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.
The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) is a key Ras activator that is autoinhibited in the cytosol and activates upon membrane recruitment. Autoinhibition release ...involves structural rearrangements of the protein at the membrane and thus introduces a delay between initial recruitment and activation. In this study, we designed a single-molecule assay to resolve the time between initial receptor-mediated membrane recruitment and the initiation of GEF activity of individual SOS molecules on microarrays of Ras-functionalized supported membranes. The rise-and-fall shape of the measured SOS activation time distribution and the long mean time scale to activation (~50 seconds) establish a basis for kinetic proofreading in the receptor-mediated activation of Ras. We further demonstrate that this kinetic proofreading is modulated by the LAT (linker for activation of T cells)-Grb2-SOS phosphotyrosine-driven phase transition at the membrane.
Triaging and prioritising patients for RT-PCR test had been essential in the management of COVID-19 in resource-scarce countries. In this study, we applied machine learning (ML) to the task of ...detection of SARS-CoV-2 infection using basic laboratory markers. We performed the statistical analysis and trained an ML model on a retrospective cohort of 5148 patients from 24 hospitals in Hong Kong to classify COVID-19 and other aetiology of pneumonia. We validated the model on three temporal validation sets from different waves of infection in Hong Kong. For predicting SARS-CoV-2 infection, the ML model achieved high AUCs and specificity but low sensitivity in all three validation sets (AUC: 89.9-95.8%; Sensitivity: 55.5-77.8%; Specificity: 91.5-98.3%). When used in adjunction with radiologist interpretations of chest radiographs, the sensitivity was over 90% while keeping moderate specificity. Our study showed that machine learning model based on readily available laboratory markers could achieve high accuracy in predicting SARS-CoV-2 infection.
Using prostate-specific antigen (PSA) for prostate cancer (PCa) screening led to overinvestigation and overdiagnosis of indolent PCa. We aimed to investigate the value of prostate health index (PHI) ...and magnetic resonance imaging (MRI) prostate in an Asian PCa screening program. Men aged 50-75 years were prospectively recruited from a community-based PSA screening program. Men with PSA 4.0-10.0 ng ml−1 had PHI result analyzed. MRI prostate was offered to men with PSA 4.0-50.0 ng ml−1. A systematic prostate biopsy was offered to men with PSA 4.0-9.9 ng ml−1 and PHI ≥35, or PSA 10.0-50.0 ng ml−1. Additional targeted prostate biopsy was offered if they had PI-RADS score ≥3. Clinically significant PCa (csPCa) was defined as the International Society of Urological Pathology (ISUP) grade group (GG) ≥2 or ISUP GG 1 with involvement of ≥30% of total systematic cores. In total, 12.8% (196/1536) men had PSA ≥4.0 ng ml−1. Among 194 men with PSA 4.0-50.0 ng ml−1, 187 (96.4%) received MRI prostate. Among them, 28.3% (53/187) had PI-RADS ≥3 lesions. Moreover, 7.0% (107/1536) men were indicated for biopsy and 94.4% (101/107) men received biopsy. Among the men received biopsy, PCa, ISUP GG ≥2 PCa, and csPCa was diagnosed in 42 (41.6%), 24 (23.8%), and 34 (33.7%) men, respectively. Compared with PSA/PHI pathway in men with PSA 4.0-50.0 ng ml−1, additional MRI increased diagnoses of PCa, ISUP GG ≥2 PCa, and csPCa by 21.2% (from 33 to 40), 22.2% (from 18 to 22), and 18.5% (from 27 to 32), respectively. The benefit of additional MRI was only observed in PSA 4.0-10.0 ng ml−1, and the number of MRI needed to diagnose one additional ISUP GG ≥2 PCa was 20 in PHI ≥35 and 94 in PHI <35. Among them, 45.4% (89/196) men with PSA ≥4.0 ng ml−1 avoided unnecessary biopsy with the use of PHI and MRI. A screening algorithm with PSA, PHI, and MRI could effectively diagnose csPCa while reducing unnecessary biopsies. The benefit of MRI prostate was mainly observed in PSA 4.0-9.9 ng ml−1 and PHI ≥35 group. PHI was an important risk stratification step for PCa screening.
The epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into induction/maintenance.
Newly-diagnosed APL from 1991 to ...2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers.
APL occurred in 374 males and 387 females at a median age of 44 (1-97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N = 139), being more with males, age > 50 years, leucocyte > 10 × 10
/L, diagnosis during 1991-2009 and fewer with oral-ATO-based regimens. After a median of 75 (interquartile range: 14-161) months, 5-year and 10-year OS were 68.1% and 63.3%, inferior with males, age > 50 years, leucocyte > 10 × 10
/L, high-risk Sanz score and superior with oral-ATO-based regimens. Factoring out EDs, 5-year and 10-year post-30-day OS were 84.0% and 78.1%, inferior with males and superior with oral-ATO-based regimens. In 607 CR1 patients, the 5-year RFS was 83.8%, superior with diagnosis in 2010-2021 and oral-ATO-based regimens. Second cancers developed in 21 patients, unrelated to oral-ATO-based regimens.
There was an increasing incidence of APL, and all survivals were superior with the use of oral-ATO-based regimens. This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier: NCT04251754).
