Feasibility Study on Constructing Dosimetric Correlated Geometric Parameters for Automatic Segmentation Evaluation.

PURPOSE: To investigate the feasibility of constructing new geometric parameters that correlate well with dosimetric parameters. METHODS: 100 rectal cancer patients were enrolled. The targets were identified manually, while the organs at risk (bladder, small bowel, left and right femoral heads) were segmented both manually and automatically. The radiotherapy plans were optimized according to the automatically contoured organs at risk. Forty cases were randomly selected to establish the relationship between dose and distance for each organ at risk, termed "dose-distance curves," which were then applied to the new geometric parameters. The correlation between these new geometric parameters and dosimetric parameters was analyzed in the remaining 60 test cases. RESULTS: The "dose-distance curves" were similar across the four organs at risk, exhibiting an inverse function shape with a rapid decrease initially and a slower rate at a later stage. The Pearson correlation coefficients of new geometric parameters and dosimetric parameters in the bladder, small intestine, and left and right femur heads were 0.96, 0.97, 0.88, and 0.70, respectively. CONCLUSIONS: The new geometric parameters predicated on "distance from the target" showed a high correlation with corresponding dosimetric parameters in rectal cancer cases. It is feasible to utilize the new geometric parameters to evaluate the dose deviation attributable to automatic segmentation.

Oculomotor Nerve Palsy Induced by a Cerebral Developmental Venous Anomaly: A Case Report and Comprehensive Review.

BACKGROUND Symptoms caused by developmental venous anomalies (DVAs) are usually mild and unspecific. Despite the benign nature of DVAs, they can occasionally be symptomatic. CASE REPORT A 67-year-old woman presented with sudden diplopia and left eyelid ptosis for 10 days. A neurologic examination revealed left complete oculomotor nerve palsy. Other neurologic deficits, including eye pain or pulsatile tinnitus, were not detected. Furthermore, the visual acuity was normal. Additionally, no retinal hemorrhage, venous dilatation, or fundus tortuosity were observed. No ischemia lesions or neoplasms were observed in MRI, and no widening or enhancement of the cavernous sinus was detected in post-contrast T1-weighted images, but magnetic resonance tomography cerebral angiography (MRTA) detected an offending vessel compressing the left oculomotor nerve in the fossa interpeduncular. We hypothesized that oculomotor nerve palsy (ONP) was caused by an abnormal arterial structure. However, digital subtraction angiography (DSA) revealed no aneurysm or abnormal arterial structure in the arterial phase, while a tortuous and dilated collecting vein was detected in the venous phase, connecting the left temporal lobe to the left cavernous sinus. This indicated a typical caput medusae appearance, suggesting the mechanism of oculomotor palsy caused by compressive impairment of the DVA. The patient refused microvascular decompression surgery, and ONP persisted after 30 days. Management was conservative, with spontaneous resolution at 60 days and no recurrence during the 2-year follow-up. CONCLUSIONS ONP is rarely caused by DVAs, which are easily ignored due to their benign nature. Cerebral vein examinations are advised for patients exhibiting clinical symptoms of unknown etiology.

Artificial Intelligence for Real-Time Prediction of the Histology of Colorectal Polyps by General Endoscopists.

