Safety and efficacy of Yaobitong capsules for lumbar disc herniation: A multicenter, randomized, double-blinded, parallel, positive-controlled clinical trial.

BACKGROUND: Lumbar disc herniation (LDH) is one of the most common diseases and is a global medical and socioeconomic problem characterized by leg or back pain, weakness in the lower extremities and paresthesia. OBJECTIVES: A multicenter, randomized, double-blinded, parallel, positive-controlled clinical trial was conducted to evaluate the efficacy and safety of Yaobitong capsules (YBT) for LDH. MATERIAL AND METHODS: Patients (n = 479) were recruited and randomized into YBT and Jingyaokang capsule (JYK) groups (the positive control), and received YBT or JYK at a dose of 3 capsules 3 times per day after a meal for 30 days. The primary efficacy outcome was the Oswestry Disability Index (ODI), with the visual analogue scale (VAS) used as the secondary efficacy outcome. The adverse events and adverse reactions were also evaluated. RESULTS: There was no significant difference in baseline characteristics between YBT (n = 358) and JYK groups (n = 120), and no difference was observed between groups for mean ODI score at day 0 (p = 0.064) or day 7 (p = 0.196), but there were differences at days 14, 21 and 30 (p < 0.001). The YBT showed more decline from baseline, and the decreased ODI score was substantially different from JYK (p < 0.001). The differences in decreased VAS scores between YBT and JYK were also significant at each time point (days 7, 14, 21, and 30), with better scores in the YBT group than in the JYK group (p < 0.001). In terms of safety, there was no obvious disparity in adverse events or adverse reactions between the 2 groups (p > 0.05). CONCLUSIONS: Yaobitong was better than JYK for LDH treatment, with no significant difference in safety. The study suggests that YBT is a promising and effective treatment for LDH.

Comparative single-cell RNA sequencing analysis of immune response to inactivated vaccine and natural SARS-CoV-2 infection.

Uncovering the immune response to an inactivated SARS-CoV-2 vaccine (In-Vac) and natural infection is crucial for comprehending COVID-19 immunology. Here we conducted an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from serial peripheral blood mononuclear cell (PBMC) samples derived from 12 individuals receiving In-Vac compared with those from COVID-19 patients. Our study reveals that In-Vac induces subtle immunological changes in PBMC, including cell proportions and transcriptomes, compared with profound changes for natural infection. In-Vac modestly upregulates IFN-α but downregulates NF-κB pathways, while natural infection triggers hyperactive IFN-α and NF-κB pathways. Both In-Vac and natural infection alter T/B cell receptor repertoires, but COVID-19 has more significant change in preferential VJ gene, indicating a vigorous immune response. Our study reveals distinct patterns of cellular communications, including a selective activation of IL-15RA/IL-15 receptor pathway after In-Vac boost, suggesting its potential role in enhancing In-Vac-induced immunity. Collectively, our study illuminates multifaceted immune responses to In-Vac and natural infection, providing insights for optimizing SARS-CoV-2 vaccine efficacy.

Narrow linewidth laser based on a sidewall grating active distributed Bragg reflector.

We demonstrated a narrow linewidth semiconductor laser based on a deep-etched sidewall grating active distributed Bragg reflector (SG-ADBR). The coupling coefficients and reflectance were numerically simulated for deep-etched fifth-order SG-ADBR, and a reflectance of 0.86 with a bandwidth of 1.04 nm was obtained by the finite element method for a 500-period SG-ADBR. Then the fifth-order SG-ADBR lasers were fabricated using projection i-line lithography processes. Single-mode lasing at 1537.9 nm was obtained with a high side-mode suppression ratio (SMSR) of 65 dB, and a continuous tuning range of 10.3 nm was verified with SMSRs greater than 53 dB. Furthermore, the frequency noise power spectral density was characterized, from which a Lorentzian linewidth of 288 kHz was obtained.

MoS2/ReS2 Hollow Heterojunction for Enhanced Aqueous Zinc-Ion Storage Performance.

