Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies.

Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy.

Formation of photonic band gaps by direct destructive interference.

We study a photonic band gap (PBG) material consisting of multiple waveguides. The multiconnected waveguides provide different paths for direct wave interference within the material. Using coaxial cables as waveguides, we are able to tune the PBG of the material. Using direct destructive interference between different paths of the waveguides, we experimentally observe a kind of PBG which is quite different from the traditional PBG that is caused by scattering in dielectrics with inhomogeneous refractive indices. Particularly, this newly observed PBG has an extremely strong wave attenuation, making electromagnetic (EM) waves in the PBG cannot even pass through one unit cell under certain conditions. We also systematically investigate the transmission of EM waves in our PBG materials and discuss the mechanism of band gap formation. Our results provide a new insight to develop new band gap materials for photons and phonons.

Five-year long-term comparison of robotic and laparoscopic gastrectomy for gastric cancer: a large single-center cohort study.

BACKGROUND: Robotic gastrectomy (RG) has been reported to be technically feasible and safe for patients with gastric cancer. However, 5-year long-term survival and recurrence outcomes for advanced gastric cancer have rarely been reported. This study aimed to compare the long-term oncologic outcomes between RG and laparoscopic gastrectomy (LG) for gastric cancer. METHODS: The general clinicopathological data of 1905 consecutive patients who underwent RG and LG were retrospectively collected at the Chinese People's Liberation Army General Hospital between November 2011 and October 2017. Propensity score matching (PSM) was used to match groups. The primary endpoints were 5-year disease-free survival (DFS) and overall survival (OS). RESULTS: After PSM, a well-balanced cohort of 283 patients in the RG group and 701 patients in the LG group were included in the analysis. The 5-year cumulative DFS rates were 67.28% in the robotic group and 70.41% in the laparoscopic group. The 5-year OS rate was 69.01% in the robotic group and 69.58% in the laparoscopic group. No significant differences in Kaplan-Meier survival curves for DFS (HR = 1.08, 95% CI 0.83-1.39, Log-rank P = 0.557) and OS (HR = 1.02, 95% CI 0.78-1.34, Log-rank P = 0.850) were observed between the 2 groups. In the subgroup analyses for potential confounding variables, there were no significant differences in 5-year DFS and 5-year OS survival between the 2 groups (P > 0.05), except for patients with pathological stage III and pathological stage N3 (P < 0.05). CONCLUSION: For patients with early gastric cancer, robotic and laparoscopic approaches have similar long-term survival. For patients with advanced gastric cancer, further studies need to be conducted to assess the long-term survival outcomes of RG.

Graphene metalens with dynamic focusing and plane focusing in the terahertz range.

We theoretically propose a high-efficiency tunable metalens based on an ellipse-shaped perforated graphene metasurface. By optimizing the axial length ratio of the elliptical aperture, we find the elliptical aperture with high reflectivity over a broad band by means of observing the reflectivity at different frequencies. Then, varying the orientation of the elliptical aperture from 0° to 180°, the reflected wave can generate a continuous 2π range phase shift while keeping its amplitude high, which is necessary to achieve focusing. The metalens exhibits extraordinary tunability of focal length via uniformly changing the Fermi energy of graphene. The focus can be shifted above 72 µm with focusing efficiency reaching over 70%. In addition, the tunable metalens is also capable of broadband focusing modulation and plane focusing. The presented metalens exhibits outstanding focusing efficiency in dynamic focusing, thereby manifesting great practicability in dynamic imaging and robust stable imaging.

Bone Marrow-Derived Mesenchymal Stem Cells Promoted Cutaneous Wound Healing by Regulating Keratinocyte Migration via ß2-Adrenergic Receptor Signaling.

