Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

Development of a Repair Enzyme Fluorescent Probe to Reveal the Intracellular DNA Damage Induced by Benzo[a]pyrene in Living Cells.

Pollutant exposure causes a series of DNA damage in cells, resulting in the initiation and progression of diseases and even cancers. An investigation of the DNA damage induced by pollutants in living cells is significant to evaluate the cytotoxicity, genotoxicity, and carcinogenicity of environmental exposure, providing critical insight in the exploration of the etiologies of diseases. In this study, we develop a repair enzyme fluorescent probe to reveal the DNA damage caused by an environmental pollutant in living cells by single-cell fluorescent imaging of the most common base damage repair enzyme named human apurinic/apyrimidinic endonuclease 1 (APE1). The repair enzyme fluorescent probe is fabricated by conjugation of an APE1 high affinity DNA substrate on a ZnO2 nanoparticle surface to form a ZnO2@DNA nanoprobe. The ZnO2 nanoparticle serves as both a probe carrier and a cofactor supplier, releasing Zn2+ to activate APE1 generated by pollutant exposure. The AP-site in the DNA substrate of the fluorescent probe is cleaved by the activated APE1, releasing fluorophore and generating fluorescent signals to indicate the position and degree of APE1-related DNA base damage in living cells. Subsequently, the developed ZnO2@DNA fluorescent probe is applied to investigate the APE1-related DNA base damage induced by benzo[a]pyrene (BaP) in living human hepatocytes. Significant DNA base damage by BaP exposure is revealed, with a positive correlation of the damage degree with exposure time in 2-24 h and the concentration in 5-150 µM, respectively. The experimental results demonstrate that BaP has a significant effect on the AP-site damage, and the degree of DNA base damage is time-dependent and concentration-dependent.

Feasibility, safety and outcomes of ambulation within 2 h postoperatively in patients with lung cancer undergoing thoracoscopic surgery.

AIMS: The aims of this study were to evaluate the safety, feasibility and outcomes of ambulation within 2 h after thoracoscopic surgery in patients with lung cancer. BACKGROUND: There are no consensus guidelines on the ideal time for early ambulation following thoracic surgery, although enhanced recovery programmes have been proposed since years. METHODS: This non-randomized, concurrent-control study was conducted on patients who underwent thoracoscopic surgery between October 2020 and February 2021. Participants were assigned to either the observation group (ambulation within 2 h of extubation) or the control group (ambulation on the first postoperative day). RESULTS: Of the 325 patients who were eligible, 227 were included in the study. Eighty-three per cent of patients were able to walk any distance within 2 h of extubation, and no adverse events occurred in patients. The length of hospital stay and time to first postoperative flatus were significantly shorter in the observation group than in the control group. There were no differences in the occurrence of postoperative complications and orthostatic hypotension, readmission rate and 6-min walk distance at discharge. CONCLUSION: Ambulation within 2 h of extubation was safe and feasible and could lead to better recovery in patients with lung cancer undergoing thoracoscopic surgery.

Influence of emotional intelligence on the clinical ability of nursing interns: a structural equation model.

BACKGROUND: Internship is a critical period during which nursing students develop clinical skills and establish professional attitudes. Requirements for nursing interns are evolving with the development of medicine and the transformation of teaching models. The emotional intelligence (EI) of nursing students has an influence on their clinical performance. This study aimed to investigate the impact of EI on the clinical ability of nursing interns. METHODS: A cross-sectional observational study was designed to include nursing students interning in a tertiary hospital in Shanghai, China from April 1, 2019 to April 30, 2020 (N = 310). Chinese versions of the EI scale (EIS) and holistic clinical assessment tool (HCAT) were used to measure the EI and clinical ability of interns, respectively. Pearson's correlation coefficient was utilized to determine the correlation between EI and clinical ability. Multiple linear regression analysis was performed to further explore the influence of EI on clinical ability, and the structural equation model (SEM) was used for multivariate path analysis. RESULTS: The mean EI and clinical ability scores of interns were 125.17 ± 14.98 and 97.91 ± 19.55, respectively, indicating an upper-moderate level in both aspects. EI scores were correlated positively with clinical ability ones (R = 0.534, p < 0.05). Multivariate path analysis showed that "managing emotions" and "facilitating thought" of EI branches have direct effects on clinical ability. Furthermore, the type of school, family financial state and the knowledge of EI indirectly influence clinical ability through their impact on "managing emotions" and "facilitating thought". CONCLUSIONS: EI is essential to enhancing the clinical ability of nursing students. EI training should focus on facilitating thought and managing emotions. It is also necessary for educators to consider the context of nursing students and the characteristics of schools.

