Broadening Eligibility Criteria and Diversity among Patients for Cancer Clinical Trials.

BACKGROUND: Certain populations have been historically underrepresented in clinical trials. Broadening eligibility criteria is one approach to inclusive clinical research and achieving enrollment goals. How broadened trial eligibility criteria affect the diversity of eligible participants is unknown. METHODS: Using a nationwide electronic health record-derived deidentified database, we identified a retrospective cohort of patients diagnosed with 22 cancer types between April 1, 2013 and December 31, 2022 who received systemic therapy (N=235,234) for cancer. We evaluated strict versus broadened eligibility criteria using performance status and liver, kidney, and hematologic function around first line of therapy. We performed logistic regression to estimate odds ratios for exclusion by strict criteria and their association with measures of patient diversity, including sex, age, race or ethnicity, and area-level socioeconomic status (SES); estimated the impact of broadening criteria on the number and distribution of eligible patients; and performed Cox regression to estimate hazard ratios for real-world overall survival (rwOS) comparing patients meeting strict versus broadened criteria. RESULTS: When applying common strict cutoffs for eligibility criteria to patients with complete data and weighting each cancer type equally, 48% of patients were eligible for clinical trials. Female (odds ratio, 1.30; 95% confidence interval [CI], 1.25 to 1.35), older (age 75+ vs. 18 to 49 years old: odds ratio, 3.04; 95% CI, 2.85 to 3.24), Latinx (odds ratio, 1.46; 95% CI, 1.39 to 1.54), non-Latinx Black (odds ratio, 1.11; 95% CI, 1.06 to 1.16), and lower-SES patients were more likely to be excluded using strict eligibility criteria. Broadening criteria increased the number of eligible patients by 78%, with the strongest impact for older, female, non-Latinx Black, and lower-SES patients. Patients who met only broadened criteria had worse rwOS versus those with strict criteria (hazard ratio, 1.31; 95% CI, 1.27 to 1.34). CONCLUSIONS: Data-driven evaluation of clinical trial eligibility criteria may optimize the eligibility of certain historically underrepresented groups and promote access to more inclusive trials. (Sponsored by Flatiron Health.).

Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC.

Importance: Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making. Objective: To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC. Exposure: All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed. Main Outcomes and Measures: End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR. Results: A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment. Conclusions and Relevance: In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.

Structural insights into branch site proofreading by human spliceosome.

Selection of the pre-mRNA branch site (BS) by the U2 small nuclear ribonucleoprotein (snRNP) is crucial to prespliceosome (A complex) assembly. The RNA helicase PRP5 proofreads BS selection but the underlying mechanism remains unclear. Here we report the atomic structures of two sequential complexes leading to prespliceosome assembly: human 17S U2 snRNP and a cross-exon pre-A complex. PRP5 is anchored on 17S U2 snRNP mainly through occupation of the RNA path of SF3B1 by an acidic loop of PRP5; the helicase domain of PRP5 associates with U2 snRNA; the BS-interacting stem-loop (BSL) of U2 snRNA is shielded by TAT-SF1, unable to engage the BS. In the pre-A complex, an initial U2-BS duplex is formed; the translocated helicase domain of PRP5 stays with U2 snRNA and the acidic loop still occupies the RNA path. The pre-A conformation is specifically stabilized by the splicing factors SF1, DNAJC8 and SF3A2. Cancer-derived mutations in SF3B1 damage its association with PRP5, compromising BS proofreading. Together, these findings reveal key insights into prespliceosome assembly and BS selection or proofreading by PRP5.

Bleeder's Femur: The Proximal Femoral Morphology in Hemophilic Patients Who Underwent Total Hip Arthroplasty.