The research of cathode materials for water-based zinc ion batteries (ZIBs) is very hot because the current mainstream electrode makes it difficult to meet the requirements of high specific discharge capacity and maintain a stable structure in the electrochemical process. In this work, the cathode properties are adjusted by the modification idea of morphology regulation and heterojunction construction. The simple hydrothermal method is used to prepare the hollow bimetallic heterojunction nanospheres, and their electrochemical properties as cathode materials for ZIBs are studied for the first time. Herein, the optimized cathode delivers high-rate performance and long-term cycling stability (∼98.9% Coulombic efficiency at 0.1 A g-1 after 200 cycles). The results indicate that the hollow bimetallic heterojunction nanospheres can support the material structure and provide a wide Zn2+ migration channel. The excellent performance is because hollow heterojunction bimetallic sulfides can provide abundant catalytic active sites, improve the mobility of electrons, and enhance the battery performance fundamentally. Therefore, we firmly believe that the combination of the different modification ideas can coordinate to adjust the electrode performance of ZIBs, enriching the electrode types and expanding the energy system application range.

RCOR1 is targeted by miR-23b-3p to modulate growth, colony formation, migration, and invasion of prostate cancer cells.

OBJECTIVES: Prostate cancer holds the second-highest incidence rate among all male malignancies, with a noticeable scarcity of effective treatment approaches. The REST Corepressor 1 (RCOR1) protein exhibits elevated expression across various tumors, acting as an oncogene. Nevertheless, its functions and mechanisms in prostate cancer have yet to be documented. While miR-23 demonstrates reduced expression in prostate cancer, the downstream genes it regulates remain unclear. METHODS: RT-qPCR and Western blotting assays were utilized to elucidate the mRNA and protein levels of miR-23b-3p and RCOR1. The luciferase reporter assay was employed to unveil the targeting relationship between miR-23b-3p and RCOR1. Additionally, a CCK-8 assay demonstrated cell growth, while colony formation and Transwell assays were performed to observe clone formation, cell migration, and invasion. RESULTS: In this study, we observed substantial mRNA and protein levels of RCOR1 in prostate cancer cells such as DU145, PC3, and LNCap. RCOR1 overexpression enhanced the growth, colony formation, migration, and invasion of prostate cancer cells, whereas genetic silencing of RCOR1 suppressed these processes. Bioinformatics analysis identified miR-23b-3p as a potential regulator of RCOR1, and luciferase assays validated RCOR1 as a downstream target of miR-23b-3p. Increasing miR-23b-3p mimics diminished RCOR1's mRNA and protein levels, while raising miR-23b-3p levels boosted RCOR1's expression. Moreover, the stimulatory impact of RCOR1 on prostate cancer cell development could be countered by elevating miR-23b-3p mimics. CONCLUSION: In summary, our findings confirm that RCOR1 is indeed under the influence of miR-23, shedding light on the miR-23/RCOR1 pathway's role in prostate cancer development. This offers novel theoretical and experimental support for comprehending the underlying mechanisms of prostate cancer and for targeted therapeutic avenues.

Regular use of aspirin and statins reduces the risk of cancer in individuals with systemic inflammatory diseases.

Aspirin has shown potential for cancer prevention, but a recent large randomized controlled trial found no evidence for a reduction in cancer risk. Given the anti-inflammatory effects of aspirin, systemic inflammatory diseases (SIDs), such as osteoporosis, cardiovascular diseases, and metabolic diseases, could potentially modify the aspirin-cancer link. To investigate the impact of aspirin in people with SIDs, we conducted an observational study on a prospective cohort of 478,615 UK Biobank participants. Individuals with at least one of the 41 SIDs displayed a higher cancer risk than those without SIDs. Regular aspirin use showed protective effects exclusively in patients with SID, contrasting an elevated risk among their non-SID counterparts. Nonetheless, aspirin use demonstrated preventative potential only for 9 of 21 SID-associated cancer subtypes. Cholesterol emerged as another key mediator linking SIDs to cancer risk. Notably, regular statin use displayed protective properties in patients with SID but not in their non-SID counterparts. Concurrent use of aspirin and statins exhibited a stronger protective association in patients with SID, covering 14 common cancer subtypes. In summary, patients with SIDs may represent a population particularly responsive to regular aspirin and statin use. Promoting either combined or individual use of these medications within the context of SIDs could offer a promising chemoprevention strategy.