Aberrant Exon 8/8a Splicing by Downregulated PTBP (Polypyrimidine Tract-Binding Protein) 1 Increases CaV1.2 Dihydropyridine Resistance to Attenuate Vasodilation.

OBJECTIVE: Calcium channel blockers, such as dihydropyridines, are commonly used to inhibit enhanced activity of vascular CaV1.2 channels in hypertension. However, patients who are insensitive to such treatments develop calcium channel blocker-resistant hypertension. The function of CaV1.2 channel is diversified by alternative splicing, and the splicing factor PTBP (polypyrimidine tract-binding protein) 1 influences the utilization of mutually exclusive exon 8/8a of the CaV1.2 channel during neuronal development. Nevertheless, whether and how PTBP1 makes a role in the calcium channel blocker sensitivity of vascular CaV1.2 channels, and calcium channel blocker-induced vasodilation remains unknown. Approach and Results: We detected high expression of PTBP1 and, inversely, low expression of exon 8a in CaV1.2 channels (CaV1.2E8a) in rat arteries. In contrast, the opposite expression patterns were observed in brain and heart tissues. In comparison to normotensive rats, the expressions of PTBP1 and CaV1.2E8a channels were dysregulated in mesenteric arteries of hypertensive rats. Notably, PTBP1 expression was significantly downregulated, and CaV1.2E8a channels were aberrantly increased in dihydropyridine-resistant arteries compared with dihydropyridine-sensitive arteries of rats and human. In rat vascular smooth muscle cells, PTBP1 knockdown resulted in shifting of CaV1.2 exon 8 to 8a. Using patch-clamp recordings, we demonstrated a concomitant reduction of sensitivity of CaV1.2 channels to nifedipine, due to the higher expression of CaV1.2E8a isoform. In vascular myography experiments, small interfering RNA-mediated knockdown of PTBP1 attenuated nifedipine-induced vasodilation of rat mesenteric arteries. CONCLUSIONS: PTBP1 finely modulates the sensitivities of CaV1.2 channels to dihydropyridine by shifting the utilization of exon 8/8a and resulting in changes of responses in dihydropyridine-induced vasodilation.

Dual-Functional Metal-Organic Framework for Luminescent Detection of Carcinoid Biomarkers and High Proton Conduction.

It remains a challenge to exploit dual-functional metal-organic frameworks (MOFs) for applications, including luminescence detection and proton conduction. With the deliberate selection of the bifunctional organic ligand 5-sulfoisophthalic acid monosodium salt (NaH2bts), and the phosphonic acid ligand N,N'-piperazine (bismethylenephosphonic acid; H4L), a robust three-dimensional (3D) noninterpenetrating dual-functional MOF, [Tb(H2L)(H2bts)(H2O)]·H2O (1), has been synthesized hydrothermally. On the basis of the excellent thermal and chemical as well as superior luminescence stabilities in water and solutions with different pHs, 1 can serve as the simple, rapid, and highly selective and sensitive luminescence detection of the carcinoid biomarkers 5-hydroxytryptamine (HT) and its metabolite 5-hydroxyindole-3-acetic acid (HIAA) with detection limits of nanomolar magnitude in water and in simulated blood plasma and urine systems. Due to the change in the signals that could be readily differentiated by the naked eye under a UV lamp, a portable test paper has been developed. The probable quenching mechanisms are discussed in detail. In addition, a great number of hydrogen-bonding networks are formed among the uncoordinated carboxylic oxygen atoms, sulfonate oxygen atoms, protonated nitrogen atoms, and water molecules, which provide potential proton-hopping sites for proton conduction, leading to a maximum proton conductivity of 2.3 × 10-4 S cm-1 at 368 K and 95% relative humidity. The above results suggest that rationally designed dual-functional MOFs can open an avenue for the development of occupational diagnostic tools and alternative energy technology.