INTRODUCTION: Patients with hemophilia (PWH) constantly suffer hemarthrosis, which leads to deformity of the hip joint. Therefore, PWH who are going to receive total hip arthroplasty (THA) should be exclusively treated before the surgery with careful measurement of their proximal femur. Hence, we conducted a retrospective study to explore the anatomical parameters of and differences in the proximal femur in hemophilic patients who underwent THA. METHODS: The retrospective study comprised data of adult patients who received total hip arthroplasty from 2020 to 2022 in the research center. Patients having a diagnosis of hemophilic arthritis and received THA were included in experimental group, and patients with hip arthritis or femoral head necrosis were taken as control group. Parameters including femoral offset, neck-shaft angle (NSA), medullary cavity of 20 mm above mid-lesser trochanter level (T+20), mid-lesser trochanter level (T), and 20 mm blow it (T-20), and canal flare index (CFI), femoral cortical index (FCI) were measured on X-ray and CT images with PACS by two independent doctors. Data was analyzed by SPSS 20. Kolmogorov-Smirnov test was used to test data normality. Student's t-test was performed between PWH and control group. p < 0.05 was considered statistically significant. RESULTS: Among the 94 hips, 39 (41.5%) were included in group hemophilia and 55(58.5%) in control group. The mean age of the patients was 49.36 ± 12.92 years. All cases were male patients. Data demonstrated significantly smaller femoral cortical index (FCI), femoral offset, medullary cavity of 20 mm above mid-lesser trochanter level, mid-lesser trochanter level, and 20 mm below it, and neck-shaft angle (NSA) was obviously larger in PWH than control group (p < 0.05). No significant difference was found in canal flare index (CFI). CONCLUSION: Hemophilic patients undergoing THA were prone to longer and thinner proximal femur. Preoperative morphological analysis of femur is recommended.

Long-term spatiotemporal variations in surface NO2 for Beijing reconstructed from surface data and satellite retrievals.

Remote sensing data from the Ozone Monitoring Instrument (OMI) and the TROPOspheric Monitoring Instrument (TROPOMI) play important roles in estimating surface nitrogen dioxide (NO2), but few studies have compared their differences for application in surface NO2 reconstruction. This study aims to explore the effectiveness of incorporating the tropospheric NO2 vertical column density (VCD) from OMI and TROPOMI (hereafter referred to as OMI and TROPOMI, respectively, for conciseness) for deriving surface NO2 and to apply the resulting data to revisit the spatiotemporal variations in surface NO2 for Beijing over the 2005-2020 period during which there were significant reductions in nitrogen oxide emissions. In the OMI versus TROPOMI performance comparison, the cross-validation R2 values were 0.73 and 0.72, respectively, at 1 km resolution and 0.69 for both at 100 m resolution. The comparisons between satellite data sources indicate that even though TROPOMI has a finer resolution it does not improve upon OMI for deriving surface NO2 at 1 km resolution, especially for analyzing long-term trends. In light of the comparison results, we used a hybrid approach based on machine learning to derive the spatiotemporal distribution of surface NO2 during 2005-2020 based on OMI. We had novel, independent passive sampling data collected weekly from July to September of 2008 for hindcasting validation and found a spatiotemporal R2 of 0.46 (RMSE = 7.0 ppb). Regarding the long-term trend of surface NO2, the level in 2008 was obviously lower than that in 2007 and 2009, as expected, which was attributed to pollution restrictions during the Olympic Games. The NO2 level started to steadily decline from 2015 and fell below 2008's level after 2017. Based on OMI, a long-term and fine-resolution surface NO2 dataset was developed for Beijing to support future environmental management questions and epidemiological research.

Twin-Field Quantum Key Distribution without Phase Locking.

Twin-field quantum key distribution (TF-QKD) has emerged as a promising solution for practical quantum communication over long-haul fiber. However, previous demonstrations on TF-QKD require the phase locking technique to coherently control the twin light fields, inevitably complicating the system with extra fiber channels and peripheral hardware. Here, we propose and demonstrate an approach to recover the single-photon interference pattern and realize TF-QKD without phase locking. Our approach separates the communication time into reference frames and quantum frames, where the reference frames serve as a flexible scheme for establishing the global phase reference. To do so, we develop a tailored algorithm based on fast Fourier transform to efficiently reconcile the phase reference via data postprocessing. We demonstrate no-phase-locking TF-QKD from short to long distances over standard optical fibers. At 50-km standard fiber, we produce a high secret key rate (SKR) of 1.27 Mbit/s, while at 504-km standard fiber, we obtain the repeaterlike key rate scaling with a SKR of 34 times higher than the repeaterless secret key capacity. Our work provides a scalable and practical solution to TF-QKD, thus representing an important step towards its wide applications.

