LDLa containing C-type lectin mediates phagocytosis of V.anguillarum and regulates immune effector genes in shrimp.

C-type lectins (CTLs) function as pattern recognition receptors (PRRs) by recognizing invading microorganisms, thereby triggering downstream immune events against infected pathogens. In this study, a novel CTL containing a low-density lipoprotein receptor class A (LDLa) domain was obtained from Litopenaeus vannamei, designed as LvLDLalec. Stimulation by the bacterial pathogen Vibrio anguillarum (V. anguillarum) resulted in remarkable up-regulation of LvLDLalec, as well as release of LvLDLalec into hemolymph. The rLvLDLalec protein possessed broad-spectrum bacterial binding and agglutinating activities, as well as hemocyte attachment ability. Importantly, LvLDLalec facilitated the bacterial clearance in shrimp hemolymph and protected shrimp from bacterial infection. Further studies revealed that LvLDLalec promoted hemocytes phagocytosis against V. anguillarum and lysosomes were involved in the process. Meanwhile, LvLDLalec participated in humoral immunity through activating and inducing nuclear translocation of Dorsal to regulate phagocytosis-related genes and antimicrobial peptides (AMPs) genes, thereby accelerated the removal of invading pathogens in vivo and improved the survival rate of L. vannamei. These results unveil that LvLDLalec serves as a PRR participate in cellular and humoral immunity exerting opsonin activity to play vital roles in the immune regulatory system of L. vannamei.

Plaque features of the middle cerebral artery are associated with periprocedural complications of intracranial angioplasty and stenting.

PURPOSE: The identification of plaque features in the middle cerebral artery (MCA) may help minimize periprocedural complications and select patients suitable for percutaneous transluminal angioplasty and stenting (PTAS). However, relevant research is lacking. METHODS: We retrospectively included patients with symptomatic MCA stenosis who received PTAS. All patients underwent intracranial vessel wall MRI (VWMRI) before surgery. Periprocedural complications (PC) included ischemic and hemorrhagic stroke within 30 days. Stenosis location, MCA shape, plaque eccentricity and distribution, plaque thickness and length, and enhancement ratio were compared between patients with and without PC. RESULTS: Sixty-six patients were included in the study, of which 12.1% (8/66) had PC. Of the eight patients with PC, seven (87.5%) had superior wall plaques. In the non-PC group (n = 58), nine (17%) patients had superior wall plaques. Compared with patients without PC, those with PC had more frequent superior wall plaques (17% vs 87.5%, p < 0.001) and s-shaped MCAs (19% vs 50%, p = 0.071), different stenosis locations (p = 0.012), thicker plaques (1.58 [1.35, 2.00] vs 1.98 [1.73, 2.43], p = 0.038), and less frequent inferior wall plaques (79.2% vs 12.5%, p < 0.001). Multivariate analysis showed that only the presence of superior wall plaques (OR = 41.54 [2.31, 747.54]) was independently associated with PC. CONCLUSION: MCA plaque features were highly correlated with PC in patients with symptomatic MCA stenosis who underwent PTAS.

Rreb1 is a key transcription factor in Sertoli cell maturation and function and spermatogenesis in mouse.

Spermatogenesis is a developmental process driven by interactions between germ cells and Sertoli cells. This process depends on appropriate gene expression, which might be regulated by transcription factors. This study focused on Rreb1, a zinc finger transcription factor, and explored its function and molecular mechanisms in spermatogenesis in a mouse model. Our results showed that RREB1 was predominantly expressed in the Sertoli cells of the testis. The decreased expression of RREB1 following injection of siRNA caused impaired Sertoli cell development, which was characterized using a defective blood-testis barrier structure and decreased expression of Sertoli cell functional maturity markers; its essential trigger might be SMAD3 destabilization. The decreased expression of RREB1 in mature Sertoli cells influenced the cell structure and function, which resulted in abnormal spermatogenesis, manifested as oligoasthenoteratozoospermia, and we believe RREB1 plays this role by regulating the transcription of Fshr and Wt1. RREB1 has been reported to activate Fshr transcription, and we demonstrated that the knockdown of Rreb1 caused a reduction in follicle-stimulating hormone receptor (FSHR) in the testis, which could be the cause of the increased sperm malformation. Furthermore, we confirmed that RREB1 directly activates Wt1 promoter activity, and RREB1 downregulation induced the decreased expression of Wt1 and its downstream polarity-associated genes Par6b and E-cadherin, which caused increased germ-cell death and reduced sperm number and motility. In conclusion, RREB1 is a key transcription factor essential for Sertoli cell development and function and is required for normal spermatogenesis.