Canonical and Interior Circular RNAs Function as Competing Endogenous RNAs in Psoriatic Skin.

(1) Background: Understanding the function of circular RNAs (circRNAs), a class of noncoding RNA, in psoriatic skin can provide important insights into the complex regulation of genes contributing to the pathogenesis of psoriasis. (2) Methods: A novel method was applied to RNA-seq datasets from 93 skin biopsy samples to comprehensively identify circRNAs of all types, i.e., canonical circRNAs from the intron-exon junctions of mRNAs and interior circRNAs (i-circRNAs) from the interior regions of exons, introns, and intergenic regions. Selected circRNAs were experimentally validated by qRT-PCR and Sanger sequencing. CircRNAs with abundant and differential expression were identified and their putative function as competing endogenous RNAs (ceRNAs) was analyzed by an integrated analysis of circRNAs, microRNAs, and mRNAs. (3) Results: With a comprehensive search using no information of splicing signals, we systematically identified 179 highly abundant circRNAs in psoriatic skin. Many of these were reported for the first time and many were differentially expressed in involved versus normal or uninvolved skin. Validation based on three additional RNA-seq datasets confirmed most of the identified circRNAs in psoriatic skin. Experimental analyses confirmed the expression of the well-known circRNA CDR1as, a canonical circRNA, and a novel i-circRNA in psoriasis. We also identified many circRNAs that may act as ceRNAs to regulate the expression of mRNA genes in psoriasis-related signaling pathways in psoriasis. (4) Conclusions: The result of the study suggested that circRNAs are abundant in psoriatic skin, have distinct characteristics, and contribute to psoriatic pathogenesis.

Interior circular RNA.

Formed by back splicing or back fusion of linear RNAs, circular RNAs (circRNAs) constitute a new class of non-coding RNAs of eukaryotes. Recent studies reveal a spliceosome-dependent biogenesis of circRNAs where circRNAs arise at the intron-exon junctions of mRNAs. In this study, using a novel de novo identification method, we show that circRNAs can originate from the interior regions of exons, introns, and intergenic transcripts in human, mouse and rice, which were referred to as interior circRNAs (i-circRNAs). Many i-circRNAs have some remarkable characteristics: multiple i-circRNAs may arise from the same genomic locus; their back fusion points may not be associated with the AG/GT splicing sites, but rather a new pair of motif AC/CT, their back fusion points are adjacent to complementary sequences; and they may circulate on short homologous sequences. We validated several i-circRNAs in HeLa cells by Polymerase Chain Reaction followed by Sanger sequencing. Our results combined showed that i-circRNAs are bona fide circRNAs, indicated novel biogenesis pathways independent of the splicing apparatus, and expanded our understanding of the origin, diversity, and complexity of circRNAs.

Inhibition of RM-1 prostate carcinoma and eliciting robust immune responses in the mouse model by using VEGF-M2-GnRH3-hinge-MVP vaccine.

