Differential response of HER2-positive breast cancer to anti-HER2 therapy based on HER2 protein expression level.

BACKGROUND: Increasing data indicate that HER2-positive (HER2 + ) breast cancer (BC) subtypes exhibit differential responses to targeted anti-HER2 therapy. This study aims to investigate these differences and the potential underlying molecular mechanisms. METHODS: A large cohort of BC patients (n = 7390) was utilised. The clinicopathological characteristics and differential gene expression (DGE) of HER2+ immunohistochemical (IHC) subtypes, specifically HER2 IHC 3+ and IHC 2 + /Amplified, were assessed and correlated with pathological complete response (pCR) and survival in the neoadjuvant and adjuvant settings, respectively. The role of oestrogen receptor (ER) status was also investigated. RESULTS: Compared to HER2 IHC 3+ tumours, BC patients with IHC 2 + /Amplified showed a significantly lower pCR rate (22% versus 57%, P < 0.001), shorter survival regardless of HER2 gene copy number, were less classified as HER2 enriched, and enriched for trastuzumab resistance and ER signalling pathway genes. ER positivity significantly decreased response to anti-HER2 therapy in IHC 2 + /Amplified, but not in IHC 3 + BC patients. CONCLUSION: In HER2 + BC, overexpression of HER2 protein is the driver of the oncogenic pathway, and it is the main predictor of response to anti-HER2 therapy. ER signalling pathways are more dominant in BC with equivocal HER2 expression. personalised anti-HER2 therapy based on IHC classes should be considered.

Acylated Ghrelin Administration Inhibits Sleeve Gastrectomy-Induced Hippocampal Oxidative Stress, Apoptosis and Tau-Hyperphosphorylation by Activating the PI3K/Akt Pathway.

This study investigated the impact of exogenous replacement therapy with acylated ghrelin (AG) post sleeve gastrectomy (SG) on the memory function in rats. In addition, we investigated the possible underlying mechanisms, including the effects on markers of oxidative stress, tau phosphorylation, and apoptosis. Adult male Wistar rats were divided into four groups (N = 18/group) as follows: sham (control), SG, SG+AG (100 µM), and SG+AG+LY294002 (0.25 µg/100 g). We continued all treatments daily for four weeks post-surgery. SG impaired the spatial, retention, and recognition memories as tested by the Morris water maze test, passive avoidance test, and novel object recognition test, respectively. Also, it enhanced the levels of reactive oxygen species and lipid peroxides, reduced glutathione and protein levels of Bcl-2, and increased the levels of Bax and cleaved caspase-3 in the hippocampus. In addition, SG reduced the hippocampal levels of acetylcholine and brain-derived neurotrophic factor. Concomitantly, it inhibited the hippocampal activity of Akt and increased the activity of glycogen synthase kinase 3ß and tau protein phosphorylation. Exogenous administration of acylated ghrelin to rats that had undergone SG prevented memory deficits. Also, it prevented the alteration in the above-mentioned biochemical parameters, an effect that was abolished by co-administration of LY294002 (phosphoinositide 3-kinase inhibitor). In conclusion, AG replacement therapy after SG in rats protects them against memory deficits and hippocampal damage by suppressing tau protein phosphorylation, mediated by activating PI3K/Aktinduced inhibition of glycogen synthase kinase 3ß.

CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA genes expression in colorectal cancer patients: novel diagnostic biomarkers.

OBJECTIVE: This study aimed to investigate the CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA mRNA expression in the blood of colorectal cancer patients in Egypt. This was performed to elucidate if there's a link between this gene expression and other clinicopathological characteristics of the tumor. PATIENTS AND METHODS: A case-control study including 50 colorectal cancer patients and 50 healthy controls was conducted. Real-time polymerase chain reaction (rt-PCR) was utilized to assess the expression of CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA mRNA in blood samples. RESULTS: Patients with colorectal cancer had significantly higher levels of mRNA for the genes CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA (p<0.001, p=0.021, p<0.001, and p<0.001, respectively) compared to controls. Remarkedly, the gene expression of AHR, TRIP13, and PIK3CA genes did not exhibit a significant correlation with the tumor stages (p=0.379, p=0.095, and p=0.526, respectively). However, there was a strong correlation between CYP24A1 and CPEB4 gene expression and tumor stages (p<0.001 and p=0.002, respectively). CONCLUSIONS: Therefore, we can conclude that increased mRNA levels of CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA in blood samples withdrawn from colorectal cancer patients could be a biomarker for the disease.

Stridor in infants with hypoxic-ischemic encephalopathy and whole body hypothermia: A case series.

BACKGROUND: Stridor is one of the rare side effects of neonatal hypothermia treatment for hypoxic-ischemic encephalopathy. We aimed to describe the clinical characteristics of the infants who underwent whole-body hypothermia and developed stridor. METHODS: We reviewed the medical records of 171 infants with moderate or severe hypoxic-ischemic encephalopathy who underwent hypothermia therapy. Demographics, as well as clinical characteristics, were documented. RESULTS: A total of 18 infants developed transient stridor out of 171 infants who underwent whole-body hypothermia (10.5%). The stridor was transient and resolved in all infants. All infants with stridor received treatment with one or more of the following: racemic epinephrine, dexamethasone, positive pressure ventilation and/or heliox. Two infants required otorhinolaryngologist (ENT) evaluation due to persistent and severe symptoms, of whom one was found to have left vocal cord paresis that improved with time. CONCLUSION: Stridor is a transient complication associated with hypoxic-ischemic encephalopathy and whole-body hypothermia in neonates. The exact mechanism is unclear and most likely multifactorial. ENT evaluation is recommended in the presence of prolonged symptoms or significant respiratory distress.