Exome sequencing confirms the clinical diagnosis of both joubert syndrome and klinefelter syndrome with keratoconus in a han Chinese family.

Introduction: Joubert syndrome a rare genetic disorder, is characterized by abnormalities in the development of the central nervous system with "molar signs" on magnetic resonance imaging of the brain and accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. Keratoconus (KC) is a kind of genetically predisposed eye disease that causes blindness characterized by a dilated thinning of the central or paracentral cornea conically projected forward, highly irregular astigmatism, and severe visual impairment. Klinefelter syndrome is caused by an extra X chromosome in the cells of male patients, and the main phenotype is tall stature and dysplasia with secondary sex characteristics. This study was intended to identify the genetic etiology and determine the clinical diagnosis of one Han Chinese family with specific clinical manifestations of keratoconus and multiorgan involvement. Methods: A comprehensive ocular and related general examination was performed on one patient and his asymptomatic parents and brother. Pathogenic genes were tested by exome sequencing. CNV-seq was used to verify the copy number variation, and peripheral blood was cultured for karyotype analysis. The pathogenicity of the identified variant was determined subject to ACMG guidelines. The Gene Expression Omnibus (GEO) dataset of keratoconus-related genes in the NCBI database was obtained to analyze the differentially expressed genes in corneal tissues of the keratoconus group and the normal control group, and analysis of protein-protein interaction networks (PPI) was performed. Results: Proband, a 25-year-old male, had sudden loss of vision in the left eye for 1 week. Best corrected visual acuity (BCVA): 0.5 (-1.00DS/-5.00DC*29°) in the right eye, counting fingers/40 cm in the left eye. Slit-lamp microscopy of the right eye showed mild anterior protrusion of the cornea and thinning of the cone-topped cornea. The left eye showed marked thinning of the central region of the cornea, rounded edema in the form of a cone-like bulge, epithelial bullae, edema and turbidity of the stroma, and bulging of the Descemet's membrane. Cranial magnetic resonance imaging (MRI) revealed changes in the midbrain and cerebellum, with a "molar sign" and a "bat-winged" ventriculus quartus cerebri. General check-up: 168 cm in height, decreased muscle tone in all four limbs, knee jerk elicited, negative Babinski sign, abdominal reflexes elicited, finger-to-nose test positive, intentional tremor evident in both hands, positive Romberg's sign, instability of gait, level I intellectual disability, poor adaptive behavior, communication disorders, teeth all dentures, a peculiar face with blepharophimosis, wide inner canthus distance, mild ptosis, severe positive epicanthus, high palatal arches, exotropia, hypotrichosis of beard and face, inconspicuous prominentia laryngea, and short upper and lower limbs. Exome sequencing detected compound heterozygous frameshift variants M1:c.9279dup:p.His3094Thrfs*18 and M2:c.6515_6522del:p.Lys2172Thrfs*37 in the patient's CPLANE1 gene and the presence of duplication-type CNV on the X chromosome. Sanger sequencing showed that the mother and father carried the M1 and M2 variants, respectively, and the younger brother carried the M2 variant, which was a novel variant. CNV-seq analysis showed the presence of a duplication-type CNV Xp22.33-Xq28 (2757837-156030895) of approximately 155 Mb on the X chromosome of the proband, which was a de novo variant and carried by neither of the parents. The two heterozygous frameshift variants and duplication-type CNV were pathogenic according to the ACMG guidelines. Differential expression analysis of keratoconus-related genes showed that CPLANE1 was upregulated in the corneal tissues of keratoconus patients compared with normal controls, and such a difference was statistically significant (p = 0.000515, <0.05). PPI analysis showed that the CPLANE1-NPHP3 complex protein acted as a bridge between cilia and extracellular matrix tissue. According to the genetic test results and clinical phenotype analysis, the family was finally diagnosed with Joubert syndrome combined with Keratoconus and Klinefelter syndrome. Discussion: In this study, we report a proband in a Han Chinese family with both Joubert syndrome and X-linked Klinefelter syndrome as well as keratoconus, and the phenotype spectrum of CPLANE1-Joubert syndrome may be expanded accordingly. Meanwhile, the significance of exome sequencing was emphasized in aiding the clinical diagnosis of complex cases, which is difficult to make.

Corrigendum: A randomized controlled trial of a coping-focused family resilience intervention program for breast cancer patients: study protocol.