Two assembly modes for SIN3 histone deacetylase complexes.

The switch-independent 3 (SIN3)/histone deacetylase (HDAC) complexes play essential roles in regulating chromatin accessibility and gene expression. There are two major types of SIN3/HDAC complexes (named SIN3L and SIN3S) targeting different chromatin regions. Here we present the cryo-electron microscopy structures of the SIN3L and SIN3S complexes from Schizosaccharomyces pombe (S. pombe), revealing two distinct assembly modes. In the structure of SIN3L, each Sin3 isoform (Pst1 and Pst3) interacts with one histone deacetylase Clr6, and one WD40-containing protein Prw1, forming two lobes. These two lobes are bridged by two vertical coiled-coil domains from Sds3/Dep1 and Rxt2/Png2, respectively. In the structure of SIN3S, there is only one lobe organized by another Sin3 isoform Pst2; each of the Cph1 and Cph2 binds to an Eaf3 molecule, providing two modules for histone recognition and binding. Notably, the Pst1 Lobe in SIN3L and the Pst2 Lobe in SIN3S adopt similar conformation with their deacetylase active sites exposed to the space; however, the Pst3 Lobe in SIN3L is in a compact state with its active center buried inside and blocked. Our work reveals two classical organization mechanisms for the SIN3/HDAC complexes to achieve specific targeting and provides a framework for studying the histone deacetylase complexes.

Structure of a SIN3-HDAC complex from budding yeast.

SIN3-HDAC (histone deacetylases) complexes have important roles in facilitating local histone deacetylation to regulate chromatin accessibility and gene expression. Here, we present the cryo-EM structure of the budding yeast SIN3-HDAC complex Rpd3L at an average resolution of 2.6 Å. The structure reveals that two distinct arms (ARM1 and ARM2) hang on a T-shaped scaffold formed by two coiled-coil domains. In each arm, Sin3 interacts with different subunits to create a different environment for the histone deacetylase Rpd3. ARM1 is in the inhibited state with the active site of Rpd3 blocked, whereas ARM2 is in an open conformation with the active site of Rpd3 exposed to the exterior space. The observed asymmetric architecture of Rpd3L is different from those of available structures of other class I HDAC complexes. Our study reveals the organization mechanism of the SIN3-HDAC complex and provides insights into the interaction pattern by which it targets histone deacetylase to chromatin.

Facile fabrication of hydrophilic covalent organic framework composites for highly selective enrichment of N-glycopeptides.

The development of facilely synthetic materials acts an essential role in glycoproteome analysis, especially for the highly efficient enrichment of N-linked glycopeptides. In this work, a facile and timesaving route was introduced in which COFTP-TAPT served as a carrier and poly (ethylenimine) (PEI) and carrageenan (Carr) were successively coated on the surface via electrostatic interaction. The resultant COFTP-TAPT@PEI@Carr showed remarkable performance in glycopeptide enrichment with high sensitivity (2 fmol µL-1), high selectivity (1:800, molar ratio of human serum IgG to BSA digests), large loading capacity (300 mg g-1), satisfactory recovery (102.4 ± 6.0%) and reusability (at least eight times). Due to the brilliant hydrophilicity and electrostatic interactions between COFTP-TAPT@PEI@Carr and positively charged glycopeptides, the prepared materials could be applied in the identification and analysis in the human plasma of healthy subjects and patients with nasopharyngeal carcinoma. As a result, 113 N-glycopeptides with 141 glycosylation sites corresponding to 59 proteins and 144 N-glycopeptides with 177 glycosylation sites corresponding to 67 proteins were enriched from 2 µL plasma trypsin digests of the control groups and patients with nasopharyngeal carcinoma, respectively. 22 glycopeptides were identified only from the normal controls and 53 glycopeptides were detected only from the other set. The results demonstrated that this hydrophilic material was promising on a large scale and further N-glycoproteome research.