Peripheral inflammatory biomarkers as predictive tools for HyperCKemia risk assessment post-seizures.

BACKGROUND: This study evaluates the potential of inflammatory biomarkers, especially the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), for early detection of hyperCKemia after seizures. Addressing the challenge of delayed hyperCKemia diagnosis, which can escalate to rhabdomyolysis, this research emphasizes the use of these accessible biomarkers. METHODS: Conducted retrospectively, data from October 1, 2022, and October 1, 2023, were extracted from electronic medical records. Following univariate analysis (P-value < 0.05 for selection), Spearman's rank correlation and binary logistics regression were employed to examine the relationship between hyperCKemia and various clinical variables. Receiver operating characteristic curves (ROCs) defined the cut-off values for seizure-related hyperCKemia. RESULTS: Among 98 seizure patients, 31 (31.63 %) developed hyperCKemia. Notable differences in leukocytes, neutrophils, CRP, and NLR levels were observed between hyperCKemia and normal CK groups (P < 0.05). Leukocytes, NLR, and CRP correlated with hyperCKemia, exhibiting odds ratios of 1.24 (95 % CI: 1.11-1.39, P < 0.001), 1.03 (95 % CI: 1.01-1.05, P = 0.001), and 1.22 (95 % CI: 1.09-1.35, P = 0.017). The optimal cut-off values were established as 9.78 × 10^9/L for leukocytes, 32.40 mg/L for CRP, and 7.35 for NLR. CONCLUSION: Elevated levels of leukocytes, CRP, and NLR post-seizure are strong indicators of hyperCKemia risk, with significant implications for enhancing clinical decision-making and patient care strategies.

Lamin B1: a novel biomarker in adult and pediatric adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis and high mortality rate. A high tumor mutational burden (TMB) has been found to be associated with poor prognosis in ACC. Thus, exploring ACC biomarkers based on TMB holds significant importance for patient risk stratification. In our research, we utilized weighted gene coexpression network analysis and an assay for transposase-accessible chromatin with high-throughput sequencing to identify genes associated with TMB. Through the comprehensive analysis of various public datasets, Lamin B1 (LMNB1) was identified as a biomarker associated with a high TMB and low chromatin accessibility. Immunohistochemical staining demonstrated high expression of LMNB1 in ACC compared to noncancerous tissues. Functional enrichment analyses revealed that the function of LMNB1 is associated with cell proliferation and division. Furthermore, cell assays suggested that LMNB1 promotes tumor proliferation and invasion. In addition, mutation analysis suggested that the high expression of LMNB1 is associated with TP53 mutations. Additionally, LMNB1 was highly expressed in the vast majority of solid tumors across cancers. In our immune analysis, we discovered that the high expression of LMNB1 might suppress the infiltration of CD8+ T cells in the ACC microenvironment. In summary, LMNB1 is a predictive factor for the poor prognosis of adult and pediatric ACC. Its high expression in ACC is positively associated with high TMB and lower chromatin accessibility, and it promotes ACC cell proliferation and invasion. Therefore, LMNB1 holds promise as a novel biomarker and potential therapeutic target for ACC.

Novel hollow MoS2@C@Cu2S heterostructures for high zinc storage performance.