[This corrects the article DOI: 10.3389/fpsyg.2022.968154.].

Electrochemical assembly of single-walled carbon nanotube/polypyrrole/tellurium/lead telluride multi-layer nanocomposite films for room-temperature flexible thermoelectric application.

With the complexity and diversification of thermoelectric (TE) application scenarios, it becomes increasingly difficult for single-component thermoelectric materials to satisfy practical demands. Therefore, recent researches have largely focused on the development of the multi-component nanocomposites, which are probably a good solution for the TE application of some materials that are not eligible when used alone. In this work, a seires of single-walled carbon nanotube (SWCNT)/polypyrrole (PPy)/tellurium (Te)/lead telluride (PbTe) multi-layer flexible composite films were fabricated via the successive electrodeposition of the flexible PPy layer with a low thermal conductivity, the ultra-thin Te induction layer, and the brittle PbTe layer with a large Seebeck coefficient over the pre-fabricated SWCNT membrane electrode with a high electrical conductivity. Through the complementary advantages between different components and the multiple synergies of the interface engineering, the SWCNT/PPy/Te/PbTe composites harvested the excellent TE performance with a maximum power factor (PF) of 929.8 ± 35.4 µW m-1 K-2 at room temperature, outperforming those of most of the electrochemically-prepared organic/inorganic TE composites reported previously. This work evidenced that the electrochemical multi-layer assembly is a feasible tactic for constructing special thermoelectric materials to meet customized requirements, which could also be applied to other material platforms.

Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: The FUTURE phase II umbrella clinical trial.

Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we report the final results of FUTURE, a phase II umbrella trial designed to explore whether the subtyping-based strategy may improve the outcomes in metastatic TNBC patients. A total of 141 patients with a median of three previous lines of therapies in the metastatic setting were enrolled in seven parallel arms. Confirmed objective responses were achieved in 42 patients (29.8%; 95% confidence interval [CI], 22.4-38.1). The median values of progression-free survival and overall survival were 3.4 (95% CI: 2.7-4.2) and 10.7 (95% CI: 9.1-12.3) months, respectively. Given Bayesian predictive probability, efficacy boundaries were achieved in four arms. Furthermore, integrated genomic and clinicopathological profiling illustrated associations of clinical and genomic parameters with treatment efficacy, and the efficacy of novel antibody-drug conjugates was explored in preclinical TNBC models of subtypes for which treatment was futile. In general, the FUTURE strategy recruits patients efficiently and provides promising efficacy with manageable toxicities, outlining a direction for further clinical exploration.

Robust Acute Pancreatitis Identification and Diagnosis: RAPIDx.

The occurrence of acute pancreatitis (AP) is increasing significantly worldwide. However, current diagnostic methods of AP do not provide a clear clinical stratification of severity, and the prediction of complications in AP is still limited. Here, we present a robust AP identification and diagnosis (RAPIDx) method by the proteomic fingerprinting of intact nanoscale extracellular vesicles (EVs) from clinical samples. By tracking analysis of circulating biological nanoparticles released by cells (i.e., EVs) via bottom-up proteomics, we obtain close phenotype connections between EVs, cell types, and multiple tissues based on their specific proteomes and identify the serum amyloid A (SAA) proteins on EVs as potential biomarkers that are differentially expressed from AP patients significantly. We accomplish the quantitative analysis of EVs fingerprints using MALDI-TOF MS and find the SAA proteins (SAA1-1, desR-SAA1-2, SAA2, SAA1-2) with areas under the curve (AUCs) from 0.92 to 0.97, which allows us to detect AP within 30 min. We further realize that SAA1-1 and SAA2, combined with two protein peaks (5290.19, 14032.33 m/z), can achieve an AUC of 0.83 for classifying the severity of AP. The RAPIDx platform will facilitate timely diagnosis and treatment of AP before severity development and persistent organ failure and promote precision diagnostics and the early diagnosis of pancreatic cancer.

Schisandra B, a representative lignan from Schisandra chinensis, improves cisplatin-induced toxicity: An in vitro study.

