Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma.

Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.

Indirect influence in social networks as an induced percolation phenomenon.

Percolation theory has been widely used to study phase transitions in network systems. It has also successfully explained various macroscopic spreading phenomena across different fields. Yet, the theoretical frameworks have been focusing on direct interactions among nodes, while recent empirical observations have shown that indirect interactions are common in many network systems like social and ecological networks, among others. By investigating the detailed mechanism of both direct and indirect influence on scientific collaboration networks, here we show that indirect influence can play the dominant role in behavioral influence. To address the lack of theoretical understanding of such indirect influence on the macroscopic behavior of the system, we propose a percolation mechanism of indirect interactions called induced percolation. Surprisingly, our model exhibits a unique anisotropy property. Specifically, directed networks show first-order abrupt transitions as opposed to the second-order continuous transition in the same network structure but with undirected links. A mix of directed and undirected links leads to rich hybrid phase transitions. Furthermore, a unique feature of the nonmonotonic pattern is observed in network connectivities near the critical point. We also present an analytical framework to characterize the proposed induced percolation, paving the way to further understanding network dynamics with indirect interactions.

Molecular phylogeny of Hesperiidae (Lepidoptera) with an emphasis on Asian and African genera.

Despite considerable research efforts in recent years, the deeper phylogenetic relationships among skipper butterflies (Hesperiidae) remain unresolved. This is primarily because of limited sampling, especially within Asian and African lineages. In this study, we consolidated previous data and extensively sampled Asian and African taxa to elucidate the phylogenetic relationships within Hesperiidae. The molecular dataset comprised sequences from two mitochondrial and two nuclear gene regions from 563 species that represented 353 genera. Our analyses revealed seven subfamilies within Hesperiidae: Coeliadinae, Euschemoninae, Eudaminae, Pyrginae, Heteropterinae, Trapezitinae, and Hesperiinae. The systematics of most tribes and genera aligned with those of prior studies. However, notable differences were observed in several tribes and genera. Overall, the position of taxa assigned to incertae sedis in Hesperiinae is largely clarified in this study. Our results strongly support the monophyly of the tribe Tagiadini (Pyrginae), and the systematics of some genera are clarified with comprehensive discussion. We recognize 15 tribes within the subfamily Hesperiinae. Of these, nine tribes are discussed in detail: Aeromachini, Astictopterini, Erionotini, Unkanini (new status), Ancistroidini, Ismini (confirmed status), Plastingini (new status), Gretnini (confirmed status), and Eetionini (confirmed status). We propose four subtribes within Astictopterini: Hypoleucina subtrib.n., Aclerosina, Cupithina, and Astictopterina. Furthermore, we describe a new genus (Hyarotoidesgen.n.) and reinstate two genera (Zeareinst.stat. and Separeinst.stat.) as valid. Additionally, we propose several new combinations: Zea mythecacomb.n.,Sepa bononiacomb.n. & reinst.stat., and Sepa umbrosacomb.n. This study, with extensive sampling of Asian and African taxa, greatly enhances the understanding of the knowledge of the skipper tree of life.

Assessing the causal relationship between 731 immunophenotypes and the risk of lung cancer: a bidirectional mendelian randomization study.