Plaque modification and stabilization after drug-coated balloon angioplasty for intracranial atherosclerotic lesions.

OBJECTIVES: A drug-coated balloon (DCB) has potential applications in the treatment of intracranial atherosclerotic disease (ICAD). We aimed to evaluate changes of vessel wall features of ICAD lesions after DCB treatment by using vessel wall MRI (VWMRI). METHODS: We retrospectively included patients with symptomatic ICAD who underwent DCB angioplasty alone. The incidences of stenosis of the lumen area, vessel wall thickening, hyperintense plaques, and prominent wall enhancement were compared between the baseline and follow-up VWMRI. RESULTS: There were 29 ICAD lesions from 29 patients, of which 22 were stenosis and 7 were occlusion. The median interval between DCB treatment and follow-up VWMRI was 4.1 [3.3, 6.7] months. After DCB treatment, follow-up VWMRI showed a significant decrease in the stenosis degree of the lumen area (83% [71%, 96%] vs 15% [3%, 41%], p < 0.001). Thirty-eight percent (11/29) of the patients observed normal appearance of the target vessel wall on follow-up VWMRI. In the stenosis group, the prevalence of hyperintense plaques decreased from 66.7% (14/21) at baseline to 23.8% (5/21) at follow-up, and prominent wall enhancement decreased from 66.7% (14/21) at baseline to 19.0%(4/21) at follow-up. The incidence of hyperintense plaques (p = 0.028) and vessel wall thickening (p = 0.018) tended to decrease with follow-up time. Although not significant (p = 0.106), a similar trend was observed between the incidence of prominent wall enhancement and follow-up time. CONCLUSION: Vascular healing with plaque modification and stabilization occurred following DCB treatment of ICAD lesions. KEY POINTS: • A drug-coated balloon (DCB) has potential applications in the treatment of intracranial atherosclerotic disease (ICAD). • Vascular healing with plaque modification and stabilization occurred following DCB treatment of ICAD lesions.

Sourcing decisions with loss aversion under yield and demand randomness.

Yield and demand randomness are common in the industry, and loss aversion has been regarded as an inherent behavior for decision-makers. We combine these two factors and investigate a retailer's ordering decisions under both yield and demand randomness with loss aversion. Before the selling season, the demand is unknown and the loss-averse retailer places an order from an unreliable supplier with an uncertain yield rate. After the demand and supply from the unreliable supplier are known, the retailer can carry out emergency replenishment from a spot market during the selling season. We characterize the retailer's optimal ordering decisions in three scenarios: (1) the retailer is risk-neutral; (2) the retailer is loss-averse and has a zero reference profit; (3) the retailer is loss-averse and has a nonzero fixed reference profit (FRP). We compare the retailer's order quantities in the three scenarios and find that the order quantity of the loss-averse retailer with a zero reference profit is always lower than that of the risk-neutral retailer. However, the order quantity of the loss-averse retailer with a nonzero fixed reference profit is higher than that of the risk-neutral retailer when the salvage value is sufficiently large. Interestingly, we find that the loss-averse retailer's optimal order quantity decreases with the reference profit and increases with the loss-averse degree and the maximum fulfillment rate from the unreliable supplier under some conditions. We investigate these conditions under a uniform demand distribution. We further study the ordering quantity of the retailer with a prospect-dependent reference point (PRP) and compare the results under FRP and PRP.

Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases.

BACKGROUND: Despite the reported efficacy of osimertinib, central nervous system (CNS) progression is still frequent in EGFR-mutated NSCLC. This study aimed to reveal site-specific resistant mechanisms to osimertinib and investigate subsequent treatments for leptomeningeal metastases (LM). METHODS: EGFR-mutated NSCLC with LM who progressed on osimertinib were included. Molecular analysis of cerebrospinal fluid (CSF) at osimertinib progression was performed. Subsequent treatments of LM were collected and analyzed. RESULTS: A total of 246 patients were identified. Only those with LM as a progression site on osimertinib were included (n=81). In 58 CSF-plasma pairs, more alterations were uniquely detected in CSF (77%) than in plasma (7%). These mechanisms led to 22 patients receiving matched targeted therapy. Among them, 16 (72.7%) had a clinical response. The median overall survival was 7.2 months. For non-matched therapy (n=59), the osimertinib combination had a longer median overall survival than the regimen switch in CNS-only progression (15.3 vs. 7 months, p=0.03). Finally, serial monitoring by CSF revealed the potential evolution of LM. CONCLUSIONS: Private resistant mechanisms in CSF might match osimertinib-resistant LM for targeted therapy. Besides, continuing osimertinib with intensification strategy might prolong survival, especially for those with CNS-only progression. Prospective  exploration is needed.

PRSS55 plays an important role in the structural differentiation and energy metabolism of sperm and is required for male fertility in mice.

Orderly and stage-specifically expressed proteins are essential for spermatogenesis, and proteases play a key role in protein activation and function. The present study aimed to investigate serine protease 55 (PRSS55), which was reported to play a role in sperm-uterotubal junction (UTJ) migration and sperm-zona pellucida (ZP) binding. We found that PRSS55 was specifically expressed in testicular spermatids and epididymal spermatozoa. By constructing knockout mice targeting all transcripts of Prss55, we demonstrated that deletion of Prss55 resulted in a serious decline of male fertility, with significantly increased sperm malformation and decreased sperm motility. In Prss55-/- mice, increased structural abnormality, including deficient "9 + 2" microtubules, damaged peripheral dense fibre, and defective mitochondrial cristae, were found in sperm. In addition, sperm showed decreased expression of electron transfer chain molecules and lower ATP contents. These could be the potential causes of the astheno/teratozoospermia phenotype of the Prss55-/- mice, and provided new evidence for the previously reported impaired sperm-UTJ migration. Moreover, preliminary studies allowed us to speculate that PRSS55 might function by activating type II muscle myosin in the testis, which is involved in many processes requiring motivation and cytoskeleton translocation. Thus, PRSS55 is essential for the structural differentiation and energy metabolism of sperm, and might be a potential pathogenic factor in astheno/teratozoospermia. Our results provide an additional explanation for the male sterility of Prss55-/- mice, and further reveal the role of PRSS55.

A diagnostic model for differentiating tuberculous spondylitis from pyogenic spondylitis on computed tomography images.

