Role of radiation in chimeric antigen receptor T-cell therapy for patients with relapsed/refractory non-Hodgkin lymphoma: Current studies and future prospects.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment approach for patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). However, the long-term prognosis has been discouraging. Moreover, the urgent resolution of two critical issues is necessary: minimize tumor burden before CAR-T infusion and control fatal toxicities post CAR-T therapy. By combining radiotherapy (RT), the safety and efficacy of CAR-T can be improved. RT can serve as bridging therapy, reducing the tumor burden before CAR-T infusion, thus enabling safe and successful CAR-T infusion, and as salvage therapy in cases of CAR-T therapy failure. This review aims to discuss the current evidence supporting the use of RT in CAR-T therapy for patients with R/R NHL. Although most studies have shown a positive role of RT in combined modality treatments for patients undergoing CAR-T therapy, the synergy gained from these remains uncertain. Furthermore, the optimal dose/fraction and radiation response require further investigation.

Early evolution of Anamorphidae (Coleoptera: Coccinelloidea): the oldest known anamorphid beetles from Upper Cretaceous amber of northern Myanmar and the first report of potential glandular pores in the family.

In order to place newly discovered fossil taxa (Palaeosymbius gen. nov. with P. groehni and P. mesozoicus spp. nov.) from the mid-Cretaceous amber from northern Myanmar, we investigated the relations of extant and extinct lineages of the coccinellid group of Coccinelloidea with emphasis on the family Anamorphidae. We assembled a taxonomic sampling of 34 taxa, including 15 genera and 19 species of Anamorphidae, the most comprehensive sampling of Anamorphidae at the generic level in a phylogenetic analysis. A morphological dataset of 47 characters was built as well as a molecular alignment of 7140 bp including fragments of eight genes (12S, 16S, 18S, 28S, COI, COII, H3 and CAD). Five anamorphid and one endomychid species were sequenced for the first time and added to the dataset. We performed parsimony-based analysis of the morphological dataset and Bayesian inference analysis of the combined matrix (morphological plus molecular data). Our results confirm that Palaeosymbius belongs to Anamorphidae and represents the oldest known member of this family so far. Among Anamorphidae, Symbiotes (with extant and known Eocene species) was recovered as the most probable closest relative of Palaeosymbius. Our morphological studies additionally revealed the presence of probable glandular openings in the anterolateral corners of the pronotal margins in Asymbius sp. and Anamorphus sp., representing the first report of secretory openings in the family Anamorphidae. Similar openings are found in other cucujiform beetles such as Cryptophagidae and Boganiidae with possible defensive purposes.

Circulating tumor DNA determining hyperprogressive disease after CAR-T therapy alarms in DLBCL: a case report and literature review.

Chimeric antigen receptor T-cell therapy (CAR-T) has been widely applied in the clinical practice of relapse/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) due to its promising effects. Hyperprogressive disease (HPD) has gained attention for rapid tumor progression and has become a therapeutic and prognostic challenge. Here, we present a patient who had suffered from several recurrences previously and controlled well with a very small tumor lesion left was infused with CD19/CD22 bispecific CAR-T, with no immune effector cell-associated neurotoxicity syndrome, or cytokine release syndrome observed. However, rapid deterioration, subsequent imaging examination, circulating tumor DNA, and serum biomarkers detection identified HPD. The patient did not respond to salvage treatment and died 40 days after infusion. To our knowledge, only one case of HPD in DLBCL after CAR-T therapy has been reported. This fatal case alarmed the risk of HPD and the ctDNA profile monitoring we used was performed as a non-invasive method to diagnose HPD, providing far-reaching practical instruction for CAR-T therapy.

Krüppel-like factor 5 activates chick intestinal stem cell and promotes mucosal repair after impairment.

The mucosal renewal, which depends on the intestinal stem cell (ISC) activity, is the foundation of mucosal repairment. Importantly, activation of reserve ISCs (rISCs) plays a vital role in initiating mucosal repair after injury. However, the underlying regulatory mechanism of rISCs activation in chickens remains unclear. In this study, immediately after lipopolysaccharide (LPS) challenge, mitochondrial morphological destruction and dysfunction appeared in the crypt, accompanied by decreased epithelial secretion (decreased Muc2 mRNA abundance and LYSOZYME protein level). However, immediately after mucosal injury, the mucosal renewal accelerated, as indicated by the increased BrdU positive rate, proliferating cell nuclear antigen (PCNA) protein level and mRNA abundance of cell cycle markers (Ccnd1, Cdk2). Concerning the ISCs activity, during the early period of injury, there appeared a reduction of active ISCs (aISCs) marker Lgr5 mRNA and protein, and an increasing of rISCs marker Hopx mRNA and protein. Strikingly, upon LPS challenge, increased mRNA transcriptional level of Krüppel-like factor 5 (Klf5) was detected in the crypt. Moreover, under LPS treatment in organoids, the KLF5 inhibitor (ML264) would decrease the mRNA and protein levels of Stat5a and Hopx, the STAT5A inhibitor (AC-4-130) would suppress the Lgr5 mRNA and protein levels. Furthermore, the Dual-Luciferase Reporter assay confirmed that, KLF5 would bind to Hopx promoter and activate the rISCs, STAT5A would trigger Lgr5 promoter and activate the aISCs. Collectively, KLF5 was upregulated during the early period of injury, further activate the rISCs directly and activate aISCs via STAT5A indirectly, thus initiate mucosal repair after injury.