BACKGROUND: Previous studies have observed a link between immunophenotypes and lung cancer, both of which are closely associated with genetic factors. However, the causal relationship between them remains unclear. METHODS: Bidirectional Mendelian randomization (MR) was performed on publicly available genome-wide association study (GWAS) summary statistics to analyze the causal relationships between 731 immunophenotypes and lung cancer. Sensitivity analyses were conducted to verify the robustness, heterogeneity, and potential horizontal pleiotropy of our findings. RESULTS: Following Bonferroni adjustment, CD14- CD16+ monocyte (OR = 0.930, 95%CI 0.900-0.960, P = 8.648 × 10- 6, PBonferroni = 0.006) and CD27 on CD24+ CD27+ B cells (OR = 1.036, 95%CI 1.020-1.053, P = 1.595 × 10 - 5, PBonferroni = 0.012) were identified as having a causal role in lung cancer via the inverse variance weighted (IVW) method. At a more relaxed threshold, CD27 on IgD+ CD24+ B cell (OR = 1.035, 95%CI 1.017-1.053, P = 8.666 × 10- 5, PBonferroni = 0.063) and CD27 on switched memory B cell (OR = 1.037, 95%CI 1.018-1.056, P = 1.154 × 10- 4, PBonferroni = 0.084) were further identified. No statistically significant effects of lung cancer on immunophenotypes were found. CONCLUSIONS: The elevated level of CD14- CD16+ monocytes was a protective factor against lung cancer. Conversely, CD27 on CD24+ CD27+ B cell was a risk factor. CD27 on class-switched memory B cells and IgD+ CD24+ B cells were potential risk factors for lung cancer. This research enhanced our comprehension of the interplay between immune responses and lung cancer risk. Additionally, these findings offer valuable perspectives for the development of immunologically oriented therapeutic strategies.

Pnpla5-knockout rats exhibit reduced expression levels of proteins involved in steroid metabolism and wound healing compared to wild-type rats.

BACKGROUND: Patatin-like phospholipase domain containing 5 (PNPLA5) is a newly-discovered lipase. Although the PNPLA family plays critical roles in diverse biological processes, the biological functions of PNPLA5 mostly unknown. We previously found that the deletion of Pnpla5 in rats causes a variety of phenotypic abnormalities. In this study, we further explored the effects of Pnpla5 knockout (KO) on male rats. RESULTS: The body weight and testicular or epididymal tissue weight of three to six 3-month-old Pnpla5 KO or wild-type (WT) male Sprague-Dawley rats were measured. The protein expression levels were also measured via western blotting and iTRAQ (isobaric tags for relative and absolute quantitation) analyses. No significant difference between Pnpla5 KO and WT rats, regarding body weight, testicular or epididymal tissue weight, or hormone levels, were found. However, the relative testicular tissue weight of the KO (Pnpla5-/-) rats was higher (P < 0.05) than that of WT rats. Significant increases in apoptotic cells numbers (P < 0.001) and BAX and Caspase-9 expression levels were observed in the testicular tissue of Pnpla5-/- rats. Moreover, iTRAQ analysis revealed that the levels of proteins involved in steroid metabolism and wound healing were significantly decreased in Pnpla5-/- rats. CONCLUSION: This study revealed that Pnpla5 knockout induced apoptosis in rat testes. We also ascertained that Pnpla5 plays an important role in lipid metabolism, wound healing, and affects reproductive organs negatively, providing new target genes and pathways that can be analyzed to unravel the biological function of Pnpla5.

Multiple Enhanced Sparse Representation via IACMDSR Model for Bearing Compound Fault Diagnosis.

For the sake of addressing the issue of extracting multiple features embedded in a noise-heavy vibration signal for bearing compound fault diagnosis, a novel model based on improved adaptive chirp mode decomposition (IACMD) and sparse representation, namely IACMDSR, is developed in this paper. Firstly, the IACMD is employed to simultaneously separate the distinct fault types and extract multiple resonance frequencies induced by them. Next, an adaptive bilateral wavelet hyper-dictionary that digs deeper into the periodicity and waveform characteristics exhibited by the real fault impulse response is constructed to identify and reconstruct each type of fault-induced feature with the help of the orthogonal matching pursuit (OMP) algorithm. Finally, the fault characteristic frequency can be detected via an envelope demodulation analysis of the reconstructed signal. A simulation and two sets of experimental results confirm that the developed IACMDSR model is a powerful and versatile tool and consistently outperforms the leading MCKDSR and MCKDMWF models. Furthermore, the developed model has satisfactory capability in practical applications because the IACMD has no requirement for the input number of the signal components and the adaptive bilateral wavelet is powerfully matched to the real fault-induced impulse response.

