👤 Sonir R Antonini

Breast cancer is the second most common cancer worldwide. Chemotherapy often causes dyslipidemia and obesity in breast cancer patients. Monitoring lipid profiles and body mass index (BMI) is crucial to evaluate chemotherapy's metabolic side effects, identify interventions to mitigate them, and understand health risks linked to weight changes during treatment. Shenling Baizhu Powder (SLBZP), a traditional Chinese medicine (TCM), treats spleen-stomach ailments by boosting spleen function, enhancing qi, and reducing dampness. SLBZP has potential benefits in managing chemotherapy-induced dyslipidemia and improving overall metabolic health in cancer patients. This study retrospectively examined the effects of SLBZP on blood lipid levels and BMI in breast cancer patients undergoing adjuvant chemotherapy. This study reviewed the medical records of patients who were diagnosed with breast cancer at the Breast Surgery Department of Zhejiang Provincial Hospital of Traditional Chinese Medicine from January 2022 to December 2023. Based on the inclusion criteria, a total of 180 eligible patients were included and divided into an observational group (which received SLBZP) and a control group (which did not receive SLBZP) during chemotherapy. Patients' clinical data, including age at diagnosis, menopausal status, tumor location, smoking and drinking habits, tumor molecular type, tumor node metastasis (TNM) stage, chemotherapy drugs, targeted therapy, lipid levels, and BMI before and after chemotherapy, were collected. Statistical analyses were conducted using SPSS 25.0. After chemotherapy, the control group showed significant increases in total cholesterol (TC) (P=0.03), triglyceride (TG) (P=0.001), low-density lipoprotein cholesterol (LDL-C) (P=0.02), and apolipoprotein B (ApoB) (P=0.01) levels. In the observational group, the TC, TG, and LDL-C levels remained stable (P>0.05), but the high-density lipoprotein cholesterol (HDL-C) (P=0.001) and apolipoprotein A1 (ApoA1) (P<0.001) levels significantly decreased, and BMI (P=0.02) significantly increased. The subgroup analysis revealed that the taxane followed by anthracycline subgroup showed significant increases in BMI (P=0.007) and significant decreases in the HDL-C (P=0.007) and ApoA1 (P<0.001) levels, while the taxane subgroup showed a significant decrease in the HDL-C level post-chemotherapy (P=0.003). In the control group, the TG (P=0.002) and LDL-C (P=0.02) levels were significantly elevated in the taxane followed by anthracycline subgroup post-chemotherapy. No significant changes were observed in BMI or the other lipid indexes in the remaining chemotherapy drug regime subgroups (P>0.05). Chemotherapy increased the TC, TG, LDL-C, and ApoB levels in breast cancer patients, but SLBZP mitigated dyslipidemia. The patients who received SLBZP also showed increased BMI post-chemotherapy, which was likely due to reduced gastrointestinal side effects. Taxane-based chemotherapy drugs had greater effects on blood lipids and BMI, while anthracycline-based drugs did not significantly affect blood lipids and BMI. Show less

Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, are a group of inherited neurodegenerative disorders that mostly arise in childhood. Each of the NCLs is a genetically distinct disease caused by variants in at least 13 different genes (CLN1-CLN14). NCLs are neurodegenerative, and symptoms can include a combination of childhood dementia, epileptic seizures, motor decline and vision loss, and eventually lead to premature death. There is currently no cure for any subtype of NCL, however, enzyme replacement therapy is available for CLN2 disease, and several treatment strategies are being explored for other NCL subtypes. Early diagnosis and initiation of supportive services (e.g. health, education, social services) are essential to preserve quality of life. Only a few studies have investigated family experiences with NCL, many of which are international in scope. A mixed-method research study was conducted in the UK to understand family experiences in CLN2 and CLN3 disease. It involved an initial literature review, followed by in-depth qualitative interviews. Interview data were analysed using a thematic analysis. Thirteen families (n = 13) participated in the interviews. This represented 16 parents (11 mothers and 5 fathers) of 18 children (10 diagnosed with CLN3 disease and 8 diagnosed with CLN2 disease). Findings were analysed jointly across CLN2 and CLN3 disease. Six overarching themes emerged from the analysis: difficulty in recognising early symptoms; the shock of a diagnosis; the demands of caring for complex and ever-changing needs; a constant battle to access appropriate and timely support services; the extensive impact on the unaffected sibling; and the all-encompassing impact on the family. This study contributes novel UK specific data on family experiences and unmet needs in CLN2 and CLN3 disease. More needs to be done to ensure NCLs are diagnosed early, and timely local support services are made available to protect quality of life for both the affected children and their families. Show less

Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. To identify methylation signatures in ACPs regarding clinical presentation and outcome. Clinical and pathology data were collected from 35 patients with ACP (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multidimensional scaling. Statistical associations between clusters and clinical features were achieved using the Fisher test and global biological process interpretations were aided by Gene Ontology enrichment analyses. Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = .0006), hypomethylated in CpG island, non-CpG Island sites, and globally (P < .001), and associated with greater tumor size (24.1 vs 9.5 cm3, P = .04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell adhesion, cytoskeleton organization, and cytokine binding, and cell type-specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. Two clusters of patients with ACP were consistently revealed by unsupervised machine learning methods, with one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment. Show less

Alpaca (Vicugna pacos), llama (Lama glama), vicugna (Vicugna vicugna) and guanaco (Lama guanicoe), are the camelid species distributed over the Andean high-altitude grasslands, the Altiplano, and the Patagonian arid steppes. Despite the wide interest on these animals, most of the loci under selection are still unknown. Using whole-genome sequencing (WGS) data we investigated the occurrence and the distribution of Runs Of Homozygosity (ROHs) across the South American Camelids (SACs) genome to identify the genetic relationship between the four species and the potential signatures of selection. A total of 37 WGS samples covering the four species was included in the final analysis. The multi-dimensional scaling approach showed a clear separation between the four species; however, admixture analysis suggested a strong genetic introgression from vicugna and llama to alpaca. Conversely, very low genetic admixture of the guanaco with the other SACs was found. The four species did not show significant differences in the number, length of ROHs (100-500 kb) and genomic inbreeding values. Longer ROHs (> 500 kb) were found almost exclusively in alpaca. Seven overlapping ROHs were shared by alpacas, encompassing nine loci (FGF5, LOC107034918, PRDM8, ANTXR2, LOC102534792, BSN, LOC116284892, DAG1 and RIC8B) while nine overlapping ROHs were found in llama with twenty-five loci annotated (ERC2, FZD9, BAZ1B, BCL7B, LOC116284208, TBL2, MLXIPL, PHF20, TRNAD-AUC, LOC116284365, RBM39, ARFGEF2, DCAF5, EXD2, HSPB11, LRRC42, LDLRAD1, TMEM59, LOC107033213, TCEANC2, LOC102545169, LOC116278408, SMIM15, NDUFAF2 and RCOR1). Four overlapping ROHs, with three annotated loci (DLG1, KAT6B and PDE4D) and three overlapping ROHs, with seven annotated genes (ATP6V1E1, BCL2L13, LOC116276952, BID, KAT6B, LOC116282667 and LOC107034552), were detected for vicugna and guanaco, respectively. The signatures of selection revealed genomic areas potentially selected for production traits as well as for natural adaptation to harsh environment. Alpaca and llama hint a selection driven by environment as well as by farming purpose while vicugna and guanaco showed selection signals for adaptation to harsh environment. Interesting, signatures of selection on KAT6B gene were identified for both vicugna and guanaco, suggesting a positive effect on wild populations fitness. Such information may be of interest to further ecological and animal production studies. Show less

Canonical and non-canonical Wnt pathways are involved in the genesis of multiple tumors; however, their role in pituitary tumorigenesis is mostly unknown. This study evaluated gene and protein expression of Wnt pathways in pituitary tumors and whether these expression correlate to clinical outcome. Genes of the WNT canonical pathway: activating ligands (WNT11, WNT4, WNT5A), binding inhibitors (DKK3, sFRP1), β-catenin (CTNNB1), β-catenin degradation complex (APC, AXIN1, GSK3β), inhibitor of β-catenin degradation complex (AKT1), sequester of β-catenin (CDH1), pathway effectors (TCF7, MAPK8, NFAT5), pathway mediators (DVL-1, DVL-2, DVL-3, PRICKLE, VANGL1), target genes (MYB, MYC, WISP2, SPRY1, TP53, CCND1); calcium dependent pathway (PLCB1, CAMK2A, PRKCA, CHP); and planar cell polarity pathway (PTK7, DAAM1, RHOA) were evaluated by QPCR, in 19 GH-, 18 ACTH-secreting, 21 non-secreting (NS) pituitary tumors, and 5 normal pituitaries. Also, the main effectors of canonical (β-catenin), planar cell polarity (JNK), and calcium dependent (NFAT5) Wnt pathways were evaluated by immunohistochemistry. There are no differences in gene expression of canonical and non-canonical Wnt pathways between all studied subtypes of pituitary tumors and normal pituitaries, except for WISP2, which was over-expressed in ACTH-secreting tumors compared to normal pituitaries (4.8x; p = 0.02), NS pituitary tumors (7.7x; p = 0.004) and GH-secreting tumors (5.0x; p = 0.05). β-catenin, NFAT5 and JNK proteins showed no expression in normal pituitaries and in any of the pituitary tumor subtypes. Furthermore, no association of the studied gene or protein expression was observed with tumor size, recurrence, and progressive disease. The hierarchical clustering showed a regular pattern of genes of the canonical and non-canonical Wnt pathways randomly distributed throughout the dendrogram. Our data reinforce previous reports suggesting no activation of canonical Wnt pathway in pituitary tumorigenesis. Moreover, we describe, for the first time, evidence that non-canonical Wnt pathways are also not mis-expressed in the pituitary tumors. Show less

