PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo.

Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.

Clinical Outcomes of 3D-Printed Bioresorbable Scaffolds for Bone Tissue Engineering-A Pilot Study on 126 Patients for Burrhole Covers in Subdural Hematoma.

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. OsteoplugTM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing osseous integration and vascular ingrowth. However, the cosmetic and safety outcomes of OsteoplugTM-C-the latest (2017) iteration, with a chamfered hole for subdural drains-remain unexplored. Data were collected from a single institution from April 2017 to March 2021. Patient-reported aesthetic outcomes (Aesthetic Numeric Analog (ANA)) and quality of life (EQ-5D-3L including Visual Analog Scale (VAS)) were assessed via telephone interviews. Clinical outcomes included SDH recurrence, postoperative infections, and drain complications. OsteoplugTM-C patients had significantly higher satisfaction and quality of life compared to those without a burrhole cover (ANA: 9 [7, 9] vs. 7 [5, 8], p = 0.019; VAS: 85 [75, 90] vs. 70 [50, 80], p = 0.021), and the absence of a burrhole cover was associated with poorer aesthetic outcomes after multivariable adjustment (adjusted OR: 4.55, 95% CI: 1.09-22.68, p = 0.047). No significant differences in other clinical outcomes were observed between OsteoplugTM-C, OsteoplugTM, or no burrhole cover. Our pilot study supports OsteoplugTM-C and its material polycaprolactone as suitable adjuncts to burrhole craniostomy, improving cosmetic outcomes while achieving comparable safety outcomes.

Primary intracranial germ cell tumours: experience of a single South-East Asian institution.

Primary intracranial germ cell tumours (ICGCT) are a rare group of brain tumours arising predominantly in the paediatric and pre-adult population, accounting for up to 9.5% of paediatric brain tumours in East Asia. The National Cancer Centre Singapore (NCCS) is a tertiary referral centre for patients from all over South-East Asia. Our study aims to describe the characteristics of ICGCT patients in South-East Asia. Data on all patients with ICGCT who were seen at the Therapeutic Radiology Department of NCCS from 2000 to 2013 were collected retrospectively. Patient demographics, disease characteristics and treatment outcomes were analysed. Characteristics and survival of our patients were similar to other centres. Pure germinomas demonstrated 5 year overall survival (OS) and disease-free survival (DFS) rates of 89.2% (95% confidence interval [CI] 60.2-97.5) and 85.2% (95%CI 60.8-95.0) respectively. Secreting germinomas, non-germinomatous germ cell tumours and mixed germ cell tumours were evaluated together and demonstrated 5 year OS of 70.6% (95%CI 41.0-87.3) and DFS of 61.4% (95%CI 31.9-81.3). Patients ⩽ 12 years had marginally better 5 year OS than their older counterparts (81.0% [95%CI 49.5-93.9] versus 77.9% [95%CI 47.3-92.0], respectively). Patients who underwent extended field radiotherapy had longer OS and DFS than those who received local field irradiation. Treatment outcomes of our ICGCT patients are comparable with those in other Asian and Western centres. Extended field radiotherapy is a pivotal component of ICGCT treatment. Adding chemotherapy confers no extra survival benefit in treating germinomas. Treatment of mixed germ cell tumours and non-germinomatous germ cell tumours involves a multidisciplinary approach that varies for each histological subtype.

Discrepancies in end-of-life decisions between elderly patients and their named surrogates.

INTRODUCTION: This study aims to determine the attitudes of Asian elderly patients towards invasive life support measures, the degree of patient-surrogate concordance in end-of-life decision making, the extent to which patients desire autonomy over end-of-life medical decisions, the reasons behind patients' and surrogates' decisions, and the main factors influencing patients' and surrogates' decision-making processes. We hypothesize that there is significant patient-surrogate discordance in end-of-life decision making in our community. MATERIALS AND METHODS: The patient and surrogate were presented with a hypothetical scenario in which the patient experienced gradual functional decline in the community before being admitted for life-threatening pneumonia. It was explained that the outcome was likely to be poor even with intensive care and each patient-surrogate pair was subsequently interviewed separately on their opinions of extraordinary life support using a standardised questionnaire. Both parties were blinded to each other's replies. RESULTS: In total, 30 patients and their surrogate decision-makers were interviewed. Twenty-eight (93.3%) patients and 20 (66.7%) surrogates rejected intensive care. Patient-surrogate concurrence was found in 20 pairs (66.7%). Twenty-four (80.0%) patients desired autonomy over their decision. The patients' and surrogates' top reasons for rejecting intensive treatment were treatment-related discomfort, poor prognosis and financial cost. Surrogates' top reasons for selecting intensive treatment were the hope of recovery, the need to complete final tasks and the sanctity of life. CONCLUSION: The majority of patients desire autonomy over critical care issues. Relying on the surrogates' decisions to initiate treatment may result in treatment against patients' wishes in up to one-third of critically ill elderly patients.

Recurrent episodic hypoxaemic respiratory failure following a stroke.

A 68-year-old man with no cardiovascular risk factors was admitted with a stroke because of multiple brain infarcts in different vascular territories. He required mechanical ventilation for hypoxia as a result of aspiration pneumonia. Subsequent recovery was hindered by episodic, unexplained hypoxia. Investigations excluded pulmonary embolism, pulmonary hypertension and severe lung diseases. Transthoracic echocardiography (TTE) with saline bubble contrast showed mild, delayed, right-to-left shunting, thought to represent an insignificant, intrapulmonary, non-cardiac shunt. Hypoxic episodes worsened, requiring admission from community rehabilitation hospital to our centre and another period of mechanical ventilation. Elevated alveolar-arterial gradients indicated a non-hypoventilatory cause. Repeat TTE bubble contrast study and transoesophageal echocardiography (TOE) demonstrated a patent foramen ovale (PFO) with large shunt potential, associated with an aneurysmal interatrial septum. This provided a unifying explanation for cryptogenic stroke and recurrent hypoxaemia. After percutaneous PFO closure hypoxic episodes ceased and he returned successfully to rehabilitation.

Anaplastic supratentorial cortical ependymoma presenting as a butterfly lesion.

BACKGROUND: Anaplastic cortical ependymomas are rare lesions with few cases reported in the literature. CASE DESCRIPTION: We present a unique case of an anaplastic cortical ependymoma in a 51-year-old female presenting as a butterfly lesion with involvement of both frontal lobes. The patient underwent gross total resection of her tumor with further adjuvant treatment. We present the findings in our case and review the literature surrounding supratentorial ependymomas and their treatment outcomes. CONCLUSION: Rarely, cortical ependymoma can present as a butterfly lesion and should be considered in the differential diagnosis of such lesions in adults.

Colorectal cancer screening: the effectiveness of education on its barriers and acceptability.

To assess the awareness and acceptability of colorectal cancer (CRC) screening in noncompliant Singaporeans and to determine if their barriers can be overcome by education. A questionnaire developed from thematic analysis of open-ended interviews with 72 subjects was administered to 580 residents in a local high-rise housing estate. Participants aware of CRC screening were assessed for barriers and acceptability of CRC screening. All participants were subsequently educated about CRC screening and reassessed for barriers and acceptance. Those keen for fecal occult blood testing (FOBT) were offered FOBT kits and followed up. CRC screening awareness was poor. Having no symptoms was the most common barrier. More barriers to FOBT than to colonoscopy were reduced with education. After education, acceptability toward FOBT increased but rejection rates rose even higher. FOBT is probably Singapore's most acceptable screening modality. Education is limited by barriers, which need to be overcome by alternative measures.