Heterostructured materials have great potential as cathodes for zinc-ion batteries (ZIBs) because of their fast Zn2+ transport channels. Herein, hollow MoS2@C@Cu2S heterostructures are innovatively constructed using a template-engaged method. The carbon layer improves the electrical conductivity, provides a high in situ growth area, and effectively restricts volume expansion during the recycling process. MoS2 nanosheets are grown on the surfaces of hollow C@Cu2S nanocubes using the in situ template method, further expanding the specific surface area and exposing more active sites to enhance the electrical conductivity. As expected, an admirable reversible capacity of 197.2 mA h g-1 can be maintained after 1000 cycles with a coulombic efficiency of 91.1%. Therefore, we firmly believe that this work points the way forward for high-performance materials design and energy storage systems.

The role of socioeconomic status and oxidative balance score in erectile dysfunction: A cross-sectional study.

Background: Erectile dysfunction (ED) is a complex disorder of biopsychosocial etiology. Approximately 3%-77 % of adult men worldwide are more or less affected by ED. Objective: This cross-sectional study investigated the association between ED and socioeconomic status (SES) based on a nationally representative adult male population. Methods: The poverty income ratio (PIR), which refers to household income ratio to the established poverty line, was used to assess SES. Oxidative stress related to diet and lifestyle was reflected by oxidative balance score (OBS). Erectile function was evaluated using a questionnaire. Based on the results of the questionnaire, participants were divided into two groups of those without ED (always or almost always be able to erect and keep erection, usually be able to erect and keep erection) and with ED (sometimes be able to erect and keep erection, never be able to erect and keep erection). Multivariate logistic regression, multiple models, and restricted cubic spline (RCS) were used to analyze and describe the interaction between ED, OBS, and SES. Results: Compared with men without ED, those with ED were more likely to be older in age (43.98 vs 37.74, P＜0.0001), and less educated (P < 0.001), and with a ratio of family income to poverty less than 3.5 (P = 0.02), higher BMI (30.11 vs 27.84, P＜0.0001), lower OBS (21.71 vs 23.17, P = 0.04), having habit of smoking (P = 0.04), with diabetes (P＜0.0001), and with hypertension (P = 0.003). Participants with higher PIR were more likely to report good erectile function than those with lower PIR through multivariate analysis (OR = 0.49, 95 % CI = 0.31-0.78, P = 0.005). The RCS model revealed a negative non-linear correlation of PIR with ED when PIR ≤3.89. It is interesting to note that PIR was＞3.89 showed a positive non-linear relationship with ED. Conclusion: The social determinants of health and intake of oxidants and antioxidants were considered as risk factors for ED and could be studied as a research focus in the future.

Modified ulnar lengthening for correction of the Masada type 2 forearm deformity in hereditary multiple exostosis.

Few articles have reported on the treatment of Masada type 2 forearm deformities in hereditary multiple exostosis, possibly because of the high redislocation rate and other complications. This study precisely declares the use of modified ulnar lengthening by an Ilizarov external fixation with tumour excision for the treatment of Masada type 2 forearm deformities. 20 children with Masada type 2 forearm deformities were admitted for surgical treatment at our hospital from February 2014 to February 2021. There were 13 girls and 7 boys, ranging in age from 3.5 to 15 years (mean: 9 years) at the time of operation. We removed the prominent osteochondromas of the distal ulna and the proximal radius, positioned a classic Ilizarov external fixator on the forearm and then performed ulnar transverse one-third proximal diaphyseal subperiosteal osteotomy. We adopted modified ulnar lengthening postoperatively. The effects of surgical correction of deformity and functional improvement of the limb were assessed via regular follow-up and X-ray. The patients were followed up for 36 months, and the ulna was lengthened 26.99 mm on average; all radial heads remained relocated. The radiographic evaluations, including relative ulnar shortening, radial articular angle, and carpal slip, were improved. The functions of the elbow and forearm were all improved after surgery. Modified ulnar lengthening by an Ilizarov external fixation with tumour excision for the treatment of Masada type 2 forearm deformities in hereditary multiple exostoses has been proven to be an effective and reliable technique in the early stage.

Effect of Intravenous Thrombolytic Dose of Alteplase on Long-Term Prognosis in Patients with Acute Ischemic Stroke.