BACKGROUND: Real-time prediction of histologic features of small colorectal polyps may prevent resection and/or pathologic evaluation and therefore decrease colonoscopy costs. Previous studies showed that computer-aided diagnosis (CADx) was highly accurate, though it did not outperform expert endoscopists. OBJECTIVE: To assess the diagnostic performance of histologic predictions by general endoscopists before and after assistance from CADx in a real-life setting. DESIGN: Prospective, multicenter, single-group study. (ClinicalTrials.gov: NCT04437615). SETTING: 6 centers across the United States. PARTICIPANTS: 1252 consecutive patients undergoing colonoscopy and 49 general endoscopists with variable experience in real-time prediction of polyp histologic features. INTERVENTION: Real-time use of CADx during routine colonoscopy. MEASUREMENTS: The primary end points were the sensitivity and specificity of CADx-unassisted and CADx-assisted histologic predictions for adenomas measuring 5 mm or less. For clinical purposes, additional estimates according to location and confidence level were provided. RESULTS: The CADx device made a diagnosis for 2695 polyps measuring 5 mm or less (96%) in 1252 patients. There was no difference in sensitivity between the unassisted and assisted groups (90.7% vs. 90.8%; P = 0.52). Specificity was higher in the CADx-assisted group (59.5% vs. 64.7%; P < 0.001). Among all 2695 polyps measuring 5 mm or less, 88.2% and 86.1% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be resected and discarded without pathologic evaluation. Among 743 rectosigmoid polyps measuring 5 mm or less, 49.5% and 47.9% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be left in situ without resection. LIMITATION: Decision making based on CADx might differ outside a clinical trial. CONCLUSION: CADx assistance did not result in increased sensitivity of optical diagnosis. Despite a slight increase, the specificity of CADx-assisted diagnosis remained suboptimal. PRIMARY FUNDING SOURCE: Olympus America Corporation served as the clinical study sponsor.

The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion.

Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.

Outcomes following allogeneic hematopoietic cell transplantation relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Improved first progression-free survival following allogeneic hematopoietic cell transplantation relapse with the use of immunotherapy.

Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease.

Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aß: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer.

Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitro and in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivo toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.

Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung Cancer.

We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18, and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared with non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared with NT NK and sIL15 NK cells. The addition of the anti-PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).

Therapy-related acute lymphoblastic leukaemia in women with antecedent breast cancer.

Therapy-related acute lymphoblastic leukaemia (tr-ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr-ALL, likely due to high prevalence and excellent curable rate for non-metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse-free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr-ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr-ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT.

Flotetuzumab as a salvage immunotherapy in advanced CD123-positive hematological malignancies, a phase 1 pilot study.

CD123 "expression" is common in hematological malignancies, including acute lymphoblastic leukemia (ALL). Flotetuzumab is a novel, investigational CD3/CD123 DART®. We conducted a phase 1 study evaluating safety and efficacy of flotetuzumab in relapsed/refractory ALL (Cohort A) and other advanced CD123-positive hematological malignancies (excluding myeloid malignancies) (cohort B). Thirteen patients (9 in Cohort A and 4 in Cohort B) were treated at dose level 1 (500 ng/kg/day) before early closure due to discontinuation of drug development by sponsor. Two dose limiting toxicities (Grade 4 thrombocytopenia and neutropenia) occurred in one patient in Cohort B. Cytokine release syndrome occurred in most patients (85%), all being grade ≤2. Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies.

A new xanthone isolated from Garcinia bracteata and its important effect on NO levels.

A new xanthone, allanxanthone F (1), and 10 known compounds were isolated from the ethanol extract of Garcinia bracteata. The structure of compound 1 was elucidated based on spectroscopic methods (UV, IR, HR-ESI-MS, and NMR). In addition, compounds 1-9 were assessed for their anti-inflammatory activities based on the expression of nitric oxide (NO) levels on lipopolysaccharide (LPS)-induced RAW264.7 macrophages, and compounds 1-3, 4 and 6-9 suggested potential anti-inflammatory activities.

Epidermal microorganisms contributed to the toxic mechanism of nZVI and TCEP in earthworms by robbing metal elements and nutrients.

Disrupting effects of pollutants on symbiotic microbiota have been regarded as an important mechanism of host toxicity, with most current research focusing on the intestinal microbiota. In fact, the epidermal microbiota, which participates in the nutrient exchange between hosts and environments, could play a crucial role in host toxicity via community changes. To compare the contributions of intestinal and epidermal symbiotic microorganisms to host toxicity, this study designed single and combined scenarios of soil contamination [nano zero-valent iron (nZVI) and tris (2-chloroethyl) phosphate (TCEP)], and revealed the coupling mechanisms between intestinal/epidermal symbiotic bacterial communities and earthworm toxicological endpoints. Microbiome analysis showed that 15% of intestinal microbes were highly correlated with host endpoints, compared to 45% of epidermal microbes showing a similar correlation. Functional comparisons revealed that key species on the epidermis were mainly heterotrophic microbes with genetic abilities to utilize metal elements and carbohydrate nutrients. Further verifications demonstrated that when facing the co-contamination of nZVI and TCEP, certain symbiotic microorganisms became dominant and consumed zinc, copper, and manganese along with saccharides and amino acids, which may be responsible for the nutritional deficiencies in the host earthworms. The findings can enrich the understanding of the coupling relationship between symbiotic microorganisms and host toxicity, highlighting the importance of epidermal microorganisms in host resistance to environmental pollution.

Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

Evaluation of sustained drug release performance and osteoinduction of magnetron-sputtered tantalum-coated titanium dioxide nanotubes.

Modifying the drug-release capacity of titanium implants is essential for maintaining their long-term functioning. Titanium dioxide nanotube (TNT) arrays, owing to their drug release capacity, are commonly used in the biomaterial sphere. Their unique half open structure and arrangement in rows increase the drug release capacity. However, their rapid drug release ability not only reduces drug efficiency but also produces excessive local and systemic deposition of antibiotics. In this study, we designed a tantalum-coated TNT system for drug-release optimization. A decreased nanotube size caused by the tantalum nanocoating was observed through SEM and analyzed (TNT: 110 nm, TNT-Ta1: 80 nm, TNT-Ta3: 40 nm, TNT-Ta5: 20 nm, TNT-Ta7: <5 nm). XPS analysis revealed the distribution of the chemical components, especially that of the tantalum element. In vitro experiments showed that the tantalum nanocoating enhanced cell proliferation; in particular, TNT-Ta5 possessed the best cell viability (about 1.18 of TNT groups at 7d). It also showed that the tantalum nanocoating had a positive effect on osteogenesis (especially TNT-Ta5 and TNT-Ta7). Additionally, hydrophilic/hydrophobic drug (vancomycin/raloxifene) release results indicated that the TNT-Ta5 group possessed the most desirable sustained release capacity. Moreover, in this drug release system, the hydrophobic drug showed more sustained release capacity than the hydrophilic drug (vancomycin: sustained release for more than 48 h, raloxifene: sustained release for more than 168 h). More importantly, TNT-Ta5 is proved to be an appropriate drug release system, which possesses cytocompatibility, osteogenic capacity, and sustained drug release capacity.

Probucol will become a New Model for Treating Cerebral Infarction with a High Risk of Hemorrhage.

Antiplatelet, antihypertensive, and lipid-lowering agents are the three foundational agents for secondary prevention of ischemic stroke, among which lipid-lowering is one of the most important cornerstones. Probucol is a potent antioxidative lipid-lowering drug used to prevent and treat atherosclerotic cardiovascular diseases and xanthomas. However, it has faded from Western markets by lowering LDL-C and HDL-C levels. Probucol alleviates atherosclerosis improving high-density lipoprotein function, and does not increase the risk of cardiovascular events. Probucol-induced pharmacological changes in HDL-C may not be a reliable prognostic marker for cardiovascular risk. Q-T interval prolongation is a rare adverse reaction as described in the manufacturer's instructions, but prolonged Q-T interval may only be an intermediate pharmacological phenomenon of electrophysiological changes, and as a result, probucol has a strong benefit for secondary prevention of cardiovascular events and can reduce mortality without increasing the risk of cardiovascular and cerebrovascular adverse events. The new mechanism is that probucol penetrates the core of lowdensity lipoprotein particles, enhancing the activity of plasma cholesteryl ester transfer protein and liver scavenger receptor type I activity, thereby reducing LDH; at the same time, increasing the activity of paraoxonase 1, strengthened the antioxidant function of HDL, and reduced the serum HDL-C. If clinical or imaging findings suggest a high risk of recurrence of cerebral ischemia with a high risk of cerebral hemorrhage, probucol may be selected for prevention. This article focuses on basic research and clinical evidence and provides new insights into the low bioavailability.