CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents.

Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFß, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.

The complete chloroplast genome sequences of six Hylotelephium species: Comparative genomic analysis and phylogenetic relationships.

To evaluate the phylogenetic relationships between Hylotelephium and Orostachys, and to provide important information for further studies, we analyzed the complete chloroplast genomes of six Hylotelephium species and compared the sequences to those of published chloroplast genomes of congeneric species and species of the closely related genus, Orostachys. The total chloroplast genome length of nineteen species, including the six Hylotelephium species analyzed in this study and the thirteen Hylotelephium and Orostachys species analyzed in previous studies, ranged from 150,369 bp (O. minuta) to 151,739 bp (H. spectabile). Their overall GC contents were almost identical (37.7-37.8%). The chloroplast genomes of the nineteen species contained 113 unique genes comprising 79 protein-coding genes (PCGs), 30 transfer RNA genes (tRNAs), and four ribosomal RNA genes (rRNAs). Among the annotated genes, fourteen genes contained one intron, and two genes contained two introns. The chloroplast genomes of the nineteen Hylotelephium and Orostachys species had identical structures. Additionally, the large single copy (LSC), inverted repeat (IR), and small single copy (SSC) junction regions were conserved in the Hylotelephium and Orostachys species. The nucleotide diversity between the Hylotelephium chloroplast genomes was extremely low in all regions, and only one region showed a high Pi value (>0.03). In all nineteen chloroplast genomes, six regions had a high Pi value (>0.03). The phylogenetic analysis showed that the genus delimitation could not be clearly observed even in this study because Hylotelephium formed a paraphyly with subsect. Orostachys of the genus Orostachys. Additionally, the data supported the taxonomic position of Sedum taqeutii, which was treated as a synonym for H. viridescens in previous studies, as an independent taxon.

The effects of etomidate on expression of high mobility group box 1 via the nuclear factor kappa B pathway in rat model of sepsis.

Etomidate is an anesthetic agent used in hemodynamically unstable patients, but its use has been controversial in septic patients. The response of high-mobility group box 1 (HMGB1), a late-phase lethal cytokine in sepsis, to etomidate has not been reported. This study investigated the effects of etomidate on the expression and release of HMGB1 and the underlying mechanism using a cecal ligation and puncture (CLP) model. Thirty-six male Sprague-Dawley rats were divided into sham, CLP, and Etomi groups. Sepsis was induced in the CLP and Etomi groups, and intravenous etomidate (4 mg/kg) was infused for 40 min immediately after operation in the Etomi group. Serum creatinine, alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and HMGB1 levels were measured 6 and 24 hours after surgery. Activation of nuclear factor (NF)-ĸB and HMGB1 mRNA expression in the liver, lung, kidney, and ileum tissues were measured, and immunohistochemical staining of HMGB1 was implemented. Increases of the TNF-α level 6 h after CLP and ALT and IL-6 levels 24 h after CLP were significantly inhibited by etomidate treatment. Etomidate treatment also significantly attenuated the increase in serum HMGB1 level at 6 and 24 h after CLP and suppressed the NF-ĸB and HMGB1 mRNA in multiple organs 24 h after CLP. Immunohistochemical staining also revealed that etomidate treatment inhibited HMGB1 expression. Etomidate inhibited the systemic release of HMGB1 and its expression in various organs. The mechanism may be associated with the inhibitory effects of etomidate on pro-inflammatory cytokine release and NF-ĸB activity.

Comparison of the efficacy of erector spinae plane block according to the difference in bupivacaine concentrations for analgesia after laparoscopic cholecystectomy: a retrospective study.