OBJECTIVES: To develop and evaluate a logistics regression diagnostic model based on computer tomography (CT) features to differentiate tuberculous spondylitis (TS) from pyogenic spondylitis (PS). METHODS: Demographic and clinical features were collected from the Electronic Medical Record System. Data of bony changes seen on CT images were compared between the PS (n = 61) and TS (n = 51) groups using the chi-squared test or t test. Based on features that were identified to be significant, a diagnostic model was developed from a derivation set (two thirds) and evaluated in a validation set (one third). The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated. RESULTS: The width of bone formation around the vertebra and sequestrum was greater in the TS group. There were significant differences between the two groups in the horizontal and longitudinal location of erosion and the morphology of axial bone destruction and sagittal residual vertebra. Kyphotic deformity and overlapping vertebrae were more common in the TS group. A diagnostic model that included eight predictors was developed and simplified to include the following six predictors: width of the bone formation surrounding the vertebra, longitudinal location, axial-specific erosive morphology, specific morphology of the residual vertebra, kyphotic deformity, and overlapping vertebrae. The simplified model showed good sensitivity, specificity, and total accuracy (85.59%, 87.80%, and 86.50%, respectively); the AUC was 0.95, indicating good clinical predictive ability. CONCLUSIONS: A diagnostic model based on bone destruction and formation seen on CT images can facilitate clinical differentiation of TS from PS. KEY POINTS: • We have developed and validated a simple diagnostic model based on bone destruction and formation observed on CT images that can differentiate tuberculous spondylitis from pyogenic spondylitis. • The model includes six predictors: width of the bone formation surrounding the vertebra, longitudinal location, axial-specific erosive morphology, specific morphology of the residual vertebra, kyphotic deformity, and overlapping vertebrae. • The simplified model has good sensitivity, specificity, and total accuracy with a high AUC, indicating excellent predictive ability.

Computed tomography imaging characteristics help to differentiate pyogenic spondylitis from brucellar spondylitis.

PURPOSE: Both pyogenic spondylitis (PS) and brucellar spondylitis (BS) can cause deformities and permanent neurologic deficits without prompt diagnosis and treatment. However, differential diagnosis is challenging. The aim of this study was to compare the computed tomography (CT) imaging features of PS with those of BS. METHODS: Thirty-two patients with PS and 44 with BS were enrolled in the study. CT images were obtained in all cases. Data on bone destruction and formation, vertebral wall destruction, and osteosclerotic changes were collected and compared using the Chi-square test or t test. A P value < 0.01 was considered statistically significant. Positive predictive values (PPV) for detecting PS or BS were reported. RESULTS: Involvement of the lumbar vertebrae and multiple spinal levels was more common in the BS group than in the PS group. Bone destruction was significantly greater in the PS group than in the BS group (30.8 vs 18.0%; t = 3.920, P = 0.000), with more extensive destruction of the vertebral body (35.8 vs 12.5%, χ2 = 12.672, P = 0.002, PPV = 63.16%). In the BS group, there was more osteosclerosis around erosions (70.5 vs 43.3%, χ2 = 11.59, P = 0.001, PPV = 67.74%) and fan-shaped osteosclerosis (27.3 vs 19.4%, χ2 = 18.556, P = 0.006, PPV = 64.86%), more bone formation around the vertebra (77.2 vs 34.3%, χ2 = 33.608, P = 0.000, PPV = 76.83%), more bone formation under the anterior longitudinal ligament (63.6 vs 19.4%, χ2 = 30.133, P = 0.000, PPV = 76.09%), more longer anterior bone formation (3.55 vs 0.78 mm, t = 3.997, P = 0.000), and more anterior and closed-bone formation with local erosion (42.0 vs 9.0%, χ2 = 74.243, P = 0.000, PPV = 74.36%). CONCLUSIONS: CT images have unique advantages of revealing the morphology of erosions, osteosclerosis, and bone formation around the vertebra and help to differentiate PS from BS. These slides can be retrieved under Electronic Supplementary Material.

Deficiency of TPPP2, a factor linked to oligoasthenozoospermia, causes subfertility in male mice.

Oligoasthenozoospermia is a major cause of male infertility; however, its etiology and pathogenesis are unclear and may be associated with specific gene abnormalities. This study focused on Tppp2 (tubulin polymerization promoting protein family member 2), whose encoded protein localizes in elongating spermatids at stages IV-VIII of the seminiferous epithelial cycle in testis and in mature sperm in the epididymis. In human and mouse sperm, in vitro inhibition of TPPP2 caused significantly decreased motility and ATP content. Studies on Tppp2 knockout (KO) mice demonstrated that deletion of TPPP2 resulted in male subfertility with a significantly decreased sperm count and motility. In Tppp2-/- mice, increased irregular mitochondria lacking lamellar cristae, abnormal expression of electron transfer chain molecules, lower ATP levels, decreased mitochondrial membrane potential and increased apoptotic index were observed in sperm, which could be the potential causes for its oligoasthenozoospermia phenotype. Moreover, we identified a potential TPPP2-interactive protein, eEf1b (eukaryotic translation elongation factor 1 beta), which plays an important role in protein translation extension. Thus, TPPP2 is probably a potential pathogenic factor in oligoasthenozoospermia. Deficiency of TPPP2 might affect the translation of specific proteins, altering the structure and function of sperm mitochondria, and resulting in decreased sperm count, motility and fertility.