CTNNB1/β-catenin mutations and activation of Wnt/β-catenin pathway are frequent in adult adrenocortical tumors (ACT), but data on childhood ACT are lacking. The aim of the study was to investigate the presence of Wnt/β-catenin pathway abnormalities in childhood ACT. Clinicopathological findings and outcome of 62 childhood ACT patients were analyzed regarding CTNNB1 mutations and the expression of Wnt-related genes (CTNNB1; WNT4, a Wnt ligand; SFRP1, DKK3, and AXIN1, Wnt inhibitors; TCF7, a transcription factor; and MYC and WISP2, target genes) by quantitative PCR and immunohistochemistry. CTNNB1-activating mutations were found in only four of 62 ACT (6%), all of them harboring TP53 mutation. There was association between the presence of CTNNB1 mutations and death (P = 0.02). Diffuse β-catenin accumulation was found in 71% of ACT, even in ACT without CTNNB1 mutations. Compared to normal adrenals, ACT presented increased expression of CTNNB1 (P = 0.008) and underexpression of Wnt inhibitor genes: DKK3 (P < 0.0001), SFRP1 (P = 0.05), and AXIN1 (P = 0.04). With regard to Wnt/β-catenin target genes, ACT presented increased expression of WISP2 but lower expression of MYC. Higher overall survival was associated with underexpression of SFRP1 (P = 0.01), WNT4 (P = 0.004), and TCF7 (P < 0.01). CTNNB1 mutations are not common in childhood ACT but appear to associate with poor prognosis. Nevertheless, most ACT exhibit increased expression of β-catenin and WISP2 and reduced expression of Wnt inhibitor genes (DKK3, SFRP1, and AXIN1). Thus, in addition to CTNNB1 mutations, other genetic events affecting the Wnt/β-catenin pathway may be involved in childhood adrenocortical tumorigenesis. Show less

The molecular mechanisms responsible for glucose-dependent insulinotrophic peptide receptor or gastric inhibitory polypeptide receptor (GIPR) ectopic expression and function in GIP-dependent Cushing's syndrome (CS) are still unknown. GIPR presumably acts, like the ACTH receptor (ACTHR), through the Gs protein/cyclic AMP/protein kinase A (PKA) pathway to stimulate steroidogenesis. We studied the expression of several genes involved in this pathway in the adrenal tissues of patients with GIP-dependent CS. RNA was extracted from adrenal tissues from nine patients with GIP-dependent CS [seven ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH), two adenomas], two control whole adult adrenals, two fasciculata cell-enriched preparations from normal adrenals, seven patients with Cushing's disease (CD) and two normal pancreas. Multiplex reverse transcriptase polymerase chain reaction (RT-PCR) evaluated the expression of GIPR, ACTHR, SF-1, Nur77, DAX-1, CYP11A, 3beta-HSD, CYP21, CREB and CREM genes. GIPR mRNA was overexpressed in all GIP-dependent cases. In normal adrenals and in the adrenal tissues from patients with CD, minimal amounts of GIPR mRNA were detected. ACTHR mRNA expression was observed in all GIP-dependent adrenal tissues. The expression of steroidogenic enzymes and some specific and ubiquitous transcription factors (TFs) involved in the ACTHR cascade was significantly reduced. Our results indicate that the expression of ACTHR and other genes located downstream in the ACTHR cascade, including steroidogenic enzymes genes and some transcription factors, are relatively suppressed in GIP-dependent CS. Although the expression of aberrant receptors plays an important role in steroidogenesis and initiation of cell proliferation, additional genetic events might occur, altering the activity of the ACTHR pathway. Show less

Gastric inhibitory polypeptide (GIP)-dependent Cushing's syndrome (CS) results from the ectopic expression of non-mutated GIP receptor (hGIPR) in the adrenal cortex. We evaluated whether mutations or polymorphisms in the regulatory region of the GIPR gene could lead to this aberrant expression. We studied 9.0kb upstream and 1.3kb downstream of the GIPR gene putative promoter (pProm) by sequencing leukocyte DNA from controls and from adrenal tissues of GIP- and non-GIP-dependent CS patients. The putative proximal promoter region (800 bp) and the first exon and intron of the hGIPR gene were sequenced on adrenal DNA from nine GIP-dependent CS, as well as on leukocyte DNA of nine normal controls. Three variations found in this region were found in all patients and controls; at position -4/-5, an insertion of a T was seen in four out of nine patients and in five out of nine controls. Transient transfection studies conducted in rat GC and mouse Y1 cells showed that the TT allele confers loss of 40% in the promoter activity. The analysis of the 8-kb distal pProm region revealed eight distal single nucleotide polymorphisms (SNPs) without probable association with the disease, since frequencies in patients and controls were very similar. In conclusion, mutations or SNPs in the regulatory region of the GIPR gene are unlikely to underlie GIP-dependent CS. Show less