Gamma-band-based dynamic functional connectivity in pigeon entopallium during sample presentation in a delayed color matching task.

Birds have developed visual cognitions, especially in discriminating colors due to their four types of cones in the retina. The entopallium of birds is thought to be involved in the processing of color information during visual cognition. However, there is a lack of understanding about how functional connectivity in the entopallium region of birds changes during color cognition, which is related to various input colors. We therefore trained pigeons to perform a delayed color matching task, in which two colors were randomly presented in sample stimuli phrases, and the neural activity at individual recording site and the gamma band functional connectivity among local population in entopallium during sample presentation were analyzed. Both gamma band energy and gamma band functional connectivity presented dynamics as the stimulus was presented and persisted. The response features in the early-stimulus phase were significantly different from those of baseline and the late-stimulus phase. Furthermore, gamma band energy showed significant differences between different colors during the early-stimulus phase, but the global feature of the gamma band functional network did not. Further decoding results showed that decoding accuracy was significantly enhanced by adding functional connectivity features, suggesting the global feature of the gamma band functional network did not directly contain color information, but was related to it. These results provided insight into information processing rules among local neuronal populations in the entopallium of birds during color cognition, which is important for their daily life.

Correction to: Gamma-band-based dynamic functional connectivity in pigeon entopallium during sample presentation in a delayed color matching task.

[This corrects the article DOI: 10.1007/s11571-022-09916-w.].

Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1.

We investigated an Amish family in which three siblings presented with an early-onset childhood retinal dystrophy inherited in an autosomal recessive fashion. Genome-wide linkage analysis identified significant linkage to marker D2S2216 on 2q11 with a two-point LOD score of 1.95 and a multi-point LOD score of 3.76. Whole exome sequencing was then performed for the three affected individuals and identified a homozygous nonsense mutation (c.C1813T, p.R605X) in the cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene located within the 2p14-2q14 Jalili syndrome locus. The initial assessment and collection of the family were performed before the clinical delineation of Jalili syndrome. Another assessment was made after the discovery of the responsible gene and the dental abnormalities characteristic of Jalili syndrome were retrospectively identified. The p.R605X mutation represents the first probable founder mutation of Jalili syndrome identified in the Amish community. The molecular mechanism underlying Jalili syndrome is unknown. Here we show that CNNM4 interacts with IQCB1, which causes Leber congenital amaurosis (LCA) when mutated. A truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. Mutation p.R605X may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis, or both. Our data, for the first time, functionally link Jalili syndrome gene CNNM4 to LCA gene IQCB1, providing important insights into the molecular pathogenic mechanism of retinal dystrophy in Jalili syndrome.

Role of methylphenidate in the treatment of fatigue in advanced pancreatic cancer population.

BACKGROUND: Fatigue is a common but devastating symptom for advanced pancreatic cancer (APC) patients. To date, no proven treatment exists. Methylphenidate (MPH) showed inconsistent results in treating other cancer related fatigue. We performed a retrospective study to assess MPH in ameliorating fatigue in APC patients. METHODS: We retrospectively reviewed our clinic APC patients' records who visited from 06/2011 - 11/2014. Fatigue was assessed by Visual Analog Fatigue Scale (VAFS) and classified as grade 1 (VAFS 1-3), grade 2 (VAFS 4-6) and grade 3 (VAFS 7-10) to correspond with CTCAE V4.0. MPH was dosed at 5 mg daily in the morning and was escalated to 10 mg after 2 weeks if needed. The primary endpoint was to assess the change of fatigue grade after 4 weeks of MPH. Secondary outcomes included MPH's effect on depression, anorexia, maintenance chemotherapy intensity and adverse effects. RESULTS: A total of 71 APC patients on concomitant chemotherapy were included, of whom 67% received doublet, 13% triplet, and 20% single-agent chemotherapy. Mean baseline VAFS was 7, which dropped to 4 after 4 weeks of MPH, 55% patients' fatigue score improved by 1 grade, 8% by 2 grades, 23% had fatigue resolved, 14% without benefit. 72% patients maintained chemotherapy intensity, 39% felt less depression and 52% had improved appetite. 13% stopped MPH due to side effects. Rare Grade 3 or 4 adverse events included insomnia, restlessness, palpitations and anorexia. CONCLUSIONS: Our findings support low-dose MPH benefits APC patients with improved fatigue, depression and anorexia. A large randomized clinical trial is needed to confirm its usage and safety.

Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study.

PURPOSE: Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. PATIENTS AND METHODS: A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. RESULTS: The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority. CONCLUSION: LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.

The PI3 kinase signaling pathway in prostate cancer.

Despite recent advances in our understanding of the biological basis of prostate cancer, the management of the disease, especially in the castration-resistant phase, remains a significant challenge. Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is increasingly implicated in a number of malignancies, including prostate carcinogenesis. In this review, we detail the role of this pathway in the pathogenesis of prostate cancer and the therapeutic implications of targeting it.

Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.

Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence. Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells. Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency owing to the loss of glucose transport. Overexpression of ERBB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and phosphatidylinositol-3-OH kinase (PI(3)K) activation, and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway. Notably, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation, which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an increase in ROS in matrix-deprived cells in the luminal space of mammary acini, and the discovery that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results show both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments by antioxidant restoration of ATP generation.