Schisandrin B (Scheme B) is the most abundant and active lignan monomer isolated from Schisandra chinensis. At present, most reports focus on its cardioprotective and hepatoprotective effects, however, the related reports on gastrointestinal protective effects are still limited. The study aims to evaluate the protective effect of Scheme B on cisplatin-induced rat intestinal crypt epithelial (IEC-6) cell injury and the possible molecular mechanisms. The results showed that Scheme B at 2.5, 5 and 10 µM could inhibit dose-dependently the reduction of cell activity induced by cisplatin exposure at 1 µM, decrease the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) to alleviate oxidative stress injury in IEC-6 cell lines. Meanwhile, Scheme B could relieve cisplatin-induced apoptosis by regulating PI3K/AKT and the downstream caspase signaling pathway. The results from flow cytometry analysis and mitochondrial membrane potential (MMP) staining also demonstrated the anti-apoptosis effect of Scheme B. Furthermore, Scheme B was found to reduce the inflammation associated with cell damage by evaluating the protein expressions of the nuclear factor-kappa B (NF-κB) signaling pathway. Importantly, Wnt/ß-catenin, as a functional signaling pathway that drives intestinal self-recovery, was also in part regulated by Scheme B. In conclusion, Scheme B might alleviate cisplatin-induced IEC-6 cell damage by inhibiting oxidative stress, apoptosis, inflammation, and repairing intestinal barrier function. The present research provides a strong evidence that Scheme B may be a useful modulator in cisplatin-induced intestinal toxicity.

A randomized controlled trial of a coping-focused family resilience intervention program for breast cancer patients: Study protocol.

Background: Breast cancer patients and their families are under various pressures in the process of disease diagnosis and treatment, which seriously threaten their physical and mental health. Findings from existing research suggest that good family resilience can help breast cancer families better adapt and cope with adversity and challenges. However, there are only a few intervention studies on family resilience and no intervention studies on resilience among the families of breast cancer patients. Therefore, this study aims to explore appropriate measures to improve the resilience level of breast cancer families and help them better cope with the disease. Objective: The purpose of this study protocol is to demonstrate a coping-focused family resilience intervention to increase the level of resilience in the families of breast cancer patients and help them better cope with adversity. Methods: The trial will recruit 80 breast cancer families and randomly assign them to experimental and control groups in a 1:1 ratio. The control group will receive routine care, and the intervention group will receive a 6-week one-on-one online family resilience intervention based on the control group. Two groups of subjects will be assessed at baseline and at 1 week, 1 month, and 3 months after the intervention. The primary outcome is family resilience, and the secondary outcomes are coping style, social support, family disease burden, and levels of anxiety and depression. Expected results: We hypothesized that after the intervention, the intervention group would have significantly higher levels of family resilience than the preintervention and control groups. In the intervention group, other aspects related to family resilience, such as family disease burden and anxiety and depression levels of patients and their families, were significantly alleviated, and disease coping and social support levels were improved accordingly. Discussion: If the program works, it can help breast cancer families identify family strengths and resources to proactively address challenges so that families can successfully navigate the crisis and patient and family recovery can be facilitated. It can also provide a practical path for clinical workers to help breast cancer families adjust rationally. Clinical Trial Registration: This study has been registered in the Chinese Clinical Trials Registry (Registration Number: http://www.chictr.org.cn/ChiCTR2100052108).

Compression Therapy for the Patients With Breast Cancer: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Compression therapy is a common method for treating breast cancer-related lymphedema. However, no specific evidence exists to guide practitioners on the morbidity of lymphedema, limb volume, and range of motion. OBJECTIVE: The aims of this study were to compare the effects of compression therapy and routine nursing during the treatment of breast cancer-related lymphedema and to provide a basis for better clinical decision-making. METHODS: The PubMed, Cochrane Library, EMBASE, Web of Science, CBM, CNKI, Wanfang, and VIP databases were searched through January 21, 2021. Meta-analysis and description of the outcomes were performed by using the RevMan 5.3 software. RESULTS: A total of 17 studies were included. A meta-analysis of 13 studies was conducted. The experimental group had a lower morbidity of lymphedema, the difference was significant, and there was no heterogeneity (P < .05; odds ratio, 0.35, I2 = 31%). There was no significant difference between the experimental group and control group in limb volume, and there was significant heterogeneity (P = .44, mean difference = 4.51, I2 = 85%). Regarding range of motion, the standardized mean difference of shoulder adduction, shoulder lift, shoulder abduction, and shoulder extension were 1.37, 0.69, 0.56, and 0.87, respectively, and the differences were significant; there was heterogeneity (P < .05, I2 = 92%). CONCLUSIONS: Compression therapy can reduce the morbidity of lymphedema and improve limb movement, but the effect on limb volume needs to be further explored. IMPLICATION FOR PRACTICE: In terms of therapeutic effectiveness and limb function, the results provide evidence that physicians can reduce the morbidity of lymphedema, reduce the degree of limb, and increase limb mobility by applying compression therapy.

