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In the 1980s, zirconia was introduced for THA with the expectation of lower polyethylene wear and better clinical results. However, several studies have reported poor survivorship of zirconia-polyethylene THA. We performed a systematic review and meta-analysis of zirconia-polyethylene THA to confirm or refute the theoretical advantages of this combination. Of 163 studies identified by a comprehensive search, seven met our selection criteria. These involved 769 hips of 586 patients with a mean age of 56.8 years and a minimum followup of 60 months (mean, 89.2 months; range, 60-155 months). The consolidated revision rate of zirconia-polyethylene THA at 89.2 months was higher than that of nonzirconia-polyethylene THA by 5% (risk difference, 0.05; 95% confidence interval, 0.02-0.08). Subgroup meta-analysis suggested THAs with zirconia heads from Ceraver had more revision surgery than nonzirconia heads (risk difference, 0.08; 95% confidence interval, 0.03-0.14), whereas zirconia heads from DePuy did not (risk difference, 0.02; 95% confidence interval, -0.01-0.06). The meta-analysis for annual linear polyethylene wear (which did not involve zirconia heads from Ceraver because of insufficient descriptions) showed no difference between zirconia and control groups. Collectively, THAs with high-quality zirconia heads appear to have prosthesis survivorship and polyethylene wear equivalent to those of THAs with traditional materials, but differing quality among zirconia heads could lead to poor survivorship of prostheses. [ABSTRACT FROM AUTHOR]

Immunotherapy has attracted considerable attention as a therapeutic strategy for cancers including acute myeloid leukemia (AML). In this study, we found that the development of several aggressive subtypes of AML is slower in Rag2 -/- mice despite the lack of B and T lymphocytes, even compared to the immunologically normal C57BL/6 mice. Furthermore, an orally active p53-activating drug shows stronger antileukemia effect on AML in Rag2 -/- mice than C57BL/6 mice. Intriguingly, Natural Killer (NK) cells in Rag2 -/- mice are increased in number, highly express activation markers, and show increased cytotoxicity to leukemia cells in a coculture assay. B2m depletion that triggers missing-self recognition of NK cells impairs the growth of AML cells in vivo. In contrast, NK cell depletion accelerates AML progression in Rag2 -/- mice. Interestingly, immunogenicity of AML keeps changing during tumor evolution, showing a trend that the aggressive AMLs generate through serial transplantations are susceptible to NK cell-mediated tumor suppression in Rag2 -/- mice. Thus, we show the critical role of NK cells in suppressing the development of certain subtypes of AML using Rag2 -/- mice, which lack functional lymphocytes but have hyperactive NK cells., (© 2023. The Author(s).)

Adjuvant therapy for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer (EBC) remains challenging. The prognostic significance of HER2-low positivity in these patients is not fully understood. In our retrospective study, we analyzed 647 patients with HR-positive, HER2-negative, node-positive EBC, stratifying them into three cohorts based on axillary lymph node involvement, tumor size, and characteristics. Cohort 1 included patients with either ≥ 4 positive axillary lymph nodes or 1-3 positive nodes with histological grade 3 or tumor size ≥ 5 cm. Cohort 2 consisted of patients with 1-3 positive nodes, histological grade < 3, tumor size < 5 cm, and Ki-67 ≥ 20%. Cohort 3 comprised patients with 1-3 positive nodes, histological grade < 3, tumor size < 5 cm, and Ki-67 < 20%. We compared invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) between HER2-low (IHC1+ or IHC2+/FISH-) and HER2-zero (IHC0) groups in each cohort. In cohort 1, HER2-low patients exhibited significantly better 5-year IDFS (84.2% vs. 73.6%, p = 0.0213) and DRFS (88.2% vs. 79.8%, p = 0.0154). However, no significant differences were observed in cohorts 2 and 3. Our findings suggest HER2-low positivity as a prognostic factor in HR-positive, HER2-negative, and node-positive EBC., (© 2023. The Author(s).)

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL-fusions are susceptible to IMPDH inhibitors in vitro. We also showed that alternate-day administration of IMPDH inhibitors suppressed the development of MLL-AF9-driven AML in vivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll-like receptor (TLR)-TRAF6-NF-κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL-fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL-fusion AMLs and potentially other aggressive tumors with active TLR signaling., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

Background: On average, patients in Japan with type 2 diabetes mellitus have a clinical consultation every month, although evidence for a favorable follow-up interval is lacking. This study investigated whether the follow-up interval can be extended by comparing the clinical outcomes and cost for monthly versus bimonthly follow-up of patients with well-controlled diabetes mellitus., Methods: We combined administrative claims data from the National Health Insurance and the Health Checkups Program data of Tsu city, Japan between 2011 and 2014 to conduct a retrospective cohort study of patients with well-controlled type 2 diabetes mellitus. Propensity scores were used to assemble a matched-pairs cohort from patients who had monthly and bimonthly follow-up. Equivalence between two groups was assessed by designating the proportion of patients who maintained good control of their diabetes in the subsequent year as a primary outcome. The proportion achieving target blood pressure and lipid levels, favorable lifestyle, and annual cost were compared as secondary outcomes., Results: Of 12,145 participants, 693 with monthly follow-up and 693 with bimonthly follow-up were matched using propensity scores. In the monthly follow-up group 654 (94.4%) remained under good diabetic control, versus 658 (95.0%) in the bimonthly group (difference: 0.6%; 95% confidence interval: - 1.8 to 2.9%). All secondary outcomes were equivalent for the monthly and bimonthly follow-up groups except the proportion achieving target blood pressure, the proportion engaging in regular exercise, and annual cost., Conclusions: For patients with well-controlled diabetes mellitus, although frequent follow-up by a physician does not affect the control of blood glucose level in the subsequent year, the annual treatment cost becomes much higher. We suggest that patients with well-controlled diabetes can be followed up less often.

We report on the sensing stability of quantum nanosensors in aqueous buffer solutions for the two detection schemes of quantum decoherence spectroscopy and nanoscale thermometry. The electron spin properties of single nitrogen-vacancy (NV) centers in 25 nm-sized nanodiamonds have been characterized by observing individual nanodiamonds during a continuous pH change from 4 to 11. We have determined the stability of the NV quantum sensors during the pH change as the fluctuations of ±12% and ±0.2 MHz for the spin coherence time ( T 2 ) and the resonance frequency ( ω 0 ) of their mean values, which are comparable to the instrument error of the measurement system. We discuss the importance of characterizing the sensing stability during the pH change and how the present observation affects the measurement scheme of nanodiamond-based NV quantum sensing., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

Capturing the fast rotational motion of single nanoparticles has been hindered owing to the difficulty of acquiring directional information under the optical diffraction limit. Here, we report the linewidth broadening of the electron spin resonance of single nitrogen vacancy (NV) centers that matches the rotational diffusion constant of the host nanodiamonds. When nanodiamonds are gradually detached from the substrates that they were fixed to, their optically detected spin resonance peaks are broadened by 1.8 MHz, which corresponds to the rotational diffusion constant of nanoparticles with a diameter of 11.4 nm from the Einstein-Smoluchowski relation.

ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.