Mesenchymal stem cells (MSCs) play an important role in cutaneous wound healing; however, the functional mechanisms involved in the healing process are poorly understood. A series of studies indicate that keratinocytes that migrate into the wound bed rely on an epithelial-mesenchymal transition (EMT)-like process to initiate re-epithelialization. We therefore examined whether bone marrow-derived MSCs (BMSCs) could affect biological behavior and induce EMT-like characteristics in the human epidermal keratinocytes (HEKs) and in the immortalized human keratinocyte cell line HaCaT cells, and we investigated the signaling pathways of BMSC-mediated phenotypic changes. By assessing the expression of EMT-related markers including E-cadherin, α-SMA, and Snail family transcription factors by ß2-adrenergic receptor (ß2-AR) blockage using ICI-118,551, a ß2-AR selective antagonist, or ß2-AR small interfering RNA (siRNA), we showed an involvement of ß2-AR signaling in the induction of EMT-like alterations in human keratinocytes in vitro. ß2-AR signaling also affected collective and individual cell migration in human keratinocyte cell lines, which was attenuated by administration of ICI-118,551. Treating the cells with BMSC-conditioned media (BMSC-CM) not only recapitulated the effect of isoproterenol (ISO) on cell migration but also induced the expression of ß2-AR and a panel of proteins associated with mesenchymal phenotype in HEKs and HaCaT cells. Similarly, a blockade of the ß2-AR by either ICI-118,551 or ß2-AR siRNAs reversed both responses of the epidermal keratinocyte cell lines relative to BMSC-CM exposure. These results were further verified in our vivo findings and indicated that the exogenous application of MSCs promoted cutaneous wound healing and endowed the keratinocytes surrounding the wound area with an increased migratory phenotype through activation of ß2-AR signaling. Our findings suggest a biochemical mechanism underlying the function of MSCs in wound re-epithelization, which provides a reliable theoretical basis for the wide application of MSCs in the treatment of chronic wounds.

Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets.

The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.

Lanthanum-Catalyzed Stereospecific Cross-Coupling of Propargylic Substrates with Grignard Reagents.

Transition-metal-catalyzed cross-coupling of propargylic electrophiles and Grignard reagents provides densely functionalized products that are extremely useful synthetic intermediates. However, examples of conversion of propargylic derivatives to form propargyl compounds remain limited due to the challenging regioselectivity. We use LaCl3·2LiCl to catalyze propargylation of Grignard reagents in the absence of ligand in high regioselectivity and stereospecificity. The approach shows a wide substrate scope using alkyl or (hetero)aryl Grignard reagents and alkynyl electrophiles with different leaving groups. Our protocol was further applied for the formal synthesis of frondosin B. It is worth exploring methodologies utilizing the naturally abundant and relatively nontoxic lanthanum catalysts.

Construction of a fecal immune-related protein-based biomarker panel for colorectal cancer diagnosis: a multicenter study.

Purpose: To explore fecal immune-related proteins that can be used for colorectal cancer (CRC) diagnosis. Patients and methods: Three independent cohorts were used in present study. In the discovery cohort, which included 14 CRC patients and 6 healthy controls (HCs), label-free proteomics was applied to identify immune-related proteins in stool that could be used for CRC diagnosis. Exploring potential links between gut microbes and immune-related proteins by 16S rRNA sequencing. The abundance of fecal immune-associated proteins was verified by ELISA in two independent validation cohorts and a biomarker panel was constructed that could be used for CRC diagnosis. The validation cohort I included 192 CRC patients and 151 HCs from 6 different hospitals. The validation cohort II included 141 CRC patients, 82 colorectal adenoma (CRA) patients, and 87 HCs from another hospital. Finally, the expression of biomarkers in cancer tissues was verified by immunohistochemistry (IHC). Results: In the discovery study, 436 plausible fecal proteins were identified. And among 67 differential fecal proteins (|log2 fold change| > 1, P< 0.01) that could be used for CRC diagnosis, 16 immune-related proteins with diagnostic value were identified. The 16S rRNA sequencing results showed a positive correlation between immune-related proteins and the abundance of oncogenic bacteria. In the validation cohort I, a biomarker panel consisting of five fecal immune-related proteins (CAT, LTF, MMP9, RBP4, and SERPINA3) was constructed based on the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. The biomarker panel was found to be superior to hemoglobin in the diagnosis of CRC in both validation cohort I and validation cohort II. The IHC result showed that protein expression levels of these five immune-related proteins were significantly higher in CRC tissue than in normal colorectal tissue. Conclusion: A novel biomarker panel consisting of fecal immune-related proteins can be used for the diagnosis of CRC.

Donor-derived and off-the-shelf allogeneic anti-CD19 CAR T-cell therapy for R/R ALL and NHL: A systematic review and meta-analysis.

Allogeneic anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has the potential for extensive clinical applications. This study aimed to evaluate its efficacy and safety in treating relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Four databases were searched for relevant studies. Among patients treated with donor-derived CAR T-cell therapy, ALL patients had a complete remission (CR) rate of 80 % and a 1-year overall survival rate of 51 %. The graft-versus-host disease (GvHD) rate was 4 %, cytokine release syndrome was 69 %, and immune effector cell-associated neurotoxicity syndrome was 8 %. For off-the-shelf CAR T-cell therapy, the CR rate for ALL was 70 %, and for NHL, it was 52 %. The objective response rate for NHL was 72 %. The pooled GvHD of off-the-shelf CAR T-cell therapy for ALL and NHL combined was 0 %. Allogeneic anti-CD19 CAR T-cell therapy are effective and safe for treating R/R ALL and NHL. AVAILABILITY OF DATA AND MATERIALS: All datasets generated in this study are included in the article/Supplementary Material.