Irreversible fatal contrast-induced encephalopathy: a case report.

BACKGROUND: Contrast-induced encephalopathy (CIE) is a well-known complication of iodinated contrast agents during angiography and vascular interventions. It can manifest as hemiparesis, cortical blindness, speech changes, Parkinsonism, confusion, seizure, and coma. Most of the reported CIE cases have been transient and reversible. Irreversible fatal CIE cases have been rarely reported. All the fatal CIE cases reported involved the use of ionic high osmolar contrast agents. Here, we document a heretofore unreported fatal CIE after digital subtraction angiography (DSA) using iopamidol, which is a type of non-ionic monomer low osmolar contrast agent. CASE PRESENTATION: A 71-year-old woman was admitted to our Department of Neurology for tinnitus in the head. The cerebral magnetic resonance angiography (MRA) detected atherosclerotic cerebral arteries and bilateral stenosis of the middle cerebral arteries. The patient underwent DSA for further diagnostic work-up. The total amount of iopamidol used during the procedure was 110 ml. The patient experienced headache during the procedure, followed by dizziness with nausea and vomiting. Despite treatment with anti-oedema medications, her clinical status was gradually deteriorating and ended up with deep coma due to irreversible cerebral oedema which was confirmed by cerebral computed tomography (CT). Finally, the patient died 56 days after the procedure due to irreversible fatal cerebral oedema. CONCLUSIONS: This report documents that iopamidol-induced encephalopathy may not always have a benign outcome and can result in irreversible fatal cerebral oedema.

A potential high risk for fatty liver disease was found in mice generated after assisted reproductive techniques.

Abnormal gametogenesis and embryonic development may lead to poor health status of the offspring. The operations involved in the assisted reproductive technologies (ARTs) occur during the key stage of gametogenesis and early embryonic development. To assess the potential risk of abnormal lipid metabolism in the liver of adult ARTs offspring, two ARTs mice models derived from preimplantation genetic diagnosis (PGD group) and in vitro cultured embryos without biopsy (IVEM group) were constructed. And control mice were from in vivo naturally conceived (Normal group). The results showed that ARTs offspring had increased body weight and body fat content comparing to normal group. An increasing volume and amount of lipid droplets as well as lipid droplet fusion were found in the hepatocytes of ARTs mice, and a significantly increased liver TG content was also shown in the ARTs mice, which due to the increased TG synthesis and decreased TG transport in the liver. All the results indicated that the manipulations involved in ARTs might play an important role in the lipid accumulation of adult offspring. By analyzing the DNA methylation profiles of 7.5dpc embryos, we proposed that methylation deregulation of the genes related to liver development in ARTs embryos might contribute to the abnormal phenotype in the offspring. The study demonstrated that ARTs procedures have adverse effect on liver development which resulted in abnormal lipid metabolism and induced the potential high risk of fatty liver in adulthood.

Long-term effects of repeated superovulation on the uterus and mammary gland in rhesus monkeys.

