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Abstract Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110α) of PI3Kα, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kα impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction.

The addition of hydroxylamine hydrochloride (HAH), ascorbic acid (ASC), sodium ascorbate (SAS) to the OA-Fe(II)/SPC system could promote the generation of HO• by accelerating Fe(II)/Fe(III) recycles and H2O2 decomposition. The enhancement of HAH on HO• generation surpasses ASC and SAS in the OA-Fe(II)/SPC system. The generation of O2•− was also enhanced by HAH, ASC and SAS, and more significant promotion of O2•− generation was observed with ASC and SAS addition. More effective benzene removal was achieved in an OA-Fe(II)/SPC system with suitable HAH, ASC and SAS addition, compared to the parent system. Excessive HAH, ASC or SAS had a negative effect on benzene removal. Results of scavenger tests showed that HO• is indeed the dominant free radical for benzene removal in every system, but the addition of HAH, ASC and SAS increased the contribution of O2•− to benzene degradation. HAH, ASC and SAS enhanced OA-Fe(II)/SPC systems could be well utilized to acidic and neutral conditions, while HCO3−, high concentration of HA and alkaline conditions were not favorable to benzene removal. Moreover, the addition of HAH, ASC and SAS are conducive to benzene removal in actual groundwater, and HAH was the optimal reducing agent for the enhancement of the OA-Fe(II)/SPC system. HIGHLIGHTS Benzene removal performance in an RA-OA-Fe(II)/SPC system was investigated.; HAH is more conducive to HO• generation than ASC and SAS.; Significant promoted generation of O2•− was observed with ASC and SAS addition.; HAH, ASC and SAS weakened negative effects of the solution matrix on benzene removal.; HAH, ASC and SAS are conducive to benzene removal in actual groundwater.;

Abstract Purpose The clinical outcomes of patients who received a cervical collar after anterior cervical decompression and fusion were evaluated by comparison with those of patients who did not receive a cervical collar. Methods All of the comparative studies published in the PubMed, Cochrane Library, Medline, Web of Science, and EMBASE databases as of 1 October 2023 were included. All outcomes were analysed using Review Manager 5.4. Results Four studies with a total of 406 patients were included, and three of the studies were randomized controlled trials. Meta-analysis of the short-form 36 results revealed that wearing a cervical collar after anterior cervical decompression and fusion was more beneficial (P 0.05) between the cervical collar group and the no cervical collar group. Conclusions This systematic review and meta-analysis revealed no significant differences in the 6-week postoperative cervical range of motion, fusion rate, or neck disability index between the cervical collar group and the no cervical collar group. However, compared to patients who did not wear a cervical collar, patients who did wear a cervical collar had better scores on the short form 36. Interestingly, at the final follow-up visit, the neck disability index scores were better in the no cervical collar group than in the cervical collar group. PROSPERO registration number: CRD42023466583.

Abstract Lumbar disc herniation (LDH) is a clinically common degenerative disease of the spine, and spinal–pelvic sagittal balance and paravertebral muscle degeneration have been a research focus in recent years. To explore the relationship between the degeneration of paravertebral muscle and the changes in the spinal–pelvic sagittal parameters in LDH patients, 105 LDH patients (experimental group) and 63 healthy volunteers (control group) hospitalized in Ordos Central Hospital from January 2020 and January 2023 were included as study subjects. All the patients underwent lumbar magnetic resonance imaging and spinal X-ray using uniform criteria. The correlation between the paravertebral muscle and sagittal–pelvic sagittal parameters of the patients with LDH was obtained from two imaging examinations, and the data were organized and grouped to explore the correlation between these parameters. No significant difference in general data existed between the groups (P > 0.05). In the L4/5 LDH patients group, the ratio of fat infiltration (FIR) in the healthy side [multifidus (MF) and erector spinae (ES)] was negatively correlated with the lumbar lordosis (LL) (r = −0.461, r = −0.486, P