Systematic analysis and case series of the diagnosis and management of trichilemmal carcinoma.

Background: Trichilemmal carcinoma (TLC) is a rare malignant cutaneous adnexal neoplasm, with no relatively comprehensive research. Objective: The aim of this study is to perform an updated statistical analysis so as to better understand TLC's epidemiology, clinical features, diagnosis, and treatment. Methods: The diagnosis and treatment of three TLC cases in our department were summarized. Then, all TLC cases published in the literature were retrieved for a comprehensive analysis, followed by the analysis of global trends and regional distribution, demographic characteristics, clinical features, pathogenesis, histopathological features, and treatment and prognosis of TLC. Results: Of the 231 cases, the incidence of TLC has shown an upward trend recently, especially in China, in Asia. The susceptible population is men aged 60-80 and women over 80, and the most prone location is head and neck. The phenotype of TLC is not always typical and may be misdiagnosed because of the coexistence of other diseases. There is a linear relationship between the diameter and its duration or thickness. UV, locally present skin lesions, trauma, scarring, organ transplantation, and genetic disorders may trigger the occurrence of TLC. Periodic acid-Schiff staining and CD34, but not Epithelial Membrane Antigen (EMA), were helpful in the diagnosis of TLC. Although effective, surgical excision and Mohs micrographic surgery need further improvement to reduce recurrence of TLC. Carcinoma history is an independent risk factor for TLC recurrence. Limitations: The limitation of this study is the lack of randomized controlled trial on TLC treatment and recurrence. Conclusion: TLC has the possibility of invasive growth and recurrence, especially in patients with longer duration and carcinoma history.

The complete mitochondrial genome of Agelasta perplexa Pascoe (Coleoptera: Cerambycidae).

Agelasta perplexa Pascoe is a mulberry borer that threatens the health of the plant. This study revealed the length of the complete mitochondrial genome of A. perplexa which consists of 15,552 bp length with 39.8% A, 12.8% C, 8.4% G, and 39.1% T, respectively. The GC content of whole mitochondrial genome is 21.1%. The complete mitochondrial genome encodes 12 protein-coding genes (PCGs), 22 tRNAs, two rRNAs, and one AT-rich region. This study can facilitate further research about genetic evolution as well as prevention and control strategy of A. perplexa.

Sweat Gland Organoids Originating from Reprogrammed Epidermal Keratinocytes Functionally Recapitulated Damaged Skin.

Restoration of sweat glands (SwGs) represents a great issue in patients with extensive skin defects. Recent methods combining organoid technology with cell fate reprogramming hold promise for developing new regenerative methods for SwG regeneration. Here, a practical strategy for engineering functional human SwGs in vitro and in vivo is provided. First, by forced expression of the ectodysplasin-A in human epidermal keratinocytes (HEKs) combined with specific SwG culture medium, HEKs are efficiently converted into SwG cells (iSwGCs). The iSwGCs show typical morphology, gene expression pattern, and functions resembling human primary SwG cells. Second, by culturing the iSwGCs in a special 3D culturing system, SwG organoids (iSwGOs) that exhibit structural and biological features characteristic of native SwGs are obtained. Finally, these iSwGOs are successfully transplanted into a mouse skin damage model and they develop into fully functioning SwGs in vivo. Regeneration of functional SwG organoids from reprogrammed HEKs highlights the great translational potential for personalized SwG regeneration in patients with large skin defects.

Sweat gland regeneration: Current strategies and future opportunities.

For patients with extensive skin defects, loss of sweat glands (SwGs) greatly decreases their quality of life. Indeed, difficulties in thermoregulation, ion reabsorption, and maintaining fluid balance might render them susceptible to hyperthermia, heatstroke, or even death. Despite extensive studies on the stem cell biology of the skin in recent years, in-situ regeneration of SwGs with both structural and functional fidelity is still challenging because of the limited regenerative capacity and cell fate control of resident progenitors. To overcome these challenges, one must consider both the intrinsic factors relevant to genetic and epigenetic regulation and cues from the cellular microenvironment. Here, we describe recent progress in molecular biology, developmental pathways, and cellular evolution associated with SwGdevelopment and maturation. This is followed by a summary of the current strategies used for cell-fate modulation, transmembrane drug delivery, and scaffold design associated with SwGregeneration. Finally, we offer perspectives for creating more sophisticated systems to accelerate patients' innate healing capacity and developing engineered skin constructs to treat or replace damaged tissues structurally and functionally.