BACKGROUND: Laparoscopic cholecystectomy (LC) is a noninvasive surgery, but postoperative pain is a major problem. Studies have indicated that erector spinae plane block (ESPB) has an analgesic effect after LC. We aimed to compare the efficacy of different ESPB anesthetic concentrations in pain control in patients with LC. METHODS: This retrospective study included patients aged 20 to 75 years scheduled for LC with the American Society of Anesthesiologists physical status classification I or II. ESPB was administered using 0.375% bupivacaine in group 1 and 0.25% in group 2. Both groups received general anesthesia. Postoperative tramadol consumption and pain scores were compared and intraoperative and postoperative fentanyl requirements in the postanesthesia care unit (PACU) were measured. RESULTS: Eighty-five patients were included in this analysis. Tramadol consumption in the first 12 hours, second 12 hours, and total 24 hours was similar between groups (p>0.05). The differences between postoperative numeric rating scale (NRS) scores at rest did not differ significantly. The postoperative NRS scores upon bodily movement were not statistically different between the two groups, except at 12 hours. The mean intraoperative and postoperative fentanyl requirements in the PACU were similar. The difference in the requirement for rescue analgesics was not statistically significant (p=0.788). CONCLUSION: Ultrasound-guided ESPB performed with different bupivacaine concentrations was effective in both groups for LC analgesia, with similar opioid consumption. A lower concentration of local anesthetic can be helpful for the safety of regional anesthesia and is recommended for the analgesic effect of ESPB in LC.

The complete chloroplast genome sequences of eight Orostachys species: Comparative analysis and assessment of phylogenetic relationships.

We analyzed the complete chloroplast genomes of eight Orostachys species and compared the sequences to those of published chloroplast genomes of the congeneric and closely related genera, Meterostachys and Hylotelephium. The total chloroplast genome length of thirteen species, including the eight species analyzed in this study and the five species analyzed in previous studies, ranged from 149,860 (M. sikokianus) to 151,707 bp (H. verticillatum). The overall GC contents of the genomes were almost identical (37.6 to 37.8%). The thirteen chloroplast genomes each contained 113 unique genes comprising 79 protein-coding genes, 30 tRNA genes, and four rRNA genes. Among the annotated genes, sixteen genes contained one or two introns. Although the genome structures of all Orostachys and Hylotelephium species were identical, Meterostachys differed in structure due to a relatively large gene block (trnS-GCU-trnS-GGA) inversion. The nucleotide diversity among the subsect. Orostachys chloroplast genomes was extremely low in all regions, and among the subsect. Appendiculatae, genus Orostachys, and all thirteen chloroplast genomes showed high values of Pi (>0.03) in one, five, or three regions. The phylogenetic analysis showed that Orostachys formed polyphyly, and subsect. Orostachys and Appendiculatae were clustered with Hylotelephium and Meterostachys, respectively, supporting the conclusion that each subsection should be considered as an independent genus. Furthermore, the data supported the taxonomic position of O. margaritifolia and O. iwarenge f. magnus, which were treated as synonyms for O. iwarenge in a previous study, as independent taxa. Our results suggested that O. ramosa and O. japonica f. polycephala were individual variations of O. malacophylla and O. japonica, respectively. The exact taxonomic position of O. latielliptica and the phylogenetic relationship among the three species, O. chongsunensis, O. malacophylla and O. ramosa, should be a topic of future study.

Successful management of a tracheomalacia patient with active endotracheal bleeding due to intraoperative innominate artery injury: A case report.

RATIONALE: Intraoperative innominate artery injury is life-threatening in tracheomalacia patients with prolonged tracheostomy. Anesthetic management is challenging in cases with massive hemorrhage into the endotracheal tube. We report a case in which we successfully managed a tracheomalacia patient with acute endotracheal bleeding due to innominate artery injury. PATIENT CONCERNS: A 24-year-old patient with tracheomalacia was scheduled to undergo exploratory thoracotomy for the treatment of intermittent bleeding at the tracheostomy site. During exploration, sudden active bleeding due to innominate artery injury was observed in the endotracheal lumen. DIAGNOSES: The patient was diagnosed with tracheomalacia. INTERVENTIONS: We immediately used the bronchoscope to place the tip of the endotracheal tube at the bleeding site and hyperinflated the cuff. OUTCOMES: The ballooned cuff compressed the active bleeding site, so no additional bleeding was detected by bronchoscopy, and no additional massive bleeding was observed in the operative field. LESSONS: Immediate and appropriate overinflation of the endotracheal tube cuff by an anesthesiologist may provide improved surgical field visibility and time for critical surgical procedures in cases of massive hemorrhaging.