PURPOSE: The aim of this study is to evaluate the effect of repeated controlled ovarian hyperstimulation (COH) on the structure and function of the uterus and mammary gland. METHODS: Three adult female rhesus monkeys were superovulated up to four times, and three spontaneously ovulating monkeys were used as controls. After a 5-year period, the uterus and mammary gland tissue samples were collected for examination of their structure and function. Further, the expression of certain tumor markers was examined to assess the cancer risk for each organ. RESULTS: Expression of Wnt7a (associated with the functional/developmental status of the uterus) was significantly decreased in the uterus of superovulated monkeys, and decreased expression of proliferation marker PCNA was found in uterine cells. Meanwhile, abnormal Golgi-derived secretory vesicles with an irregular shape were observed in the mammary glands of the superovulated monkeys, and decreased PCNA expression together with increased expression of caspase-3 (an apoptosis marker) was indicated in the mammary cells. The expression of tumor molecular markers of the uterus and mammary gland was not significantly different between the two groups. CONCLUSIONS: Repeated COH affects the expression of the uterine development-related gene several years later, and uterine cells exhibited a low proliferation status. The ultrastructure of the mammary gland epithelial cells was abnormal, and the cells exhibited both low proliferation and high apoptosis status. Cancer risk for these organs was not observed. Given that primates are the closest relatives of humans, the results obtained from this study provide more intuitive information for optimization of clinical COH.

Patellar non-eversion in primary TKA reduces the complication rate.

PURPOSE: This study was designed to evaluate the isolated benefits of patellar non-eversion in total knee arthroplasty (TKA). METHODS: This systematic review and meta-analysis was conducted following the PRISMA statement. A comprehensive search of the MEDLINE/PubMed, Cochrane Library, and Embase databases was performed in August 2014. Randomized controlled trials (RCTs) that considered the handling of the patella as the only variable were included in our review. Quality assessment of RCTs was performed according to the CONSORT statement. The meta-analysis was performed to pool the available data for some parameters. RESULTS: The searches of the MEDLINE/PubMed, Cochrane Library, and Embase databases yielded 10 RCTs, and five RCTs were selected for inclusion in the review. This results suggested that tourniquet time [mean difference (MD) = -5.69; 95% confidence interval (CI) -9.77 to -1.60], length of hospitalization (MD = 1.24; 95% CI 0.54-1.94) and the incidence of complications [odds ratio (OR) = 2.23; 95% CI 1.12-4.44] differed significantly between the eversion group and non-eversion group. No differences in postoperative pain, alignment, and the Insall-Salvati ratio were observed between the groups. CONCLUSION: The patellar non-eversion approach offers a shorter length of hospitalization and lower incidence of postoperative complications, but requires more operative time. The merits of patellar non-eversion for recovery of knee function remain controversial, and more high-quality RCTs are needed to draw clear conclusions. In general, avoidance of patellar eversion is recommended when exposing the knee joint for TKA.

Cross-reactivity between human cytomegalovirus peptide 981-1003 and myelin oligodendroglia glycoprotein peptide 35-55 in experimental autoimmune encephalomyelitis in Lewis rats.

Multiple sclerosis (MS) has been documented to have various clinical and pathological presentations. However the underlying mechanisms remain unknown. Viral infections may play a certain role in the etiopathogenesis of MS. This study was designed to explore whether different phospholipid peptides and viral mimic peptides induce antigen specific lesion in experimental autoimmune encephalomyelitis (EAE), an MS animal model. In the present study, Lewis rats immunized with myelin basic protein (MBP) 82-99 or MBP68-86 exhibited clinical signs of EAE and inflammatory infiltrates throughout CNS. Immunization with myelin oligodendroglia glycoprotein (MOG) 35-55 also induced inflammatory infiltrates in spinal cords. Although cytomegalovirus (CMV) 981-1003 failed to induce clinical signs of EAE and inflammatory infiltrates, immunological examination revealed that CMV981-1003 cross-reacted with serum from rats immunized with MOG35-55, and vice versa. Further, MOG35-55 triggered CMV981-1003 specific lymphocytes recruitment in spleen. Together these, this study provides certain evidences for various pathological manifestations of EAE and the linkage of viral mimic peptides with phospholipid peptides. Molecular mimicry may be an explanation the pathogenesis of MS.