INTRODUCTION: This study aimed to investigate the long-term prognostic effects of different alteplase doses on patients with acute ischemic stroke (AIS). METHODS: In this cohort study, we enrolled 501 patients with AIS treated with intravenous thrombolysis with alteplase, with the primary endpoint event of recurrence of ischemic stroke and the secondary endpoint event of death. The effects of different doses of alteplase on recurrence of ischemic stroke and death were analyzed using a Cox proportional risk model. RESULTS: Among 501 patients with AIS treated with thrombolysis, 295 patients (58.9%) and 206 patients (41.1%) were treated with low-dose and standard-dose alteplase, respectively. During the study period, 61 patients (12.2%) had a confirmed recurrence of ischemic stroke. Multivariate Cox proportional risk analysis showed that standard-dose alteplase thrombolysis (HR 0.511, 95% CI 0.288-0.905, P = 0.021) was significantly associated with a reduced risk of long-term recurrence of AIS, whereas atrial fibrillation was associated with an increased risk of long-term recurrence of AIS. Thirty-nine (7.8%) patients died during the study period. Multivariate Cox proportional risk analysis showed that age, baseline National Institutes of Health Stroke Scale (NIHSS) score, and symptomatic steno-occlusion were associated with an increased long-term risk of death from AIS. The alteplase dose was not associated with the risk of death from AIS. CONCLUSIONS: Standard-dose alteplase treatment reduced the risk of long-term recurrence of AIS after hospital discharge and the alteplase dose was not associated with the long-term risk of death from AIS.

Behavioral adaptation of sympatric rodents to early germination of oak acorns: radicle pruning and embryo excision.

The seed germination schedule is a key factor affecting the food-hoarding behavior of animals and the seedling regeneration of plants. However, little is known about the behavioral adaptation of rodents to the rapid germination of acorns. In this study, we provided Quercus variabilis acorns to several rodent species to investigate how food-hoarding animals respond to seed germination. We found that only Apodemus peninsulae adopted embryo excision behavior to counteract seed germination, which is the first report of embryo excision in nonsquirrel rodents. We speculated that this species may be at an early stage of the evolutionary response to seed perishability in rodents, given the low rate of embryo excision in this species. On the contrary, all rodent species preferred to prune the radicles of germinating acorns before caching, suggesting that radicle pruning is a stable and more general foraging behavior strategy for food-hoarding rodents. Furthermore, scatter-hoarding rodents preferred to scatter-hoard and prune more germinating acorns, whereas they consumed more nongerminating acorns. Acorns with embryos excised rather than radicles pruned were much less likely to germinate than intact acorns, suggesting a behavioral adaptation strategy by rodents to the rapid germination of recalcitrant seeds. This study provides insight into the impact of early seed germination on plant-animal interactions.

CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy.

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.

Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

Organochlorine pesticides and polycyclic aromatic hydrocarbons in serum of Beijing population: Exposure and health risk assessment.

Organochlorine pesticides (OCPs) and polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants, but large-scale human biomonitoring and health risk assessment data on these contaminants remain limited. In this study, concentrations of 6 OCPs and 5 PAHs were determined by GC-MS/MS in 1268 human serum samples which were collected from the participants in 2017 Beijing Chronic Disease and Risk Factor Surveillance. The detection frequencies of OCPs and PAHs ranged from 64.7 % to 96.5 % and 89.4 % to 99.6 %, respectively. The most abundant contaminants in OCPs and PAHs were pentachlorophenol (PCP) and pyrene (Pyr) with median concentrations reaching up to 3.13 and 8.48 µg/L, respectively. Nonparametric tests were employed to assess the correlations among contaminants levels, demographic characteristics (age, gender, body mass index, residence) and serum biochemical indexes. Significantly higher serum levels of all PAHs were observed in suburb residents than that in urban residents (P < 0.001). Binary logistic regression analysis demonstrated that exposure to benzo(a)pyrene (OR 2.17 [1.29, 3.63]), phenanthrene (OR 1.06 [1.02, 1.11]), fluoranthene (OR 1.04 [1.02, 1.07]) and Pyr (OR 1.02 [1.01, 1.03]) might increase the occurrence of hyperglycemia, and exposure to hexachlorobenzene (HCB) (OR 1.53 [1.05, 2.22]) and pentachlorobenzene (OR 1.14 [1.02, 1.27]) were positively associated with hyperlipidemia. Furthermore, the hazard quotients (HQs) for serum HCB, PCP and p,p'-dichlorodiphenyldichloroethylene were calculated based on health-based guidance values to predict health risks. 0.2 % and 4.3 % of serum samples showed HQ values exceeding 1 for HCB and PCP, respectively, in case of the non-carcinogenic risk, while 23.1 % of HQs for HCB were above 1 in case of the carcinogenic risk for a risk level 10-5. Our study reveals that the body burden of the Beijing general population relative to OCPs and PAHs was nonnegligible. The past exposure of HCB and PCP might adversely affect the health status of the Beijing population.