Structural basis of pre-tRNA intron removal by human tRNA splicing endonuclease.

Removal of the intron from precursor-tRNA (pre-tRNA) is essential in all three kingdoms of life. In humans, this process is mediated by the tRNA splicing endonuclease (TSEN) comprising four subunits: TSEN2, TSEN15, TSEN34, and TSEN54. Here, we report the cryo-EM structures of human TSEN bound to full-length pre-tRNA in the pre-catalytic and post-catalytic states at average resolutions of 2.94 and 2.88 Å, respectively. Human TSEN features an extended surface groove that holds the L-shaped pre-tRNA. The mature domain of pre-tRNA is recognized by conserved structural elements of TSEN34, TSEN54, and TSEN2. Such recognition orients the anticodon stem of pre-tRNA and places the 3'-splice site and 5'-splice site into the catalytic centers of TSEN34 and TSEN2, respectively. The bulk of the intron sequences makes no direct interaction with TSEN, explaining why pre-tRNAs of varying introns can be accommodated and cleaved. Our structures reveal the molecular ruler mechanism of pre-tRNA cleavage by TSEN.

LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia.

BACKGROUND: Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins (e.g., interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome. METHODS: First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2, were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting. RESULTS: Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2, prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice. CONCLUSIONS: Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.

A rare lymphoplasmacyte-rich meningioma involving the dura of the skull base and cervical spinal cord: A case report.

Lymphoplasmacyte-rich meningioma (LPRM) is a rare subtype of meningioma, the specific pathogenesis of which remains unclear. Herein, we report the case of a 48-year-old Asian man who experienced progressive deafness and limb weakness. Magnetic resonance imaging revealed extramedullary masses diffusely growing, wrapping, and compressing the cervical spinal cord. The dural lesion was partially excised by surgery, and postoperative pathological examination confirmed the diagnosis of LPRM. Diffuse LPRM is extremely rare, and its treatment is challenging owing to difficulties associated with surgery and the uncertain efficacy of traditional therapies. Therefore, further clinical practice and basic research are needed to improve the prognosis of diffuse LPRM.

Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex.

Human cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice. Two-photon imaging shows vascularization of the transplanted organoid. Visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in multi-unit activity (MUA) and gamma power and phase locking of stimulus-evoked MUA with slow oscillations indicate functional integration between the organoid and the host brain. Immunostaining confirms the presence of human-mouse synapses. Implantation of transparent microelectrodes with organoids serves as a versatile in vivo platform for comprehensive evaluation of the development, maturation, and functional integration of human neuronal networks within the mouse brain.

First-principle calculations of the structural, vibrational, mechanical, electronic, and optical properties of ε-O8 under pressure.

The vibrational, mechanical, electronic, and optical properties of the ε-O8 phase in the pressure range of 11.4-70 GPa were studied by the first-principle calculation method. The phonon dispersion curves have a tiny virtual frequency at 60 GPa, which indicates that ε-O8 is dynamically unstable at 60 GPa. However, the 3-BM EOS demonstrates that the unit cell is stable up to 70 GPa. It has been shown that ε-O8 remains ductile within the whole applied pressure range. Concurrently, we calculated the variation of the band gap of ε-O8 in the pressure range of 11.4-70 GPa. The results show that the band gap of ε-O8 decreases with increasing pressure. Notably, the band gap disappears within the range of 50-60 GPa, which reveals that the metallic phase transition occurs within this pressure range.

E-Cannula reveals anatomical diversity in sharp-wave ripples as a driver for the recruitment of distinct hippocampal assemblies.