GnRH and VEGF have been investigated as prostate carcinoma enhancers that support tumor spread and progression. Although both have documented roles in prostate carcinoma and many cancer types, the weak immunogenicity of these peptides has remained a major challenge for use in immunotherapy. Here, we describe a novel strategy to inhibit GnRH and VEGF production and assess the effect on the immune responses against these hormones using the RM-1 prostate cancer model. We designed a novel recombinant fusion protein which combined GnRH and VEGF as a vaccine against this tumor. The newly constructed fusion protein hVEGF121-M2-GnRH3-hinge-MVP contains the human vascular endothelial growth factor (hVEGF121) and three copies of GnRH in sequential linear alignment and T helper epitope MVP as an immunogenic vaccine. The effectiveness of the vaccine in eliciting an immune response and attenuating the prostate tumor growth was evaluated. Results showed that administration of a new vaccine effectively elicited humoral and cellular immune responses. We found that, a novel fusion protein, hVEGF121-M2-GnRH3-hinge-MVP, effectively inhibited growth of RM-1 prostate model and effectively promoted immune response. In conclusion, hVEGF121-M2-GnRH3-hinge-MVP is an effective dual mechanism tumor vaccine that limits RM-1 prostate growth. This vaccine may be a promising strategy for the treatment of hormone refractory prostate malignancies.

[Diagnostic Values and Reliability of Cardiac Magnetic Resonance Tissue Tracking 2D and 3D Strain Assessments for Experimental Autoimmune Myocarditis in Rats].

OBJECTIVE: To determinethe diagnostic valuesand reliabilityof cardiac magnetic resonance tissue tracking (CMR-TT) derived two-dimensional(2D) and three-dimensional(3D) strains in assessing experimental autoimmunity myocarditis (EAM) in rats. METHODS: 20 Lewis rats were randomly divided into model and control groups. The animal model of autoimmune myocarditis was induced by injecting porcine cardiac myosin into the footpads of the rats.On day 35, all of the rats were examined using the 7.0T CMR cine scan. The cardiac function and global strain of the left ventricular of the rats were analyzed with specific cardiac post-processing. The rats were then sacrificed and myocardial samples were taken and stained with HE and Masson. The diagnostic values of the strain parameters were assessed by receiver operating characteristic (ROC) curves with the pathological results as diagnostic criteria.The reliability of the strain parameters were tested using interclass correlation coefficient (ICC), coefficients of variation (CV) and Bland-Altman. RESULTS: No abnormal pathological changes in myocardial cells were found in the control group. Myocarditis was successfully induced in all of the rats in the model group, showing myocardial fiber arrangement disorder, degeneration, necrosis, inflammatory cell infiltration and interstitial fibrosis. The ROC showed that 2D global strain parameters possessed higher diagnostic values than 3D strain parameters. The 2D had an area under the curve (AUC) of 0.96 in global circumferential strain (GCS), 0.95 in global radial strain (GRS), and 0.90 in global longitudinal strain (GLS), compared with 0.87 GCS, 0.85 GRS, and 0.77 GLS in the 3D, respectively.The reliability of the 2D strain parameters was high, except for inter-observer 2D GRS(ICC=0.893). The 3D strain parameters had lower reliability (ICCs:0.421-0.79) than the 2D strain parameters (ICCs:0.893-0.986). CONCLUSION: The diagnostic values of 2D strain parameters are higher than 3D strain parameters in diagnosing myocarditis.

Potent Inhibitory Effect of Chinese Dietary Spices on Fatty Acid Synthase.

Dietary spices have been adopted in cooking since ancient times to enhance flavor and also as food preservatives and disease remedies. In China, the use of spices and other aromatic plants as food flavoring is an integral part of dietary behavior, but relatively little is known about their functions. Fatty acid synthase (FAS) has been recognized as a remedy target, and its inhibitors might be applied in disease treatment. The present work was designed to assess the inhibitory activities on FAS of spices extracts in Chinese menu. The in vitro inhibitory activities on FAS of 22 extracts of spices were assessed by spectrophotometrically monitoring oxidation of NADPH at 340 nm. Results showed that 20 spices extracts (90.9 %) exhibited inhibitory activities on FAS, with half inhibition concentration (IC(50)) values ranging from 1.72 to 810.7 µg/ml. Among them, seven spices showed strong inhibitory effect with IC(50) values lower than 10 µg/ml. These findings suggest that a large proportion of the dietary spices studied possess promising inhibitory activities on FAS, and subsequently might be applied in the treatment of obesity and obesity-related human diseases.

Toxicity assessment of 7 anticancer compounds in zebrafish.