Type 2 diabetes (T2D) is a worldwide prevalent metabolic disorder defined by high blood glucose levels due to insulin resistance (IR) and impaired insulin secretion. Understanding the mechanism of ...insulin action is of great importance to the continuing development of novel therapeutic strategies for the treatment of T2D. Disturbances of gut microbiota have been widely found in T2D patients and contribute to the development of IR. In the present article, we reviewed the pathological role of gut microbial metabolites including gaseous products, branched-chain amino acids (BCAAs) products, aromatic amino acids (AAAs) products, bile acids (BA) products, choline products and bacterial toxins in regulating insulin sensitivity in T2D. Following that, we summarized probiotics-based therapeutic strategy for the treatment of T2D with a focus on modulating gut microbiota in both animal and human studies. These results indicate that gut-microbial metabolites are involved in the pathogenesis of T2D and supplementation of probiotics could be beneficial to alleviate IR in T2D via modulation of gut microbiota.
Purpose
To compare two-year treatment outcomes of subthreshold micropulse (577 nm) laser and aflibercept for diabetic macular edema (DME).
Study design
Retrospective case–control study.
Methods
A ...total 164 eyes in 164 DME patients treated with either micropulse laser (86 eyes) or intravitreal aflibercept monotherapy (78 eyes) were recruited. Main outcome measures included at least five Early Treatment Diabetic Retinopathy Study (ETDRS) letters’ improvement from baseline at 6, 12 and 24 months.
Results
Rescue aflibercept was initiated in 24% of eyes in micropulse laser group. At 6-month visit the aflibercept group achieved a higher percentage of eyes with at least 5-letter visual acuity improvement than micropulse laser group (56% vs 38%, P = 0.044), however, this was not the case at 12-month (45% vs 49%, P = 0.584) and 24-month visits (49% vs 57%, P = 0.227). At 6-month visit the aflibercept group achieved a higher percentage of eyes with at least 10% improvement of central macular thickness (73% vs 49%, P = 0.005), but this was not the case at 12-month (73% vs 70%, P = 0.995) and 24-month visits (85% vs 84%, P = 0.872).
Conclusion
Aflibercept achieved faster and higher rates of anatomical and functional improvement than micropulse laser in DME patients. Long term efficacy of treatment did not result in significant differences between aflibercept monotherapy and micropulse laser in DME patients. Primary treatment of micropulse laser with deferred rescue aflibercept might be the treatment option without reducing the chance of visual improvement in DME eyes.
Summary
Melanoma has been shown to require arginine for growth, thus providing a potential Achilles’ heel for therapeutic exploitation. Our investigations show that arginine depletion, using a ...recombinant form of human arginase I (rhArg), efficiently inhibits the growth of mammalian melanoma cell lines in vitro. These cell lines are consistently deficient in ornithine transcarbamylase (OTC) expression, correlating with their sensitivity to rhArg. Cell cycle distribution of A375 human melanoma cells treated with rhArg showed a remarkable dual‐phase cell cycle arrest in S and G2/M phases, in contrast to the G2/M single‐phase arrest observed with arginine deiminase (ADI), another arginine‐degrading enzyme. rhArg and ADI both induced substantial apoptosis in A375 cells, accompanied by global modulation of cell cycle‐ and apoptosis‐related transcription. Moreover, PEGylated rhArg dramatically inhibited the growth of A375 and B16 melanoma xenografts in vivo. Our results establish for the first time that (PEGylated) rhArg is a promising candidate for effective melanoma treatment, with fewer safety issues than ADI. Insight into the mechanism behind the antiproliferative activity of rhArg could inform us in designing combination therapies for future clinical trials.
Left atrial enlargement (LAE) reflects diastolic dysfunction and predicts mortality in end-stage renal disease patients. However, little is known of its prevalence and factors associated with ...subclinical LAE in earlier stages of chronic kidney disease (CKD).
We conducted a prospective, cross-sectional study in 261 Stage 3-5 non-dialysis CKD patients without symptomatic cardiovascular disease with two-dimensional echocardiography performed to estimate left atrial volume index and other cardiac parameters.
One hundred and nine (41.8%) patients had LAE. Mild and moderate/severe LAEs were observed in 22.9 and 41.3% of patients with left ventricular (LV) hypertrophy (n = 109) versus 13.2 and 12.5% of patients with no LV hypertrophy (n = 152), respectively (P < 0.001). On univariate analysis, plasma sodium concentration showed a significant association with LAE odds ratio (OR) 1.22, 95% confidence interval (95% CI) 1.09-1.37; P = 0.001. In the stepwise multiple logistic regression, plasma sodium concentration emerged as one of the most significant factors associated with LAE (adjusted OR 1.29, 95% CI 1.14-1.47; P < 0.001. Its significance was well maintained (adjusted OR 1.23, 95% CI 1.07-1.43; P = 0.005) when including LV mass and volume index and N-terminal pro-brain natriuretic peptide in the model, while blood haemoglobin and systolic blood pressure were displaced.
This study for the first time alerted to a very high prevalence of subclinical LAE and reported a strong novel, independent relationship between plasma sodium concentration and subclinical LAE in Stage 3-5 CKD patients. Longitudinal studies are needed to establish causality between high plasma sodium concentration and LAE and their usefulness as therapeutic targets in CKD.
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