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UNLABELLED: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

BackgroundChronic nonspecific low back pain (CNLBP) is one of the most common complex pain conditions, and it is strongly associated with high rates of disability. Even though several studies on Tui na for CNLBP have been reported, to our knowledge there has been no systematic review of the currently available publications. ObjectiveThis study aims to develop a protocol for a systematic review and meta-analysis that will evaluate the effectiveness and safety of Tui na therapy for patients with CNLBP. MethodsAn electronic literature search of PubMed, Embase, MEDLINE, Cochrane Library, Springer, Scopus, World Health Organization International Clinical Trials Registry Platform, Physiotherapy Evidence Database (PEDro), Clarivate Analytics, and Chinese biomedical databases (the China National Knowledge Infrastructure, Wan-fang database, Chinese Scientific Journals Database, and Chinese Biomedical Literature Databases) will be conducted. Studies will be screened by two reviewers independently based on titles and abstracts, followed by a full-text reading with eligibility criteria. Randomized controlled trials involving Tui na for patients with CNLBP will be reviewed. The primary outcomes of the study are improvement of pain, analgesic medication reduction, improvement of functional disability, and degree of satisfaction with the intervention. A secondary outcome is any adverse event of Tui na intervention. Methodological quality and risk of bias will be assessed with the Cochrane Collaboration Risk of Bias Tool. If studies are sufficient, a meta-analysis of the effectiveness will be performed. If possible, we will evaluate publication bias using funnel plots. If substantial heterogeneity between studies is present, and there are sufficient studies, subgroup analyses will be conducted to explain the study findings. ResultsThe review database searches will be initiated in December 2020, with findings expected by January 2021. ConclusionsThis protocol will establish a framework of a high-quality literature synthesis on the impact of Tui na treatment in patients with CNLBP. The proposed review will determine whether Tui na is effective and safe for CNLBP patients. Trial RegistrationPROSPERO CRD42020166731; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=166731 International Registered Report Identifier (IRRID)PRR1-10.2196/20615

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.

Objective To analyze the effect of Bushen Jianpi prescription on serum osteoclast, osteogenesis related factors and intestinal flora in postmenopausal osteoporosis (PMOP). Methods Eighty patients with PMOP admitted to the Third Affiliated Hospital of Guangzhou University of Chinese Medicine from March 2021 to December 2022 were randomly divided into combined group and control group by simple randomization method, with 40 patients in each group. The control group was treated with calcium carbonate vitamin D3 tablets, while the combined group was supplemented with Bushen Jianpi prescription on the basis of the control group. The treatment of both groups lasted for 8 weeks. The changes of serum osteoclast and osteogenesis-related factors ［β-isomer of C-terminal telopeptide of type Ⅰ collagen（β-CTX）, procollagen type Ⅰ Nterminal propeptide (P1NP)］in the two groups before and after treatment were detected, and the changes of Chinese medicine symptom score before and after treatment were evaluated, and the changes of intestinal flora were compared. Results After 8 weeks of treatment, β-CTX and P1NP in both groups decreased compared with those before treatment,and in the combined group were lower than those in the control group, and the difference was statistically significant (P＜0.05). After 8 weeks of treatment, the scores of symptoms of low back pain, weakness of waist and knees, lower limb cramps, difficulty in walking and difficulty in carrying weight in both groups decreased compared with those before treatment,and in the combined group were lower than those in the control group, the difference was statistically significant (P＜0.05). After 8 weeks of treatment, the total effective rate of the combined group was 92.50%, which was higher than that of the control group (75.00%) (P＜0.05). After 8 weeks of treatment, the number of Bifidobacterium and Lactobacillus in feces in both groups increased compared with that before treatment, while the number of Escherichia coli decreased compared with that before treatment. After 8 weeks of treatment, the number of Bifidobacterium and Lactobacillus in feces of the combined group was higher than that of the control group, and the number of Escherichia coli was lower than that of the control group (P＜0.05). There was no obvious adverse reactions in both groups during treatment. Conclusion For patients with PMOP, Bushen Jianpi prescription on the basis of calcium supplementation is helpful to regulate the levels of serum osteoclast, osteogenesis-related factors and intestinal flora, improve the clinical symptoms of patients and further improve the therapeutic effect, and it is safe.