The hippocampus plays a critical role in spatial navigation and episodic memory. However, research on in vivo hippocampal activity dynamics mostly relies on single modalities, such as electrical recordings or optical imaging, with respectively limited spatial and temporal resolution. Here, we develop the E-Cannula, integrating fully transparent graphene microelectrodes with imaging cannula, which enables simultaneous electrical recording and two-photon calcium imaging from the exact same neural populations across an anatomically extended region of the mouse hippocampal CA1 stably across several days. The large-scale multimodal recordings show that sharp wave ripples (SWRs) exhibit spatiotemporal wave patterns along multiple axes in two-dimensional (2D) space with different spatial extents and temporal propagation modes. Notably, distinct SWR wave patterns are associated with the selective recruitment of orthogonal CA1 cell assemblies. These results demonstrate the utility of the E-Cannula as a versatile neurotechnology with the potential for future integration with other optical components.

Objectively determined physical activity and adiposity measures in adult women: A systematic review and meta-analysis.

The prevalence of adiposity is increasing among adult women. Although emerging evidence suggest that all patterns of heightened physical activity (PA) are important to benefit adiposity, the relationship between objectively assessed intensities of PA and adiposity in women has not yet been assessed. Therefore, this systematic review and meta-analysis aims to qualitatively synthesize and quantitatively assess the evidence for any relationship between objectively measured PA and a wide range of adiposity indicators to guide PA prescription in adult women. Four databases (PubMed, Web of Science, Scopus, and the Cochrane library) were searched for eligible studies. 35 studies were included (25 observational and 10 interventional studies), with a total of 9,176 women from 20 countries included. The overall pooled correlation for random effects model (n = 1 intervention and n = 15 cross-sectional studies) revealed that the total volume of physical activity (TPA) was moderately associated with percentage body fat (%BF) (r = -0.59; 95% CI: -1.11, -0.24; p = 0.003). There was a weak but significant association between MVPA with body mass index (BMI), waist circumference (WC), and visceral adiposity. Daily steps were significantly associated with BMI, %BF, WC, and fat mass, with the strongest association with %BF (r = -0.41; 95% CI: -0.66, -0.19; p < 0.001). Walking programs resulting in increasing daily steps only had a significant effect on WC (SMD = -0.35; 95% CI: -0.65, -0.05; p = 0.02). Overall, objectively determined PA in terms of steps, TPA and MVPA were favorably associated with adiposity outcomes. The improvement in adiposity can be achieved by simply accumulating more PA than previously and adiposity is more likely to be benefited by PA performed at higher intensity. Nonetheless, these results should be interpreted with caution as there were a small number of studies included in the meta-analysis and the majority of studies included utilized cross-sectional designs.

The Effect of Standing Mats on Biomechanical Characteristics of Lower Limbs and Perceived Exertion for Healthy Individuals during Prolonged Standing.

Objective: To identify the effect of standing mats on biomechanical characteristics of lower limbs and perceived exertion for healthy adult individuals during a prolonged standing task. Methods: 32 healthy college students were recruited in the randomized and cross-over designed trial according to the effect size and statistical power. After collecting the anthropometric data, each participant was asked to finish 2 sessions of 4-hour prolonged standing tasks on standing mats (MS) and hard ground (GS) in a random order and with a 72-hour interval rest. The plantar pressure distribution, foot morphology, and scores of the BESS (balance error scoring system) would be recorded pre- and posteach task. The Borg Rating of Perceived Exertion (RPE) would be collected during the whole task. Paired-samples t test was adopted to analyse the before and after difference within group and independent-samples t test was adopted to analyse the difference between groups separately. Results: (1) A prolonged standing task on both MS and GS have a negative effect on RPE and balance performance. (2) The negative effect on RPE and balance performance induced by MS is significantly smaller than that induced by GS. (3) Compared to GS, prolonged standing on MS has a lower peak plantar pressure and an implicit decrease in navicular drop and AHI (arch index). Conclusion: Standing mat tends to alleviate the fatigue induced by prolonged standing in lower limbs, optimize the distribution of plantar pressure, and maintain the stability.