Numerical Model Driving Multi-Domain Information Transfer Method for Bearing Fault Diagnosis.

Given the complexity of the application scenarios of rolling bearing and the severe scarcity of fault samples, a solution to the issue of fault diagnosis under varying working conditions along with the absence of fault samples is required. A numerical model-driven cross-domain fault diagnosis method targeting variable working conditions is proposed based on the cross-Domain Nuisance Attribute Projection (cDNAP). Firstly, the simulation datasets consisting of multiple fault types under variable working conditions are constructed to solve the problem of incomplete fault samples. Secondly, the simulation datasets are expanded by means of generating adversarial network to ensure sufficient samples for subsequent model training. Finally, cDNAP is used to obtain the cross-domain simulation projection matrix, which eliminates the variance in the distribution of measured and simulated sample features under varying working conditions. The experimental results of cross-domain for variable working conditions show that the diagnostic accuracy reaches up to 99%. Compared with DANN, DSAN, and DAAN domain adversarial neural networks, the proposed method performs better in bearing fault diagnosis.

Comparison of the outcome of different bone grafts combined with modified core decompression for the treatment of ARCO II stage femoral head necrosis.

PURPOSE: Treatment of ONFH at an early stage is a challenging issue. The modified minimally invasive core decompression combined with bone graft implantation remains controversial. This study aimed to compare the early-middle outcomes of four groups with different bone grafts. METHODS: A total of 182 patients (192 hips) with ONFH at the ARCO II stage were randomly divided into four groups. The free fibular graft group (FFG), free vascularized fibular graft group (FVFG), autologous iliac bone group (ABG), and ß-tricalcium bioceramics phosphate graft (ß-TCPG) group. Each group was treated with the modified minimally invasive core decompression and bone graft implantation. The operation time and blood loss were recorded by the same observer. The clinical outcome was evaluated by the Harris Hip Score and VAS score (before, 14 days after surgery, and at the last follow-up). The radiographic progression of ONFH was evaluated at least 36 months of follow-up. RESULTS: All cases were successful without any complications after the operation. The patients were followed up for 42 to 48 (44.62 ± 1.81) months. There were statistically significant differences among the four groups in operation time (F value = 1520.67; P < 0.01) and blood loss (F value = 5366.81; P < 0.01). The Harris Hip Score in each group was improved significantly from pre-operation to last follow-up (all P < 0.01). At the last follow-up, the difference in the Harris Hip Score in each group was not statistically significant (F value = 0.54; P = 0.984). The VAS scores in each group were decreased significantly from the pre-operation to14 days after surgery (all P < 0.01). At 14 days after surgery, the difference in the VAS score in each group was not statistically significant (F value = 0.64; P = 0.59). At the last follow-up, three hips collapsed on the femoral head in the FFG group, two in the FVFG group, two in the ABG group, and three in the ß-TCPG group. CONCLUSION: The four different bone graft implantation showed satisfactory early-middle outcomes. As compared to other bone grafts, the ß-TCP bioceramics graft has the advantages of shorter operation time and lesser blood loss. It may be a choice as a bone graft for the treatment of ONFH at an early stage.

Integrative Proteomic and Phosphoproteomic Profiling of Testis from Wip1 Phosphatase-Knockout Mice: Insights into Mechanisms of Reduced Fertility.

Mice lacking wild-type p53-induced phosphatase 1 (Wip1) display male reproductive defects including smaller testes, subfertility and spermatogenesis defects at the round- and elongating-spermatid stages. However, the molecular mechanisms underlying these abnormalities remain unclear. Here we examined the proteome and phosphoproteome of testes from Wip1-knockout mice using a quantitative proteomic approach. From a total of 6872 proteins and 4280 phosphorylation sites identified, 58 proteins and 159 phosphorylation sites were found to be differentially regulated compared with wild type mice. Pathway enrichment analyses revealed that these regulated proteins and phosphosites were mainly involved in adherens/tight junctions, apoptosis, inflammatory response, spermatogenesis, sperm motility, and cytoskeletal assembly and depolymerization. Wip1-knockout mice showed decreased expression of junction-associated proteins (occludin, ZO-1, and N-cadherin) and impaired integrity of the blood-testis barrier. In addition, Wip1 deficiency was associated with elevated levels of cytokines and germ cell apoptosis in the testis. These results suggest that proinflammatory cytokines may impair the blood-testis barrier dynamics by decreasing the expression of junction-associated proteins, which could lead to subfertility and spermatogenesis defects. Collectively, these findings help to explain the low reproductive function caused by Wip1 deletion and provide novel insights into our understanding of causes of male infertility.