Vitamin D is commonly used to prevent and treat osteoporosis, with studies indicating its potential to reduce fractures, falls, and mortality. However, meta-analyses present inconsistent findings regarding its efficacy, particularly reflecting significant variability in data and outcomes related to various dosing regimens. In this meta-analysis, we assessed the impact of high-dose intermittent oral administration of vitamin D3 on serum 25(OH)D levels, fractures, falls, and mortality among elderly individuals. We included 14 randomized controlled trials and employed Review Manager 5.4 for statistical analysis. Our findings indicate that intermittent monthly administration of vitamin D3 (over 800 IU per day) significantly raised serum 25(OH)D levels at all timepoints after six months, maintaining levels above 75 nmol/L throughout the year. This regimen showed no increase in all-cause mortality, with a risk ratio (95% CI) of 0.95 (0.87-1.04). Likewise, it did not significantly reduce the risks of falls and fractures, with risk ratios of 1.02 (0.98-1.05) and 0.95 (0.87-1.04) respectively. Although one-year intermittent administration significantly increased the concentration of 25(OH)D in serum, further research is needed to determine if this method would increase the incidence of falls. Therefore, it is not recommended at this stage due to the lack of demonstrated safety in additional relevant RCTs. This study had been registered on PROSPERO (CRD42022363229).

Abstract Purpose The clinical outcomes of using a tubular microdiscectomy for lumbar disc herniation were evaluated by comparison with conventional microdiscectomy. Methods All of the comparative studies published in the PubMed, Cochrane Library, Medline, Web of Science, and EMBASE databases as of 1 May 2023 were included. All outcomes were analysed using Review Manager 5.4. Results This meta-analysis included four randomized controlled studies with a total of 523 patients. The results showed that using tubular microdiscectomy for lumbar disc herniation was more effective than conventional microdiscectomy in improving the Oswestry Disability Index (P 0.05) between the tubular microdiscectomy and conventional microdiscectomy groups. Conclusions Based on our meta-analysis, it was found that the tubular microdiscectomy group had better outcomes than the conventional microdiscectomy group in terms of Oswestry Disability Index. However, there were no significant differences between the two groups in terms of operating time, intraoperative blood loss, hospital stay, Visual Analogue Scale, reoperation rate, postoperative recurrence rate, dural tear incidence, and complications rate. Current research suggests that tubular microdiscectomy can achieve clinical results similar to those of conventional microdiscectomy. PROSPERO registration number is: CRD42023407995.

Abstract Background Circular RNAs are implicated in modulating the progression of various malignant tumors. However, the function and underlying mechanisms of circ_0005615 in multiple myeloma (MM) remain unclear. Methods The expression levels of circ_0005615, miR-331-3p and IGF1R were tested by quantitative real-time polymerase chain reaction or western blot assay. Cell counting kit-8 and 5-ethynyl-2′-deoxyuridine (EdU) assay were performed for cell proliferation detection. Cell apoptosis and cell cycle were measured by flow cytometry. The protein expressions of Bax and Bcl-2 were detected by western blot assay. Glucose consumption, lactate production and ATP/ADP ratios were estimated to disclose cell glycolysis. The interaction relationship among miR-331-3p and circ_0005615 or IGF1R was proved by dual-luciferase reporter assay. Results The abundance of circ_0005615 and IGF1R was increased in MM patients and cells, while the expression of miR-331-3p was decreased. Circ_0005615 inhibition retarded the proliferation and cell cycle progression, while reinforced the apoptosis of MM cells. Molecularly, circ_0005615 could sponge miR-331-3p, and the repressive trends of circ_0005615 deficiency on MM progression could be alleviated by anti-miR-331-3p introduction. Additionally, IGF1R was validated to be targeted by miR-331-3p, and IGF1R overexpression mitigated the suppressive function of miR-331-3p on MM development. Furthermore, IGF1R was mediated by circ_0005615/miR-331-3p axis in MM cells. Conclusion Circ_0005615 downregulation blocked MM development by targeting miR-331-3p/IGF1R axis.

Extensive studies in prostate cancer and other malignancies have revealed that L-methionine (L-Met) and its metabolites play a critical role in tumorigenesis. Preclinical and clinical studies have demonstrated that systemic restriction of serum L-Met, either via partial dietary restriction or with bacterial L-Met-degrading enzymes exerts potent antitumor effects. However, administration of bacterial L-Met-degrading enzymes has not proven practical for human therapy because of problems with immunogenicity. As the human genome does not encode L-Met-degrading enzymes, we engineered the human cystathionine-γ-lyase (hMGL-4.0) to catalyze the selective degradation of L-Met. At therapeutically relevant dosing, hMGL-4.0 reduces serum L-Met levels to >75% for >72 h and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity. We demonstrate that in vitro, hMGL-4.0 causes tumor cell death, associated with increased reactive oxygen species, S-adenosyl-methionine depletion, global hypomethylation, induction of autophagy, and robust poly(ADP-ribose) polymerase (PARP) cleavage indicative of DNA damage and apoptosis. [ABSTRACT FROM AUTHOR]