The role of pirfenidone in the treatment of interstitial pneumonia with autoimmune features.

OBJECTIVES: No approved pharmacotherapies are available for patients with interstitial pneumonia with autoimmune features (IPAF). In the present work, we aimed to evaluate the efficacy and safety of pirfenidone for the treatment of IPAF. METHODS: A retrospective cohort study consisting of patients who met diagnostic criteria for IPAF was performed after a multidisciplinary review, and the patients receiving pirfenidone were compared with those in the non-pirfenidone group. The baseline data and diagnostic characteristics of patients were assessed. Pulmonary function and prednisone dose were analysed by a mix-effects model. RESULTS: A total of 184 patients, who met the diagnostic criteria of IPAF, were divided into two groups: pirfenidone group (n=81) and non-pirfenidone group (n=103). Patients in the pirfenidone group had a lower forced vital capacity (FVC%, p<0.001) and a lower diffusion capacity for carbon monoxide (DLCO%, p=0.003). The pirfenidone group exhibited a greater increase of FVC% at 6 (p=0.003), 12 (p=0.013), and 24 (p=0.003) months. After adjustment for sex, age, UIP pattern, baseline FVC% and DLCO%, patients in the pirfenidone group continued to show a greater improvement in FVC% (χ2(1)=4.59, p=0.032). Subgroup analysis identified superior therapeutic effects of pirfenidone in patients with dosage >600 mg/day (p=0.010) and medication course >12 months (p=0.007). Besides, the pirfenidone group had a lower prednisone dose than the non-pirfenidone group after 12 months of treatment (p=0.002). Moreover, 17 patients (19.32%) experienced side effects after taking pirfenidone, including one case of anaphylactic shock. CONCLUSIONS: Pirfenidone (600-1,800 mg/day) might help improve FVC, with an acceptable safety and tolerability profile in IPAF patients.

Development and assessment of the efficacy and safety of human lung-targeting liposomal methylprednisolone crosslinked with nanobody.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

Taxonomic description of Pseudomonas rhizovicinus sp. nov., isolated from the rhizosphere of a desert shrub Haloxylon ammodendron.

A Gram-negative aerobic bacterium, strain M30-35 T, was isolated from the rhizosphere of Haloxylon ammodendron in Tengger desert, Gansu province, northwest China. Our previous research indicated that strain M30-35 T can promote the growth of ryegrass (Lolium perenne L.). In this study, strain M30-35 T was subjected to a polyphasic taxonomic study. Phylogenetic analysis of the 16S rRNA gene and two other housekeeping genes (gyrB, rpoD) showed that strain M30-35 T is a member of Pseudomonas anguilliseptica group. The average nucleotide identity (ANI) scores for strains KMM 3042 T and FR1439T were 76.5% and 83.7%, respectively, and DNA-DNA hybridization (DDH) were 21.6% and 26.6%, respectively, and the rates were less than the threshold range for species determination. The dominant cellular fatty acids of strain M30-35 T were C16:0 (22.7%), summed feature 3 (C16:1ω7c and/or C16:1ω6c; 18.5%), summed feature 8 (C18:1ω7c and/or C18:1ω6c; 23.1%). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phospholipid and aminophospholipid and the predominant respiratory quinone was ubiquinone (Q9). On the basis of above data, it can be concluded that strain M30-35 T represents a novel species in the genus Pseudomonas, for which the name Pseudomonas rhizovicinus sp. nov. is proposed. The type strain is M30-35 T (= MCCC 1K03247T = KCTC 52664 T).

Family resilience, perceived social support, and individual resilience in cancer couples: Analysis using the actor-partner interdependence mediation model.