Early psychiatric referral after attempted suicide helps prevent suicide reattempts: A longitudinal national cohort study in South Korea.

Introduction: Although people who attempted suicide tend to repeat suicide attempts, there is a lack of evidence on the association between psychiatric service factors and suicide reattempt among them. Methods: We used a nationwide, population-based medical record database of South Korea to investigate the use of psychiatric services before and after the index suicide attempt and the association between psychiatric service factors after the index suicide attempt with the risk of suicide reattempt. Results: Among 5,874 people who had attempted suicide, the all-cause mortality within 3 months after the suicide attempt was 11.6%. Among all subjects who attempted suicide, 30.6% of them had used psychiatric services within 6 months before the suicide attempt; 43.7% of them had used psychiatric services within 3 months after the suicide attempt. Among individuals who had visited clinics following attempted suicide, the cumulative incidence of suicide reattempt over a mean follow-up period of 5.1 years was 3.4%. About half of suicide reattempts occurred within 1 year after the index suicide attempt. Referral to psychiatric services within 7 days was associated with a decreased risk of suicide reattempt (adjusted hazard ratio, 0.51; 95% confidence intervals, 0.29-0.89). Conclusion: An early psychiatric referral within 1 week after a suicide attempt was associated with a decreased risk of suicide reattempt.

Effects of Positive End-Expiratory Pressure on Intraocular Pressure during One-Lung Ventilation in the Lateral Decubitus Position-A Prospective Randomized Trial.

Background and Objectives: The effect of positive end-expiratory pressure (PEEP) on intraocular pressure (IOP) is debatable. There have been no studies investigating the effects of PEEP on IOP during one-lung ventilation (OLV). We aimed to investigate the effects of PEEP on IOP in patients undergoing OLV for video-assisted thoracoscopic surgery (VATs). Materials and Methods: Fifty-two patients undergoing VATs were divided into a zero-PEEP (ZEEP) and a 6 cmH2O of PEEP (PEEP) groups. IOP, ocular perfusion pressure (OPP), and respiratory and hemodynamic parameters were measured before induction (T1), immediately following endotracheal intubation (T2), 30 min (T3) and 60 min (T4) after a position change to the lateral decubitus position (LDP) and OLV, and 10 min following two-lung ventilation near the end of the surgery (T5). Results: There was no significant difference in IOP and OPP between the two groups. The IOP of the dependent eye was significantly higher than that of the non-dependent eye during LDP in both groups. Peak inspiratory pressure was significantly higher in the PEEP group than in the ZEEP group at T3-T5. Dynamic compliance was significantly higher in the PEEP group than in the ZEEP group at T2-T5. The ratio of arterial oxygen partial pressure to fractional inspired oxygen was significantly higher in the PEEP group than in the ZEEP group at T4. Conclusions: Applying 6 cmH2O of PEEP did not increase IOP but enhanced dynamic compliance and oxygenation during OLV. These results suggest that 6 cmH2O of PEEP can be safely applied during OLV in LDP.

Drug Utilization Pattern of Oral Anticoagulants in Patients with Atrial Fibrillation: A Nationwide Population-Based Study in Korea.

INTRODUCTION: Treatment persistence for anticoagulant therapy is important in preventing thromboembolism in nonvalvular atrial fibrillation (NVAF) patients. Understanding drug utilization pattern and treatment changes in oral anticoagulant (OAC) users may facilite better NVAF management. Thus, our study aimed to examine OAC treatment patterns preceding events leading to switch or discontinuation and medication adherence in Korean NVAF patients. METHODS: We conducted a drug utilization study on all Korean patients with atrial fibrillation (AF) newly prescribed OACs between July 2015 and November 2016 using the national claims data. We assessed treatment changes such as switching and discontinuation from index OAC and relevant events preceding the change and examined patient characteristics as predictors of changes that occurred among OAC users. Medication adherence was compared among OAC users by calculating the medication possession ratio (MPR). RESULTS: A total of 48,389 NVAF patients were identified who initiated OACs within the study period. Most initiated nonvitamin K antagonist oral anticoagulants (NOACs) (22% apixaban, 24% dabigatran, 37% rivaroxaban), and 18% initiated warfarin. The frequency of switch to another OAC was 8.8% for apixaban, 16.1% for dabigatran, 6.6% for rivaroxaban, and 19.1% for warfarin. The frequency of discontinuation was lower for apixaban (22.9%), dabigatran (26.3%), and rivaroxaban (25.7%) than warfarin (31.6%). Compared to warfarin, NOAC users were less likely to switch treatment. Thromboembolic event was the most common clinical event preceding switch from warfarin to NOAC and from NOAC to warfarin. Discontinuation of OAC was often preceded by a bleeding event. Patients who initiated apixaban showed significantly higher mean MPR compared to those on dabigatran and warfarin. CONCLUSION: In real-world practice in Korea, we have observed treatment change to be common in OAC users. Our results indicate better medication adherence with NOACs than with warfarin. (ClinicalTrials.gov registration number NCT03572972).