Toxicity is one of the major reasons for failure in drug development. Zebrafish, as an ideal vertebrate model, could also be used to evaluate drug toxicity. In this study, we aimed to show the predictability and highlight novel findings of toxicity in zebrafish model. Seven anticancer compounds, including triptolide (TP), gambogic acid (GA), mycophenolic acid (MPA), curcumin, auranofin, thalidomide, and taxol, were assessed in zebrafish for their toxicity. Three compounds (GA, TP, and taxol) showed highest acute lethality, with 50% lethal concentration ≈ 1 µmol/L. Missing tails, severe pericardial edema, and enlarged yolk sacs were observed in MPA-treated embryos. The development of pectoral fins was severely disturbed in thalidomide-, GA-, and TP-treated embryos. Bradycardia was observed in MPA- and thalidomide-treated groups. Our findings suggested that the zebrafish are a good model for toxicity assessment of anticancer compounds.

Zinc Deficiency Causes Glomerulosclerosis and Renal Interstitial Fibrosis Through Oxidative Stress and Increased Lactate Metabolism in Rats.

Chronic kidney disease (CKD) is a highly prevalent condition characterized by renal fibrosis as its ultimate manifestation. Zinc deficiency is closely associated with CKD, evidenced by its link to renal fibrosis. Recently, local lactic acidosis has been demonstrated to promote renal fibrosis. Under zinc-deficient conditions, mitochondrial function is compromised and abnormal lactate metabolism might be induced potentially. However, it remains unclear whether zinc deficiency leads to renal fibrosis through local lactic acidosis. Zinc deficiency rat models were successfully established by feeding zinc-deficient diet. Western blot, qPCR, IHC, and other experiments were employed to investigate the key markers and molecular mechanisms of glomerulosclerosis and renal interstitial fibrosis. Our results indicate that zinc deficiency reduces specific markers of podocytes (podocalyxin, WT1, and nephrin) and activates the Wnt3a/ß-catenin pathway, a key pathway in podocyte injury. Concurrently, glomerulosclerosis is indicated by increased urinary microalbumin and serum creatinine levels along with histological alteration observed through PAS and Masson staining in zinc-deficient rats. Furthermore, various degrees of upregulation for several markers of interstitial fibrosis including α-SMA, FN1 and collagen III are also revealed. These findings were further confirmed by Masson staining and IHC. Additionally, alterations in four markers in the EMT process, N-cadherin, E-cadherin, Vimentin, and snail, were consistent with expectations. We then confirmed the activation of the non-canonical TGF-ß1 pathway known as the PI3K/AKT/mTOR pathway. An elevation in renal ROS levels accompanied by increased mitochondrial marker cytochrome C expression as well as an elevated NADH/NAD + ratio is also observed within the kidneys. Furthermore, the activity of both MMP/TIMP system and fibrinolytic system was abnormally enhanced under zinc deficiency conditions. Finally, we find zinc supplementation could significantly ameliorate relevant pathological alterations induced by zinc deficiency. These results collectively point that zinc deficiency causes podocyte damage ultimately resulting in glomerulosclerosis via accumulation of ROS and induces interstitial fibrosis via lactic acidosis.

Systemic immune-inflammation Index is associated with chronic kidney disease in the U.S. population: insights from NHANES 2007-2018.

Objectives: The systemic immune-inflammation index (SII), a novel and systematic inflammatory biomarker that is associated with chronic kidney disease (CKD), has not received much attention. This study aimed to investigate the relationship between SII and CKD in the United States (U.S.) population. Methods: Our study ultimately included a nationally representative sample of 10,787 adults who participated in the 2007-2018 National Health and Nutrition Examination Survey. Weighted multivariate logistic regression was used to assess the correlation between SII and CKD, and a restricted cubic spline (RCS) model was subsequently used to explore the non-linear relationship between SII and CKD. Subgroup analyses were performed to further the effects of other covariates on the relationship between SII and CKD. Results: Following confounder adjustment, a higher SII was related to the incidence of CKD (OR =1.36; 95% CI, 1.07-1.73; p =0.01), as validated by multivariable logistic regression. The RCS curve revealed a non-linear positive correlation between SII/1000 and CKD incidence (p for non-linear =0.0206). Additionally, subgroup analysis confirmed a stronger correlation for male participants (OR =2.628; 95% CI, 1.829-3.776) than for female participants (OR =1.733; 95% CI, 1.379-2.178) (p for interaction =0.046). Conclusions: SII is positively associated with the incidence of CKD among U.S. adults, especially in males. However, further studies are needed to confirm our findings and explore the causal factors that can contribute to the prevention and treatment of CKD.