Museomics unveil systematics, diversity and evolution of Australian cycad-pollinating weevils.

Weevils have been shown to play significant roles in the obligate pollination of Australian cycads. In this study, we apply museomics to produce a first molecular phylogeny estimate of the Australian cycad weevils, allowing an assessment of their monophyly, placement and relationships. Divergence dating suggests that the Australian cycad weevils originated from the Late Oligocene to the Middle Miocene and that the main radiation of the cycad-pollinating groups occurred from the Middle to the Late Miocene, which is congruent with the diversification of the Australian cycads, thus refuting any notion of an ancient ciophilous system in Australia. Taxonomic studies reveal the existence of 19 Australian cycad weevil species and that their associations with their hosts are mostly non-species-specific. Co-speciation analysis shows no extensive co-speciation events having occurred in the ciophilous system of Australian cycads. The distribution pattern suggests that geographical factors, rather than diversifying coevolution, constitute the overriding process shaping the Australian cycad weevil diversity. The synchronous radiation of cycads and weevil pollinators is suggested to be a result of the post-Oligocene diversification common in Australian organisms.

Lactobacillus salivarius Promotion of Intestinal Stem Cell Activity in Hens Is Associated with Succinate-Induced Mitochondrial Energy Metabolism.

Currently, the regulation of Lactobacillus on intestinal stem cells (ISCs) attracts broad attention, but their active ingredients and the underlying mechanism are worthy of further study. Previously, host intestinal commensal bacteria were verified to drive the differentiation of ISCs. In this study, the strong bacteriostatic activity of Lactobacillus salivarius and Lactobacillus agilis were illustrated, and the components (supernatant, precipitation) of L. salivarius or L. agilis were further demonstrated to decrease the differentiation of ISCs in vivo. Interestingly, antibiotics feeding decreased ISCs differentiation in vivo as well. However, the administration of L. salivarius supernatant following antibiotics feeding was shown to promote ISCs differentiation dramatically when compared with the antibiotics feeding group, indicating that some active ingredients existed in its supernatant to promote ISCs activity. Strikingly, in vitro, the treatment of L. salivarius supernatant was further confirmed to promote the intestinal organoids' size, budding, and LGR5 expression. Next, the metabolomics analysis of Lactobacilli' supernatants suggested that succinate might be a crucial metabolite to promote ISCs activity. Further, the succinate treatment in vitro (1000 µM) and in vivo (50 mM) was confirmed to enhance the expression of LGR5 and PCNA. SLC13A3 (a sodium/dicarboxylate cotransporter) was detected in the intestinal organoids and demonstrated to transport succinate into ISCs, as confirmed by the contact of FITC-succinate with ISCs nucleus. Subsequently, high mitochondrial membrane potential and reactive oxygen species levels appeared in the intestinal organoids upon succinate treatment. Collectively, the promotion of L. salivarius on ISCs activity is associated with succinate-induced mitochondrial energy metabolism. IMPORTANCE In our previous study, Lactobacillus salivarius and Lactobacillus agilis were demonstrated to regulate intestinal stem cell activity in hens, but their active ingredients and the underlying mechanism remain unclear. In this study, L. salivarius supernatant was shown to directly promote intestinal stem cell activity. Furthermore, the succinate (a critical metabolite of L. salivarius) was screened out to promote intestinal stem cell activity. Moreover, the succinate was confirmed to enter intestinal stem cells and induce high mitochondrial energy metabolism, finally promoting intestinal stem cell activity. These findings will advance uncovering the mechanism by which Lactobacillus regulate intestinal stem cell activity in chickens.

Transplantion of predominant Lactobacilli from native hens to commercial hens could indirectly regulate their ISC activity by improving intestinal microbiota.

In poultry, HyLine (HL) Hens are known for their excellent laying performance. However, ZhenNing (ZN) Hens, a native chicken breed in China, are known for their unique flavour. The intestinal mucosa, which is the main organ for nutrient absorption, could affect livestock product quality. In ZN Hens' intestinal mucosa, we found more villus wrinkles, larger villus circumference and higher amino acid transporters mRNA abundance compared with HL Hens. Among three laying periods of ZN Hens, in the intestinal lumen, Lactobacillus salivarius (L. sa.), Lactobacillus agilis (L. ag.) and Lactobacillus aviarius were the predominant species in the laying peak period. Furthermore, multiple-antibiotics feeding in ZN Hens and predominant Lactobacillus feeding in HL Hens suggested that these Lactobacilli could indeed increase villus wrinkles and improve intestinal absorption. In HL Hens, L. sa. + L. ag. treatment could promote organoids budding in vitro, and promote epithelial proliferation in vivo. Collectively, the unique intestinal mucosa morphology in ZN Hens was due to the high abundance of intestinal L. sa. and L. ag. Transplant these Lactobacilli to HL Hens could increase their intestinal probiotics abundance, fine adjust the intestinal stem cell function and promote the epithelial proliferation, in turn, increase villus winkles and mucosal absorption area.