PURPOSE: This study aimed to examine the impact of family resilience on the individual resilience of couples during cancer and explore the potential mediating role of perceived social support and the moderating role of sex in this association in cancer patient-spouse dyads. METHOD: The participants were 272 cancer patients and their spouses (N = 544) who completed the Family Resilience Assessment Scale, the Perceived Social Support Scale and the Resilience Scale. We adopted the actor-partner interdependence mediation model to examine whether and how patients' and their spouses' family resilience was associated with their own and their partners' perceived social support and individual resilience. RESULTS: The results indicated that the patients' and their spouses' level of family resilience was positively associated with their own individual resilience directly and indirectly by increasing their own perceived social support. The family resilience of the spouses was associated with an increase in the patients' individual resilience only indirectly by increasing the patients' perceived social support. The spouse-actor effects between family resilience and individual resilience differed significantly by sex. CONCLUSION: Enhancing family resilience and perceived social support within the family can improve individual resilience. The findings regarding the sex differences serve as a rationale for gender-based approaches to improving individual resilience in the family context.

Feasibility and effect of a guided self-disclosure intervention designed to facilitate benefit finding in breast cancer patients: A pilot study.

PURPOSE: This pilot study aimed to evaluate the feasibility and effect of a guided self-disclosure intervention (GSDI) promoting benefit finding (BF) for breast cancer patients. METHODS: A total of 40 women with breast cancer were randomized either to a GSDI group, which included a 6-session face-to-face self-disclosure intervention, or to a control group. The Benefit Finding Scale (BFS) was used to measure BF, the Distress Disclosure Index (DDI) was used to measure self-disclosure, and the Impact of Event Scale-Revised (IES-R) was used to measure cognitive reappraisal. The outcomes were evaluated at baseline and the 3rd and 6th months. RESULTS: The GSDI group had more satisfaction (t = 2.35, P = .02) than the control group and had significant group effects of higher BF (t = 2.214, P = .03) and a lower avoidance of the IES-R (t = -2.353, P = .024) at the 3rd month. There was a significant difference of BF (t = 2.036, P = .049) between the two groups at the 6th month, and other outcomes were not significant (P > .05). Intention-to treat (ITT) analysis showed significant time effects for all outcomes (P < .05); there were slightly significant time × group effects for BF (F = 4.15, P = .052) and disclosure (F = 2.719, P = .090). There were no time × group effects for the other outcomes (all P > .05). CONCLUSION: This study suggests that the GSDI intervention may be feasible in the clinic and might improve BF for breast cancer patients. However, future research needs to further refine the intervention and expand the sample to carry out a full-scale randomized controlled trial.

Platycodin D suppresses cisplatin-induced cytotoxicity by suppressing ROS-mediated oxidative damage, apoptosis, and inflammation in HEK-293 cells.

Cisplatin, a proven effective chemotherapeutic agent, has been used clinically to treat malignant solid tumors, whereas its clinical use is limited by serious side effect including nephrotoxicity. Platycodin D (PD), the major and marked saponin isolated from Platycodon grandiflorum, possesses many pharmacological effects. In this study, we evaluated its protective effect against cisplatin-induced human embryonic kidney 293 (HEK-293) cells injury and elucidated the related mechanisms. Our results showed that PD (0.25, 0.5, and 1 µM) can dose-dependently alleviate oxidative stress by decreasing malondialdehyde and reactive oxygen species, while increasing the levels of glutathione, superoxide dismutase, and catalase. Moreover, the elevation of apoptosis including Bax, Bad, cleaved caspase-3,-9, and decreased protein levels of Bcl-2, Bcl-XL induced by cisplatin were reversed after PD treatment. Importantly, PD pretreatment can also regulate PI3K/Akt and ERK/JNK/p38 signaling pathways. Furthermore, PD was found to reduce NF-κB-mediated inflammatory relative proteins. Our finding indicated that PD exerted significant effects on cisplatin induced oxidative stress, apoptosis and inflammatory, which will provide evidence for the development of PD to attenuate cisplatin-induced nephrotoxicity.

Peripheral cytotoxic T lymphocyte predicts first-line progression free survival in HER2-positive advanced breast cancer.