The Potential Mediating Effect of Symptom Burden on Demoralization Through Locus of Control and Coping Strategies in Chinese Patients With Cancer.

BACKGROUND: Demoralization is a psychological syndrome that is highly prevalent in patients with cancer and detrimental to individuals' physical and mental health. To explore effective intervention, we first determined the relationships between locus of control, coping strategies, symptom burden, and demoralization. OBJECTIVE: The aim of this study was to determine the relationship between symptom burden, locus of control, coping strategies, and demoralization in patients with cancer. METHODS: In this descriptive-correlational study, 273 valid patients were selected with convenience sampling method from a hospital in China. Data were collected using the Chinese version of the M.D. Anderson Symptom Inventory, the Chinese version of the Multidimensional Health Locus of Control Scale, the Chinese version of the Medical Coping Modes Questionnaire, and the Mandarin version of the Demoralization Scale. Data were analyzed using descriptive and inferential statistics using SPSS and AMOS. RESULTS: A total of 115 patients (42.12%) experienced clinical demoralization (Mandarin version of the Demoralization Scale > 30). Symptom burden (ß = 0.295, P < .001), confrontation (ß = -0.117, P = .028), and resignation (ß = 0.456, P < .001) had direct effects on demoralization. Symptom burden also had an indirect effect on demoralization through the mediating role of resignation (ß = 0.026, P = .002). Meanwhile, locus of control can affect demoralization entirely through the indirect mediating role of coping strategies (chance locus of control via resignation [ß = 0.138, P < .01], powerful locus of control via confrontation [ß = -0.017, P < .05]). CONCLUSIONS: Symptom burden affects demoralization not only directly but also indirectly. Coping strategies play an important mediating role between symptom burden, locus of control, and demoralization in patients with cancer. IMPLICATIONS FOR PRACTICE: It is urgent to screen demoralization and identify patients with high symptom burden, maladaptive locus of control, or coping strategies. For the patients targeted, a more comprehensive and systematic approach to symptom management and more appropriate guidance related to adaptive coping strategies are needed.

Effects of respiratory muscle training on post-stroke rehabilitation: A systematic review and meta-analysis.

BACKGROUND: Stroke often results in significant respiratory dysfunction in patients. Respiratory muscle training (RMT) has been proposed as a rehabilitative intervention to address these challenges, but its effectiveness compared to routine training remains debated. This systematic review and meta-analysis aim to evaluate the effects of RMT on exercise tolerance, muscle strength, and pulmonary function in post-stroke patients. AIM: To systematically assess the efficacy of RMT in improving exercise tolerance, respiratory muscle strength, and pulmonary function in patients recovering from a stroke, and to evaluate whether RMT offers a significant advantage over routine training modalities in enhancing these critical health outcomes in the post-stroke population. METHODS: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, a comprehensive search across PubMed, Embase, Web of Science, and the Cochrane Library was conducted on October 19, 2023, without temporal restrictions. Studies were selected based on the predefined inclusion and exclusion criteria focusing on various forms of RMT, control groups, and outcome measures [including forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), maximal voluntary ventilation (MVV), peak expiratory flow (PEF), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and 6-min walking test (6MWT)]. Only randomized controlled trials (RCTs) were included. Data extraction and quality assessment were conducted independently by two reviewers using the Cochrane Collaboration's risk of bias tool. Statistical analyses, including those using the fixed-effect and random-effects models, sensitivity analysis, and publication bias assessment, were performed using Review Manager software. RESULTS: A total of 15 RCTs were included. Results indicated significant improvements in MIP (12.51 cmH2O increase), MEP (6.24 cmH2O increase), and various pulmonary function parameters (including FEV1, FVC, MVV, and PEF). A substantial increase in 6MWT distance (22.26 meters) was also noted. However, the heterogeneity among studies was variable, and no significant publication bias was detected. CONCLUSION: RMT significantly enhances walking ability, respiratory muscle strength (MIP and MEP), and key pulmonary function parameters (FEV1, FVC, MVV, and PEF) in post-stroke patients. These findings support the incorporation of RMT into post-stroke rehabilitative protocols.