GARP-mediated active TGF-ß1 induces bone marrow NK cell dysfunction in AML patients with early relapse post-allo-HSCT.

Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor ß1 (TGF-ß1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-ß1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-ß1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-ß1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-ß1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-ß1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.

Opportunistic osteoporosis screening using chest CT with artificial intelligence.

Osteoporosis has a high incidence and a low detection rate. If it is not detected in time, it will cause osteoporotic fracture and other serious consequences. This study showed that the attenuation values of vertebrae on chest CT could be used for opportunistic screening of osteoporosis. This will be beneficial to improve the detection rate of osteoporosis and reduce the incidence of adverse events caused by osteoporosis. INTRODUCTION: To explore the value of the attenuation values of all thoracic vertebrae and the first lumbar vertebra measured by artificial intelligence on non-enhanced chest CT to do osteoporosis screening. METHODS: On base of images of chest CT, using artificial intelligence (AI) to measure the attenuation values (HU) of all thoracic and the first vertebrae of patients who underwent CT examination for lung cancer screening and dual-energy X-ray absorptiometry (DXA) examination during the same period. The patients were divided into three groups: normal group, osteopenia group, and osteoporosis group according to the results of DXA. Clinical baseline data and attenuation values were compared among the three groups. The correlation between attenuation values and BMD values was analyzed, and the predictive ability and diagnostic efficacy of attenuation values of thoracic and first lumbar vertebrae on osteopenia or osteoporosis risk were further evaluated. RESULTS: CT values of each thoracic vertebrae and the first lumbar vertebrae decreased with age, especially in menopausal women and presented high predictive ability and diagnostic efficacy for osteopenia or osteoporosis. After clinical data correction, with every 10 HU increase of CT values, the risk of osteopenia or osteoporosis decreased by 32 ~ 44% and 61 ~ 80%, respectively. And the combined diagnostic efficacy of all thoracic vertebrae was higher than that of a single vertebra. The AUC of recognizing osteopenia or osteoporosis from normal group was 0.831and 0.972, respectively. CONCLUSIONS: The routine chest CT with AI is of great value in opportunistic screening for osteopenia or osteoporosis, which can quickly screen the population at high risk of osteoporosis without increasing radiation dose, thus reducing the incidence of osteoporotic fracture.

Identification of a pyroptosis-related prognosis gene signature and its relationship with an immune microenvironment in gliomas.

BACKGROUND: Glioma is the most common type of primary brain cancer, and the prognosis of most patients with glioma is poor. Pyroptosis is a newly discovered inflammatory programmed cell death. However, the expression of pyroptosis-related genes (PRGs) in glioma and its correlation with prognosis are unclear. METHODS: 27 pyroptosis genes differentially expressed between glioma and adjacent normal tissues were identified. All glioma cases could be stratified into 2 subtypes based on these differentially expressed PRGs. The prognostic value of each PRG was evaluated to construct a prognostic model. RESULTS: A novel 16-gene signature was constructed by using the least absolute shrinkage and selection operator Cox regression method. Then, patients with glioma were divided into low- and high-risk groups in the TCGA cohort. The survival rate of patients in the low-risk group was significantly higher than that in the high-risk group (P = .001). Patients with glioma from the Gene Expression Omnibus (GEO) cohort were stratified into 2 risk groups by using the median risk score. The overall survival (OS) of the low-risk group was longer than that of the high-risk group (P = .001). The risk score was considered an independent prognostic factor of the OS of patients with glioma. Gene ontology and Kyoto Encylopedia of Genes and Genomes analysis showed that the differentially expressed PRGs were mainly related to neutrophil activation involved in immune responses, focal adhesion, cell cycle, and p53 signaling pathway. CONCLUSION: PRGs could predict the prognosis of glioma and play significant roles in a tumor immune microenvironment.