Efficacy and Safety of Tirofiban Before Stenting for Symptomatic Intracranial Atherosclerotic Stenosis: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Acute stent thrombosis (AST) is not uncommon and even catastrophic during intracranial stenting angioplasty in patients with symptomatic high-grade intracranial atherosclerotic stenosis (ICAS). The purpose of this study was to investigate whether adjuvant intravenous tirofiban before stenting could reduce the risk of AST and periprocedural ischemic stroke in patients receiving stent angioplasty for symptomatic ICAS. METHODS: A prospective, multicenter, open-label, randomized clinical trial was conducted from September 9, 2020, to February 18, 2022, at 10 medical centers in China. Patients intended to receive stent angioplasty for symptomatic high-grade ICAS were enrolled and randomly assigned to receive intravenous tirofiban or not before stenting in a 1:1 ratio. The primary outcomes included the incidence of AST within 30 minutes after stenting, periprocedural new-onset ischemic stroke, and symptomatic intracranial hemorrhage. The outcomes were analyzed using logistic regression analysis to obtain an odds ratio and 95% confidence interval. RESULTS: A total of 200 participants (122 men [61.0%]; median [interquartile ranges] age, 57 [52-66] years) were included in the analysis, with 100 participants randomly assigned to the tirofiban group and 100 participants to the control (no tirofiban) group. The AST incidence was lower in the tirofiban group than that in the control group (4.0% vs 14.0%; adjusted odds ratio, 0.25; 95% CI 0.08-0.82; p = 0.02). No significant difference was observed in the incidence of periprocedural ischemic stroke (7.0% vs 8.0%; p = 0.98) or symptomatic intracranial hemorrhage between the 2 groups. DISCUSSION: This study suggests that adjuvant intravenous tirofiban before stenting could lower the risk of AST during stent angioplasty in patients with symptomatic high-grade ICAS. TRIAL REGISTRATION INFORMATION: URL: chictr.org.cn; Unique identifier: ChiCTR2000031935. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with symptomatic high-grade ICAS, pretreatment with tirofiban decreases the incidence of acute stent thrombosis. This study is Class II due to the unequal distribution of involved arteries between the 2 groups.

Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC.

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1_M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1_M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs.

Drug-Coated Balloon Treatment for Delayed Recanalization of Symptomatic Intracranial Artery Occlusion.

Patients with medically refractory non-acute intracranial artery occlusion (ICAO) are difficult to treat. The optimal intervention for these patients is not known. We evaluated the feasibility and safety of drug-coated balloon (DCB) treatment for non-acute ICAO. Consecutive patients with symptomatic medically refractory atherosclerotic non-acute ICAO from January 2015 to July 2021 who underwent DCB treatment were retrospectively analyzed. The rates of stroke, transient ischemic attack, and death within 30 days and the follow-up results were evaluated. A total of 148 patients were enrolled in this study. The 30-day rate of stroke, transient ischemic attack, and death was 8.8%. During the 25.8 ± 15.8-month clinical follow-up period, the rate of outcome beyond 30 days was 4.7%. In the 66 patients with vessel imaging follow-up, 13.6% (9/66) had restenosis. The present study suggests that DCB dilatation is a feasible and effective alternative in carefully selected patients with symptomatic non-acute ICAO.

Emerging evidence and treatment paradigm of non-small cell lung cancer.

Research on biomarker-driven therapy and immune check-point blockade in non-small cell lung cancer (NSCLC) is rapidly evolving. The width and depth of clinical trials have also dramatically improved in an unprecedented speed. The personalized treatment paradigm evolved every year. In this review, we summarize the promising agents that have shifted the treatment paradigm for NSCLC patients across all stages, including targeted therapy and immunotherapy using checkpoint inhibitors. Based on recent evidence, we propose treatment algorithms for NSCLC and propose several unsolved clinical issues, which are being explored in ongoing clinical trials. The results of these trials are likely to impact future clinical practice.