Effect of oxidative stress induced by 2,3,7,8- tetrachlorodibenzo-p-dioxin on DNA damage.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic persistent organic pollutant (POP) that can induce DNA damage within cells. Although oxidative stress is one of the primary mechanisms causing DNA damage, its role in the process of TCDD-induced DNA damage remains unclear. In this study, the TCDD-induced production of reactive oxygen species (ROS) and the occurrence of DNA damage at the AP site were monitored simultaneously. Further investigation revealed that TCDD impaired the activities of superoxide dismutase (SOD) and catalase (CAT), compromising the cellular antioxidant defense system. Consequently, this led to an increase in the production of O2.- and NO, thus inducing DNA damage at the AP site under oxidative stress. Our findings were further substantiated by the upregulation of key genes in the base excision repair (BER) pathway and the absence of DNA AP site damage after inhibiting O2.- and NO. In addition, transcriptome sequencing revealed that TCDD induces DNA damage by upregulating genes associated with oxidative stress in the mitogen-activated protein kinase (MAPK), cyclic adenosine monophosphate (cAMP), and breast cancer pathways. This study provides important insights into the toxicity mechanisms of TCDD.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Postoperative delirium and its influencing factors in elderly patients with lung cancer in the intensive care unit.

Background: In 2020, there were 2,206,771 new cases of lung cancer worldwide, ranking first in mortality rate postoperative delirium (POD) is a common surgical complication and typically occurs 1-3 days after surgery which leads to prolonged hospital stay. The currently available research on POD in elderly patients was mainly carried out in cardiac surgery, orthopedic, and gastroenterology departments. It is necessary to study the incidence and risk factors of delirium in intensive care unit (ICU) elderly patients after lung cancer surgery. Methods: This study is a single-center and singe-arm observational study which examined the incidence of and factors affecting POD in elderly patients with lung cancer in ICU at our center from September 2019 to May 2020. 22 relevant variables including arterial oxygen partial pressure, postoperative sedative drug use, and other data were collected. The Confusion Assessment Method of Intensive Care Unit was used to assess the occurrence of POD, the Chinese version of the Richards-Campbell Sleep Questionnaire was used to assess patients' postoperative sleep quality, and the Mini-Mental State Examination was used to assess patients' preoperative cognitive level. Univariate and multivariate logistic regression analyses were conducted to identify the factors affecting POD in elderly ICU patients with lung cancer. Results: Among the 208 elderly ICU patients who underwent surgery for lung cancer, 32 (15.38%) had POD. The results showed that postoperative blood oxygen level, preoperative cognitive level score and postoperative sleep quality score in delirium group were significantly lower than those in non-delirium group (P values were 0.002, 0.000, 0.000, respectively). The proportion of previous coronary heart disease and postoperative sedation use in delirium group was significantly higher than that in non-delirium group (P=0.008 and 0.008, respectively). Conclusions: It was observed that the preoperative Mini-Mental State Examination (MMSE) score and postoperative Richards-Campbell Sleep Questionnaire (RCSQ) score of the delirium group were significantly lower than those of the non-delirium group, and this trend was still observed after adjusting for influencing factors. It is suggested that the difference of cognitive level in elderly lung cancer population has a significant effect on the occurrence of POD. In clinical work, we should pay more attention to patients with preoperative cognitive impairment, hypoxic state, and postoperative sleep disturbance.