumonitis, pruritus, rash) were less than 1%, except for adrenal insufficiency (1.70%, 95%CI: 0.50–5.61%) in the PD-1 or PD-L1 groups. PD-1 or PD-L1 inhibitors significantly increased the risk of serious pneumonitis (OR = 2.52, 95%CI: 1.02–6.26), hypothyroidism (OR = 5.92, 95%CI: 1.22–28.86), alanine aminotransferase (ALT) elevation (OR = 1.66, 95%CI: 1.12–2.45), and adrenal insufficiency (OR = 18.81, 95%CI: 3.42–103.40). For non-serious adverse events, the patients treated with PD-1 or PD-L1 inhibitors had higher risk of aspartate aminotransferase (AST) elevation (OR =1.26, 95%CI: 1.02–1.57), hypothyroidism (OR = 3.63, 95%CI: 2.92–4.51), pruritus (OR = 1.84, 95%CI: 1.30–2.59), rash (OR = 1.29, 95%CI: 1.08–1.55), and fever (OR = 1.77, 95%CI: 1.13–2.77), compared with chemotherapy alone. (4) Conclusions: The incidence of serious immune-related adverse events in PD-1 or PD-L1 inhibitors groups is low but significantly higher than in chemotherapy groups. When using PD-1 or PD-L1 inhibitors for the treatment of TNBC, serious pneumonitis, hypothyroidism, ALT elevation, and adrenal insufficiency should be considered. Non-serious adverse events, such as AST elevation, rash, and fever, should also be taken into consideration

Two-Dose Vaccination Significantly Prolongs the Duration from Symptom Onset to Death: A Retrospective Study Based on 173,894 SARS-CoV-2 Cases in Khyber Pakhtunkhwa, Pakistan

This research was carried out to quantify the duration from symptom onset to recovery/death (SOR/SOD) during the first four waves and the Alpha/Delta period of the epidemic in Khyber Pakhtunkhwa, Pakistan, and identify the associated factors. A total of 173,894 COVID-19 cases were admitted between 16 March 2020 and 30 November 2021, including 458 intensive care unit (ICU) cases. The results showed that the case fatality rate (CFR) increased with age, and females had a higher CFR. The median SOR of ICU cases was longer than that of non-ICU cases (27.6 vs. 17.0 days), while the median SOD was much shorter (6.9 vs. 8.4 days). The SOR and SOD in the Delta period were slightly shortened than the Alpha period. Age, cardiovascular diseases, chronic lung disease, diabetes, fever, breathing issues, and ICU admission were risk factors that were significantly associated with SOD (p &lt; 0.001). A control measure, in-home quarantine, was found to be significantly associated with longer SOD (odds ratio = 9.49, p &lt; 0.001). Infected vaccinated individuals had longer SOD than unvaccinated individuals, especially for cases that had received two vaccine doses (p &lt; 0.001). Finally, an advice on getting full-dose vaccination is given specifically to individuals aged 20&ndash;59 years

Triple-Negative Apocrine Breast Carcinoma Has Better Prognosis despite Poor Response to Neoadjuvant Chemotherapy

Apocrine carcinoma is a rare subtype of invasive ductal breast cancer that shows apocrine differentiation and largely triple-negative immunohistology. Triple-negative breast cancers are known to have more aggressive clinical courses. However, unlike most other subtypes, it is reported that triple-negative apocrine carcinoma (TNAC) has a better prognosis. Due to the scarcity of reported studies, our knowledge regarding its clinical behavior, prognosis and response to therapy is very limited. In this study, we retrospectively retrieved 41 triple-negative apocrine carcinoma cases from our breast cancer database, with an average follow-up of 32.8 months. It was found that TNAC had a poorer response to neoadjuvant therapy but a better prognosis than other nonapocrine types of triple-negative breast cancer. Meanwhile, TNAC has a low proliferative nature, as indicated by its low Ki-67 index. An updated analysis of the Surveillance, Epidemiology, and End Results database showed that chemotherapy did not improve breast-cancer-specific survival in TNAC patients. Our results suggest that TNAC is a special subtype of triple-negative breast cancer with a better short-term prognosis despite poor response to neoadjuvant chemotherapy

Using Whole Slide Gray Value Map to Predict HER2 Expression and FISH Status in Breast Cancer

Accurate detection of HER2 expression through immunohistochemistry (IHC) is of great clinical significance in the treatment of breast cancer. However, manual interpretation of HER2 is challenging, due to the interobserver variability among pathologists. We sought to explore a deep learning method to predict HER2 expression level and gene status based on a Whole Slide Image (WSI) of the HER2 IHC section. When applied to 228 invasive breast carcinoma of no special type (IBC-NST) DAB-stained slides, our GrayMap+ convolutional neural network (CNN) model accurately classified HER2 IHC level with mean accuracy 0.952 ± 0.029 and predicted HER2 FISH status with mean accuracy 0.921 ± 0.029. Our result also demonstrated strong consistency in HER2 expression score between our system and experienced pathologists (intraclass correlation coefficient (ICC) = 0.903, Cohen’s κ = 0.875). The discordant cases were found to be largely caused by high intra-tumor staining heterogeneity in the HER2 IHC group and low copy number in the HER2 FISH group

AR Expression Correlates with Distinctive Clinicopathological and Genomic Features in Breast Cancer Regardless of ESR1 Expression Status

Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression in breast cancer remains unclear. This study analyzed the clinicopathological and molecular features associated with AR negativity in both ER-positive and ER-negative breast cancer, trying to elucidate the molecular correlation between AR and ER. Our results showed that AR negativity was associated with different clinicopathological characteristics and molecular features in ER-positive and ER-negative breast cancer. Moreover, AR-positive breast cancer has better clinicopathological features than AR-negative breast cancer, especially in the ER-negative subtype. These results suggest that the role of AR in ER-negative breast cancer is distinctive from that in ER-positive breast cancer