Anticoagulants are drugs that thin blood with the purpose of preventing thromboembolic disease (e.g., stroke), which is a disease occurring when a blood clot forms or blocks vessel. Maintaining treatment for anticoagulation is important to prevent stroke in atrial fibrillation (AF) patients. To understand current drug usage pattern and treatment changes related to oral anticoagulants (OAC) we examined OAC treatment patterns and preceding events that led to drug switch or stop and medication maintenance by Korean AF patients.The study was conducted by utilizing the Korean national claims data from July 2015 to November 2016. All AF patients who newly started taking OAC were included in the analysis. In total, 48,389 patients were identified with most (83%) taking nonvitamin K antagonist oral anticoagulants (NOAC), which are newer generation blood thinners, including apixaban, dabigatran, and rivaroxaban, and 18% taking warfarin, the conventional blood thinner. Compared to warfarin, NOAC users were less likely to switch to other treatment. NOAC users discontinued the treatment less frequently than warfarin users. Thromboembolic events commonly preceded switch between OACs. Patients who stopped taking OACs were often confronted with a bleeding event before stopping treatment. Apixaban takers showed higher treatment persistence compared to dabigatran or warfarin users. In this study, we determined that treatment change is common in OAC-using patients. The results suggest that NOAC users may better adhere to treatment than warfarin users.

Drug repositioning of polaprezinc for bone fracture healing.

Fractures and related complications are a common challenge in the field of skeletal tissue engineering. Vitamin D and calcium are the only broadly available medications for fracture healing, while zinc has been recognized as a nutritional supplement for healthy bones. Here, we aimed to use polaprezinc, an anti-ulcer drug and a chelate form of zinc and L-carnosine, as a supplement for fracture healing. Polaprezinc induced upregulation of osteogenesis-related genes and enhanced the osteogenic potential of human bone marrow-derived mesenchymal stem cells and osteoclast differentiation potential of mouse bone marrow-derived monocytes. In mouse experimental models with bone fractures, oral administration of polaprezinc accelerated fracture healing and maintained a high number of both osteoblasts and osteoclasts in the fracture areas. Collectively, polaprezinc promotes the fracture healing process efficiently by enhancing the activity of both osteoblasts and osteoclasts. Therefore, we suggest that drug repositioning of polaprezinc would be helpful for patients with fractures.

Characterization of the chloroplast genome of Meterostachys sikokianus (Makino) Nakai (Crassulaceae) and its phylogenetic analysis.

Meterostachys is a monotypic genus of Crassulaceae, though its phylogenetic position remains unclear. Here, we report the complete chloroplast (cp) genome sequence of Meterostachys sikokianus using the Illumina high-throughput sequencing approach. The cp genome was 149,860 bp in length, containing a large single copy (LSC) of 82,293 bp and a small single copy (SSC) of 16,879 bp, which were separated by a pair of 25,344 bp inverted repeats (IRs). The overall GC content of the M. sikokianus cp genome was 37.6%. A total of 113 unique genes were annotated, consisting of 79 protein coding genes (PCGs), 30 transfer RNAs (tRNAs), and four ribosomal RNAs (rRNAs). Among these genes, eighteen contained one or two introns. A maximum-likelihood (ML) phylogenetic analysis based on 30 accessions of Crassulaceae showed that M. sikokianus was most closely related to Orostachys japonica and Orostachys fimbriata.