Local structure can identify and quantify influential global spreaders in large scale social networks.

Measuring and optimizing the influence of nodes in big-data online social networks are important for many practical applications, such as the viral marketing and the adoption of new products. As the viral spreading on a social network is a global process, it is commonly believed that measuring the influence of nodes inevitably requires the knowledge of the entire network. Using percolation theory, we show that the spreading process displays a nucleation behavior: Once a piece of information spreads from the seeds to more than a small characteristic number of nodes, it reaches a point of no return and will quickly reach the percolation cluster, regardless of the entire network structure; otherwise the spreading will be contained locally. Thus, we find that, without the knowledge of the entire network, any node's global influence can be accurately measured using this characteristic number, which is independent of the network size. This motivates an efficient algorithm with constant time complexity on the long-standing problem of best seed spreaders selection, with performance remarkably close to the true optimum.

Subcutaneous botulinum toxin-A injection for treating postherpetic neuralgia.

Postherpetic neuralgia (PHN) is a debilitating disease characterized by continuous, intense pain following an outbreak of herpes zoster. The pain associated with PHN can severely affect a patient's quality of life, quality of sleep, and ability to participate in activities of daily living. The aim of this study was to explore the clinical efficacy of the subcutaneous injection of botulinum toxin-A (BTX-A) for the treatment of PHN. Thirteen patients with PHN were enrolled in this study and treated once with BTX-A. The effects of BTX-A on pain were measured with the visual analogue scale (VAS) 1, 2, 4, 8, 12, and 16 weeks after administration. Compared with pretreatment scores, VAS pain scores decreased at 2 weeks post-treatment in all patients. All patients felt varying degrees of pain relief but remained comfortable. Compared with oral analgesic drugs, VAS scores were significantly different at 2, 4, 8, 12, and 16 weeks post-treatment (p < .05). These results demonstrated that subcutaneous administration of BTX-A can decrease pain in patients with PHN.

Eradicating catastrophic collapse in interdependent networks via reinforced nodes.

In interdependent networks, it is usually assumed, based on percolation theory, that nodes become nonfunctional if they lose connection to the network giant component. However, in reality, some nodes, equipped with alternative resources, together with their connected neighbors can still be functioning after disconnected from the giant component. Here, we propose and study a generalized percolation model that introduces a fraction of reinforced nodes in the interdependent networks that can function and support their neighborhood. We analyze, both analytically and via simulations, the order parameter-the functioning component-comprising both the giant component and smaller components that include at least one reinforced node. Remarkably, it is found that, for interdependent networks, we need to reinforce only a small fraction of nodes to prevent abrupt catastrophic collapses. Moreover, we find that the universal upper bound of this fraction is 0.1756 for two interdependent Erdos-Rényi (ER) networks: regular random (RR) networks and scale-free (SF) networks with large average degrees. We also generalize our theory to interdependent networks of networks (NONs). These findings might yield insight for designing resilient interdependent infrastructure networks.

Coevolution spreading in complex networks.