Abstract Purpose The clinical outcomes of using a zero-profile for anterior cervical decompression and fusion were evaluated by comparison with anterior cervical plates. Methods All of the comparative studies published in the PubMed, Cochrane Library, Medline, Web of Science, EBSOChost, and EMBASE databases as of 1 October 2021 were included. All outcomes were analysed using Review Manager 5.4. Results Seven randomized controlled studies were included with a total of 528 patients, and all studies were randomized controlled studies. The meta-analysis outcomes indicated that the use of zero-profile fixation for anterior cervical decompression and fusion was better than anterior cervical plate fixation regarding the incidence of postoperative dysphagia (P 0.05) between the zero-profile and anterior cervical plate groups. Conclusions The systematic review and meta-analysis indicated that zero-profile and anterior cervical plates could result in good postoperative outcomes in anterior cervical decompression and fusion. No significant differences were found in intraoperative blood loss, Visual Analogue Scale, Neck Disability Index, or Japanese Orthopaedic Association scale. However, the zero-profile is superior to the anterior cervical plate in the following measures: incidence of postoperative dysphagia, adjacent-level ossification, and operational time. PROSPERO registration CRD42021278214.

The biosynthesis of the C ring of the antitumor antibiotic agent, tomaymycin, is proposed to proceed through five enzyme-catalyzed steps from l-tyrosine. The genes encoding these enzymes have recently been cloned and their functions tentatively assigned, but there is limited biochemical evidence supporting the assignments of the last three steps. One enzyme, TomN, shows 58% pairwise sequence similarity with 4-oxalocrotonate tautomerase (4-OT), an enzyme found in a catabolic pathway for aromatic hydrocarbons. The TomN sequence includes three amino acids (Pro-1, Arg-11, and Arg-39) that have been identified as critical catalytic residues in 4-OT. However, the proposed substrate for TomN is very different from that processed by 4-OT. To establish the function and mechanism of TomN and its relationship with 4-OT, we conducted kinetic, mutagenic, and structural studies. The kinetic parameters for TomN, and four alanine mutants, P1A, R11A, R39A, and R61A, were determined using 2-hydroxymuconate, the substrate for 4-OT. The TomN-catalyzed reaction using this substrate compares favorably to that of 4-OT. In addition, the kinetic parameters for the P1A, R11A, and R39A mutants of TomN parallel the trends observed for the corresponding 4-OT mutants, implicating an analogous mechanism. A high-resolution crystal structure (1.4 Å) of TomN shows that the overall structure and the active site region are highly similar to those of 4-OT with a root-mean-square deviation of 0.81 Å. Moreover, key active site residues are positionally conserved. The combined results suggest that the tentative assignment for TomN and the proposed sequence of events in the biosynthetic pathway leading to the formation of the C ring of tomaymycin might not be correct. An alternative pathway that awaits biochemical confirmation is proposed. [ABSTRACT FROM AUTHOR]

Phosphagen kinase (PK) family members catalyze the reversible phosphoryl transfer between phosphagen and ADP to reserve or release energy in cell energy metabolism. The structures of classic quaternary complexes of dimeric creatine kinase (CK) revealed asymmetric ligand binding states of two protomers, but the significance and mechanism remain unclear. To understand this negative cooperativity further, we determined the first structure of dimeric arginine kinase (dAK), another PK family member, at 1.75 Å, as well as the structure of its ternary complex with AMPPNP and arginine. Further structural analysis shows that the ligand-free protomer in a ligand-bound dimer opens more widely than the protomers in a ligand-free dimer, which leads to three different states of a dAK protomer. The unexpected allostery of the ligand-free protomer in a ligand-bound dimer should be relayed from the ligand-binding-induced allostery of its adjacent protomer. Mutations that weaken the inter-protomer connections dramatically reduced the catalytic activities of dAK, indicating the importance of the allosteric propagation mediated by the homodimer interface. These results suggest a reciprocating mechanism of dimeric PK, which is shared by other ATP related oligomeric enzymes, e.g., ATP synthase. [ABSTRACT FROM AUTHOR]