Ultrasound-guided pulsed radiofrequency of the saphenous nerve in a complex regional pain syndrome patient with lower limb pain.

Complex regional pain syndrome is a painful and debilitating syndrome in which the patient presents with disabling pain, edema, and/or vasomotor or sudomotor abnormalities. The mechanism is complex and not well understood. There is no definitive treatment for the condition yet. Pulsed radiofrequency is a minimally invasive, minimal destructive, and safe intervention. It can be used for neuropathic pain. A 40-year-old man with complex regional pain syndrome complained of intractable pain of the lower limb secondary to injury to the saphenous nerve due to a third-degree burn. Conventional medications, epidural block, and sympathetic nerve block provided temporary relief. We performed pulsed radiofrequency of the saphenous nerve for the management of lower limb pain, and the symptoms remained under control at 3 months. To the best of our knowledge, this is the first application of ultrasound-guided pulsed radiofrequency of the saphenous nerve for the management of complex regional pain syndrome.

Population Genomics Study and Implications for the Conservation of Zabelia tyaihyonii Based on Genotyping-By-Sequencing.

Zabelia tyaihyonii (Nakai) Hisauti and H. Hara is a perennial shrub endemic to Republic of Korea that grows naturally in only a very limited region of the dolomite areas of Gangwon-do and Chungcheongbuk-do Provinces in the Republic of Korea. Given its geographical characteristics, it is more vulnerable than more widely distributed species. Despite the need for comprehensive information to support conservation, population genetic information for this species is very scarce. In this study, we analyzed the genetic diversity and population structure of 94 individuals from six populations of Z. tyaihyonii using a genotyping-by-sequencing (GBS) approach to provide important information for proper conservation and management. Our results, based on 3088 single nucleotide polymorphisms (SNPs), showed a mean expected heterozygosity (He) of 0.233, no sign of within-population inbreeding (GIS that was close to or even below zero in all populations), and a high level of genetic differentiation (FST = 0.170). Analysis of molecular variance (AMOVA) indicated that the principal molecular variance existed within populations (84.5%) rather than among populations (17.0%). We suggested that six management units were proposed for conservation considering Bayesian structure analysis and phylogenetic analysis, and given the various current situations faced by Z. tyaihyonii, it is believed that not only the in situ conservation but also the ex situ conservation should be considered.

The complete chloroplast genome sequence of Adenophora kayasanensis Kitam. (Campanulaceae), an endemic to Korea.

Adenophora kayasanensis Kitam., belonging to the family Campanulaceae, is an important species because it is used as a type of herbal medicine and is endemic to Korea. Here, we report the complete chloroplast genome sequence of A. kayasanensis as determine by means of Illumina high-throughput sequencing. The complete cp genome was 169,433 bp in length, containing a large single copy (LSC) of 123,110 bp and a small single copy (SSC) of 8619 bp, which were separated by a pair of 29,085 bp inverted repeats (IRs). A total of 112 unique genes were annotated, consisting of 78 protein-coding genes, 30 tRNA genes, and four rRNA genes. The overall GC content is 37.7%. A maximum-likelihood (ML) tree based on 76 protein-coding genes indicated that A. kayasanensis is closely related to Adenophora racemosa. This newly sequenced chloroplast genome will be useful to those engaged in research on the phylogenetic position of A. kayasanensis and the evolution of the genus Adenophora.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation: A nationwide, population-based study in Korea.