The propagations of diseases, behaviors and information in real systems are rarely independent of each other, but they are coevolving with strong interactions. To uncover the dynamical mechanisms, the evolving spatiotemporal patterns and critical phenomena of networked coevolution spreading are extremely important, which provide theoretical foundations for us to control epidemic spreading, predict collective behaviors in social systems, and so on. The coevolution spreading dynamics in complex networks has thus attracted much attention in many disciplines. In this review, we introduce recent progress in the study of coevolution spreading dynamics, emphasizing the contributions from the perspectives of statistical mechanics and network science. The theoretical methods, critical phenomena, phase transitions, interacting mechanisms, and effects of network topology for four representative types of coevolution spreading mechanisms, including the coevolution of biological contagions, social contagions, epidemic-awareness, and epidemic-resources, are presented in detail, and the challenges in this field as well as open issues for future studies are also discussed.

Clinical efficacy of paiteling in the treatment of condyloma acuminatum infected with different subtypes of HPV.

Condyloma acuminatum (CA) is a type of mucosal benign hyperplasia skin disease that is caused by human papillomavirus (HPV) infection, which mainly occurs in the genitalia and anus. The aim of the present study was to explore the clinical efficacy underlying the traditional Chinese medicine paiteling in the treatment of CA via the detection of HPV. One hundred CA patients were enrolled in the current study and were externally treated with paiteling for 5 weeks. HPV subtypes were examined both before the treatment and at 6 months after the treatment. After the external paiteling therapy, 92 cases were cured, and the apparent efficiency was 92.0% (92/100), while 8 cases exhibited recurrence. Before the external paiteling therapy, the numbers of cases of low-risk, high-risk, and mixed types of HPV were 40, 35, and 25, respectively. At 6 months after treatment, the numbers of negative cases of low-risk, high-risk, and mixed types of HPV were 38, 32, and 20, respectively. The results demonstrated that external paiteling treatment has a good curative effect on the treatment of CA.

Effects of CO2 fractional laser therapy on peripheral blood cytokines in patients with vitiligo.

Vitiligo is a disease pathologically characterized by specific damage to melanocytes. The aim of this study was to explore the mechanism underlying CO2 fractional laser treatment of vitiligo by detecting the levels of Th1 cytokines (IL-2 and IFN-γ), Th2 cytokines (IL-4 and IL-10), and Th17 cytokines (IL-17 and IL-23) in peripheral blood. Twenty five vitiligo patients were enrolled in this study and were treated with a CO2 fractional laser four to eight times. The cytokines of 25 vitiligo patients and 20 healthy volunteers were measured by enzyme-linked immunosorbent assay. After CO2 fractional laser therapy, six cases were cured, and the apparent efficiency was 72.0% (18/25), while the efficiency was 92.0% (23/25). Before CO2 fractional laser therapy, IL-2 and IFN-γ levels in vitiligo patients were higher than those in the control group, but the difference was not statistically significant (p > .05). IL-4, IL-10, IL-17, and IL-23 levels were also higher in vitiligo patients than those in the control group (p < .05). After treatment, IL-2 and IFN-γ levels in vitiligo patients were lower than before treatment, but the difference was not statistically significant (p > .05), while IL-4, IL-10, IL-17, and IL-23 levels were significantly lower compared with before treatment (p < .05). The results show that CO2 fractional laser treatment has a good curative effect in the treatment of vitiligo.

Eradicating abrupt collapse on single network with dependency groups.

The dependency among nodes has significant effects on the cascading failures of complex networks. Although the prevention of cascading failures on multilayered networks in which the failures of nodes in one layer affect the functioning of nodes in other layers has been widely investigated, the prevention of catastrophic cascade has rarely been addressed to single-layer networks where nodes are grouped and nodes within the same group are dependent on each other. For such networks, we find that it is already enough to prevent abrupt catastrophic collapses by randomly reinforcing a constant density of nodes. More importantly, we give the analytical solutions to the proportion of needed reinforced nodes for three typical networks, i.e., dependent Erdos-Rényi (ER), random regular (RR), and scale-free (SF) networks. Interestingly, the density of reinforced nodes is a constant 0.1756, which holds true for ER networks with group size 2 regardless of average degree, RR, and SF networks with a large average degree. Also, we find the elegant expression of the density with any group size. In addition, we find a hybrid phase transition behavior, which is present in RR and SF networks while absent in ER networks. Our findings might shed some new light on designing more resilient infrastructure networks.