BACKGROUND: The role of peripheral blood lymphocyte (pBL) in breast cancer has long been studied. However, the predictive role of pBL in advanced breast cancer (ABC) is poorly understood. METHODS: A total of 303 patients with ABC were consecutively recruited at our center between January 2015 and September 2019. At baseline, pBL subtypes were detected in all patients with 229 blood samples available for circulating tumor DNA (ctDNA) detection. pBL was analyzed through flow cytometry. ctDNA-based gene mutations were detected using next generation sequencing. The cutoff value of pCTL was estimated by X-tile software. Progression free survival (PFS) was estimated by Kaplan-Meier curve and Cox hazard proportion regression model, with difference detection by log-rank test. RESULTS: Median follow-up time of the study was 21.0 months. The median age of diagnosis was 52.0 years. Among the pBL subtypes, only pCTL level was found predictive for PFS in the HER2+ patients whom received anti-HER2 therapy (13.1 vs. 5.6 months, P = 0.001). However, the predictive role of pCTL was not found in HR-positive (P = 0.716) and TNBC (P = 0.202). pCTL high associated with suppressive immune indictors including lower CD4/CD8 ratio (P = 0.004) and high level of Treg cell (P = 0.004). High occurrence of FGFR1 amplification which has been reported as immune suppressor was also found in HER2+ patients with pCTL high (22.2% vs. 4.3%, P = 0.048). CONCLUSIONS: Higher pCTLs level associated with shorter PFS and FGFR1 mutation in HER2+ ABC patients.

MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2- advanced breast cancer: the multinational randomized phase III study.

AIM: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. METHODS: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. RESULTS: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346-0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240-0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). CONCLUSION: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Pulchinenoside B4 exerts the protective effects against cisplatin-induced nephrotoxicity through NF-κB and MAPK mediated apoptosis signaling pathways in mice.

Cisplatin (cis-Dichlorodiammine platinum, CP), as the first-line chemotherapy drug of choice for many cancers such as urogenital system tumors and digestive tract tumors, also causes toxicity and side effects to the kidney. Previous studies have shown that Pulsatilla chinensis has significant anti-inflammatory and antioxidant activities, but the mechanism of cisplatin induced acute kidney injury (AKI) in vivo has not been thoroughly studied. The purpose of this study is to investigate the protective effect of pulchinenoside B4 (PB4), a representative and major component with a content of up to 10% in root of P. chinensis, on AKI induced by CP in mice. Our results indicated the significant protective effect of PB4 by evaluating renal function indicators, inflammatory factor levels and renal histopathological changes. In addition, PB4 may mainly act on NF-κB signaling pathway to reduce the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in the kidney after CP exposure, thus exerting anti-inflammatory activity. Furthermore, PB4 regulated MAPK signaling pathway and its downstream apoptotic factors to inhibit the occurrence of apoptosis, such as Bax, Bcl-2, caspase 3 and caspase 9. Notably, the activations of caspase 3 induced by cisplatin were strikingly reduced in PB4-treated mice. Therefore, the above evidence suggested that PB4 is a potential renal protectant with significant anti-inflammatory and anti-apoptotic effects.

Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice.

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.

[Effect of early electroacupuncture intervention on conscious state of patients after traumatic brain injury surgery].

OBJECTIVE: To evaluate recovering consciousness effect of electroacupuncture (EA) on patients after traumatic brain injury (TBI) surgery. METHODS: A total of 100 patients with traumatic coma were randomly divided into an observation group and a control group, 50 cases in each group. The control group was mainly treated with awakening drugs and neurotrophic drugs; on the basis of treatment in the control group, the observation group was treated with EA at Neiguan (PC 6) and Shuigou (GV 26) with disperse-dense wave, 2 Hz/100 Hz in frequency, 0.1-5 mA in intensity. After 30 min of EA, the needles were stayed 60 min. The treatment was performed once a day for 14 consecutive days. The changes in Glasgow coma score (GCS) was observed in the two groups before treatment and after 7, 14 days of treatment; and the two groups were followed up for 3 months after treatment to evaluate the Glasgow outcome scale (GOS) and Barthel index (BI) scores. RESULTS: After 7, 14 days of treatment, the GCS scores of the two groups were higher than those before treatment (P<0.05), and the increase degree in the observation group was significantly larger than that in the control group (P<0.05). At 3 months of follow-up, the GOS and BI scores of the observation group were better than those of the control group (P<0.05). CONCLUSION: Early electroacupuncture intervention can effectively promote the recovery of consciousness after traumatic brain injury surgery, and has a curative long-term effect.

PRMT1 promotes neuroblastoma cell survival through ATF5.

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.