BACKGROUND: To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF), this retrospective study was conducted using the Korean Health Insurance Review & Assessment Service (HIRA) claims database. METHODS: Patients with AF who initiated NOACs (apixaban, dabigatran, and rivaroxaban) from July 1, 2015 to November 30, 2016 were included. We applied inverse probability of treatment weighting (IPTW) method using propensity score to make weighted populations having similar characteristics between groups. Hazard ratio (HR) of S/SE and MB were estimated by Cox proportional hazard model. RESULTS: Of the 39 783 patients with AF, 10 564; 11 418; and 17 801 used apixaban, dabigatran, and rivaroxaban, respectively. The mean CHA2DS2-VASc and HAS-BLED scores were 4.59 ~ 4.69 and 3.58 ~ 3.62, respectively, among all patients after applying IPTW. For S/SE, there were no significant differences between NOACs (HR [95% confidence interval (CI)]): apixaban vs dabigatran (0.99 [0.87-1.13]), apixaban vs rivaroxaban (0.95 [0.84-1.07]), and dabigatran vs rivaroxaban (0.96 [0.85-1.08]). For MB (HR [95% CI]), both apixaban (0.77 [0.68-0.86]) and dabigatran (0.88 [0.79-0.98]) had a significantly lower risk compared with rivaroxaban. Apixaban also had a significantly lower risk of MB compared with dabigatran (0.87 [0.76-0.99]). CONCLUSIONS: In real-world practice among Korean AF patients with relatively high risk of stroke and bleeding, there were no significant differences in the risk of S/SE between all NOAC comparisons. Apixaban was associated with lower risk of MB than dabigatran and rivaroxaban.

Treatment Pattern of Antithrombotic Therapy over Time after Percutaneous Coronary Intervention in Patients with Atrial Fibrillation in Real-World Practice in Korea.

We examined antithrombotic treatment patterns with clinical characteristics and therapy changes over time in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). Using the Health Insurance Review and Assessment service claims database (01JAN2007-30NOV2016) in Korea, we included adult patients with AF and PCI: (1) who underwent PCI with stenting between 01JAN2008 and 30NOV2016; (2) with ≥1 claim for AF (ICD code: I48) (3) with antithrombotics 1 day prior to or at the date of PCI; and (4) with CHADS2-VASc of ≥2. In this study, 7749 patients with AF who underwent PCI, triple therapy, dual therapy, dual antiplatelet therapy (DAPT), and single antiplatelet therapy were prescribed to 24.6%, 3.4%, 60.8%, and 11.0%, respectively. In the triple therapy group, 23.1% persisted with triple therapy for 12 months, whereas the remaining patients switched to a different therapy. In the entire cohort and several subgroups, the median treatment duration of triple therapy was 55-87 days. DAPT use for 12 months was the most common treatment pattern (62.6%) in the DAPT group (median treatment duration, 324-345 days). A significant discrepancy exists between the current guidelines and real-world practice regarding antithrombotic treatment with PCI for patients with AF. Appropriate use of anticoagulants should be emphasized.

Impact of Reduced-Dose Nonvitamin K Antagonist Oral Anticoagulants on Outcomes Compared to Warfarin in Korean Patients with Atrial Fibrillation: A Nationwide Population-Based Study.

Reduced-dose nonvitamin K antagonist oral anticoagulants (NOACs) are commonly prescribed to Asian patients with nonvalvular atrial fibrillation (NVAF). We aimed to compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between patients treated with reduced-dose NOACs and those treated with warfarin, using the claims database in Korea. Patients with NVAF newly initiated on oral anticoagulants (OACs; apixaban, dabigatran, rivaroxaban, and warfarin) between 1 July 2015 and 30 November 2016 were included. Among all patients with NVAF treated with OACs, 5249, 6033, 7602, and 8648 patients were treated with reduced-dose apixaban, dabigatran, rivaroxaban, and warfarin, respectively. Patients treated with reduced-dose NOACs were older and had higher CHA2DS2-VASc and HAS-BLED scores than those treated with warfarin. Compared to warfarin, all reduced-dose NOACs showed significantly lower risk of S/SE (hazard ratios (95% confidence interval), 0.63 (0.52-0.75) for apixaban; 0.51 (0.42-0.61) for dabigatran; and 0.67 (0.57-0.79) for rivaroxaban) and MB (0.54 (0.45-0.65) for apixaban; 0.58 (0.49-0.69) for dabigatran; 0.73 (0.63-0.85) for rivaroxaban). In the real-world practice among Asians with NVAF, all reduced-dose NOACs were associated with a significantly lower risk of S/SE and MB compared to those of warfarin.

Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer.

Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8+ T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8+ T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.