Lower bound of network dismantling problem.

The network dismantling problem is one of the most fundamental problems in network science. It aims to identify the minimum number of nodes, such that after their removal the network is broken into many disconnected pieces with a sub-extensive size. However, the identification of the minimum removed nodes belongs to the class of nondeterministic polynomial problems. Although many heuristic algorithms have been proposed to identify the removed nodes, the smallest dismantling set remains unknown. Therefore, the determination of a good lower bound of dismantling sets is of great significance to evaluating the performances of heuristic algorithms. The minimum number of deleted nodes to dismantle a network is strictly no smaller than that to dismantle its any subnetwork in nature. Any lower bound of a subnetwork is indeed a lower bound of the original network. Utilizing the heterogeneous degree distribution and 2-core properties, we find that with previous removal of some appropriate nodes, the lower bound obtained on the basis of the subnetwork is counterintuitively significantly better than the one obtained directly on the original network, especially for the real-world networks.

A Case Report of Penile Infection Caused by Fluconazole- and Terbinafine-Resistant Candida albicans.

Candida albicans is the most common pathogen that causes balanoposthitis. It often causes recurrence of symptoms probably due to its antifungal resistance. A significant number of balanitis Candida albicans isolates are resistant to azole and terbinafine antifungal agents in vitro. However, balanoposthitis caused by fluconazole- and terbinafine-resistant Candida albicans has rarely been reported. Here, we describe a case of a recurrent penile infection caused by fluconazole- and terbinafine-resistant Candida albicans, as well as the treatments administered to this patient. The isolate from the patient was tested for drug susceptibility in vitro. It was sensitive to itraconazole, voriconazole, clotrimazole and amphotericin B, but not to terbinafine and fluconazole. Thus, oral itraconazole was administrated to this patient with resistant Candida albicans penile infection. The symptoms were improved, and mycological examination result was negative. Follow-up treatment of this patient for 3 months showed no recurrence.

Oral perfluorooctane sulfonate (PFOS) lessens tumor development in the APCmin mouse model of spontaneous familial adenomatous polyposis.

BACKGROUND: Colorectal cancer is the second most common cause of cancer deaths for both men and women, and the third most common cause of cancer in the U.S. Toxicity of current chemotherapeutic agents for colorectal cancer, and emergence of drug resistance underscore the need to develop new, potentially less toxic alternatives. Our recent cross-sectional study in a large Appalachian population, showed a strong, inverse, dose-response association of serum perfluorooctane sulfonate (PFOS) levels to prevalent colorectal cancer, suggesting PFOS may have therapeutic potential in the prevention and/or treatment of colorectal cancer. In these preliminary studies using a mouse model of familial colorectal cancer, the APCmin mouse, and exposures comparable to those reported in human populations, we assess the efficacy of PFOS for reducing tumor burden, and evaluate potential dose-response effects. METHODS: At 5-6 weeks of age, APCmin mice were randomized to receive 0, 20, 250 mg PFOS/kg (females) or 0, 10, 50 and 200 mg PFOS/kg (males) via their drinking water. At 15 weeks of age, gastrointestinal tumors were counted and scored and blood PFOS levels measured. RESULTS: PFOS exposure was associated with a significant, dose-response reduction in total tumor number in both male and female mice. This inverse dose-response effect of PFOS exposure was particularly pronounced for larger tumors (r2 for linear trend = 0.44 for males, p's <0.001). CONCLUSIONS: The current study in a mouse model of familial adenomatous polyposis offers the first experimental evidence that chronic exposure to PFOS in drinking water can reduce formation of gastrointestinal tumors, and that these reductions are both significant and dose-dependent. If confirmed in further studies, these promising findings could lead to new therapeutic strategies for familial colorectal cancer, and suggest that PFOS testing in both preventive and therapeutic models for human colorectal cancer is warranted.