Self-supporting 1T-MoS2@WS2@CC composite materials for potential high-capacity sodium storage system.

Pure phase MoS2 has low conductivity, but with high theoretical specific capacity, and WS2 possesses a high intrinsic conductivity, but suffer from rapid capacity fading. Predictably, the combination of these two transition metal sulfide compounds can complement each other and improve electrochemical performance comprehensively. Whereas, bimetallic phase sulfide of MoS2 and WS2 composites have not been researched in SIBs. In this paper, 1T metallic phase MoS2 and WS2 vertically growth on flexible carbon cloth (CC) surface (1T-MoS2@WS2@CC) by a simple hydrothermal method. The electrochemical performance was improved by heterojunction synergistic effect and the enhanced interlayers of the composite material. Specifically, the superelevation reversible capacity of 529.4 mAh/g can be obtained even after 100 cycles at the current density of 100 mA g-1, and the 259.2 mAh/g capacity can be maintained even at high current density of 1000 mA g-1 after 60 cycles. Besides, the designed 1T-MoS2@WS2@CC composite material has excellent rate performance and cycle stability which are guarantee for battery core performance. Thus, there is every reason to believe that the advanced 1T-MoS2@WS2@CC electrode material has great potential in the future high performance energy storage devices.

An Effective Technique for Managing the Calcaneus Osteomyelitis Combined with Soft-Tissue Defect.

The treatment of the Cierny-Mader (C-M) type III-IV calcaneus osteomyelitis combining with the soft-tissue defect is sophisticated and difficult. The aim of this study is to introduce the application and availability of the modified distally based sural flap with an adipofascial extension to reconstruct these defects. We retrospectively reviewed the data of 37 patients with C-M type III-IV calcaneus osteomyelitis accompanied with soft-tissue defect between December 2004 and December 2019. A modified distally based sural flap with an adipofascial extension was conducted to reconstruct the defect. The patient's demographics, duration of the diseases, etiology, reconstruction outcomes, infection control rate, recurrence rate, amputation rate, and follow-up data were collected to evaluate the effectiveness and reliability of the modification. The American Orthopedic Foot and Ankle Society (AOFAS) ankle and hindfoot scale was applied to assess the function of the ankle and hindfoot. Thirty-four flaps survived uneventfully, 1 flap displayed marginal necrosis and 2 flaps (5.41%) developed partial necrosis. Using this modified flap alone or combining with some simple salvage methods reconstructed all of the defects successfully. The calcaneus osteomyelitis was cured successfully, and no recurrences were observed during the follow-up period. The AOFAS ankle and hindfoot scores were excellent in 27 patients and good in 8 patients. The distally based sural flap with an adipofacial extension is a simple and effective technique to reconstruct the calcaneus osteomyelitis combined with soft-tissue defect in 1 stage. Applications of the adipofacial extension to obliterate the dead space and the well-vascularized skin island to cover the defect are the guarantee of achieving good ankle and foot functions. However, this technique is not appropriate for the patients with calcaneum less than half weight-bearing area.

PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer.

Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. SIGNIFICANCE: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.