Lactobacillus salivarius and Lactobacillus agilis feeding regulates intestinal stem cells activity by modulating crypt niche in hens.

Previously, we found that Lactobacillus salivarius, Lactobacillus agilis, and Lactobacillus aviarius were associated with excellent egg nutrition in native chicken. Next, the optimal Lactobacillus combination is worth studying. Here, a total of 120 HyLine hens (30 hens per group contained 3 replicate cells, 10 hens/cell) in the laying peak period were randomly divided into (1) control, (2) L. salivarius + L. agilis, (3) L. salivarius + L. aviarius, and (4) L. agilis + L. aviarius groups, fed with diet only or with corresponding Lactobacilli (108 colony-forming units/hen/day) for 30 days. As a result, L. salivarius + L. agilis feeding could (1) improve egg-laying rate, egg weight, and albumen's amino acid levels; (2) increase Lactobacillus abundance, decrease Escherichia coli abundance, upregulate the tryptophan metabolism pathway-related molecules, and downregulate the primary bile acid biosynthesis pathway-related molecules in intestinal contents; and (3) upregulate oxidative-phosphorylation pathway-related genes, reactive oxygen species levels, and mRNA abundance of Wnt3a, Dll1, Lgr5, CCDN1, and CDK2 in the crypt. Collectively, L. salivarius + L. agilis feeding in hens could improve intestinal microflora and metabolism profile, promote crypt's local energy metabolism and reactive oxygen species levels, and thus enhance Paneth cells and intestinal stem cells activity.Key points• Lactobacilli co-feeding could improve laying performance and egg nutrition.• Lactobacilli co-feeding could improve intestinal microflora and metabolism profile.• Lactobacilli co-feeding could enhance Paneth cells and intestinal stem cells activity.

Paneth cells mediated the response of intestinal stem cells at the early stage of intestinal inflammation in the chicken.

The rapid renewal and repair of the intestinal mucosa are based on intestinal stem cells (ISC), which are located at the crypt bottom. Paneth cells are an essential component in the crypt, which served as the niche for ISC development. However, in the chicken, how the function of Paneth cells changes during intestinal inflammation is unclear and is the key to understand the mechanism of mucosal repair. In the present study, 36 HyLine White chickens (7 d of age, n = 6) were randomly divided into 1 control and 5 lipopolysaccharide (LPS) injection groups. The chickens were injected (i.p.) with PBS in the control group, however, were injected (i.p.) with LPS (10 mg/kg BW) in the LPS injection groups, which would be sampled at 5 time points (1 h postinjection [hpi], 2 hpi, 4 hpi, 6 hpi, and 8 hpi). Results showed that tumor necrosis factor-α mRNA transcription in duodenal tissue increased gradually since 1 hpi, peaked at 4 hpi, and then reduced remarkably, indicating that 4 hpi of LPS was the early stage of intestinal inflammation. Meanwhile, the MUC2 expression in duodenal tissue was dramatically reduced since 1 hpi of LPS. The ISC marker, Lgr5 and Bmi1, in the duodenal crypt were reduced from 1 hpi to 4 hpi and elevated later. Accordingly, the hydroethidine staining showed that the reactive oxygen species level, which drives the differentiation of ISC, in the duodenal crypt reduced obviously at 1 hpi and recovered gradually since 4 hpi. The analysis of Paneth cells showed that many swollen mitochondria appeared in Paneth cells at 4 hpi of LPS. Meanwhile, the Lysozyme transcription in the duodenal crypt was substantially decreased since 1 hpi of LPS. However, the Wnt3a and Dll1 in duodenal crypt decreased at 1 hpi of LPS, then increased gradually. In conclusion, Paneth cells were impaired at the early stage of intestinal inflammation, then recovered rapidly. Thus, the ISC activity was reduced at first and recovery soon.

Phylogeny and evolution of Mesozoic and extant lineages of Histeridae (Coleoptera), with discovery of a new subfamily Antigracilinae from the Lower Cretaceous.

In order to place a newly discovered species Antigracilus costatus gen. sp. n. from the Lower Cretaceous Yixian Formation (China) and to assess previously unplaced fossil taxa, we investigated the relationships of extant and extinct lineages of Histeridae based on three data sets: (i) 69 morphological characters belonging to 48 taxa (representing all 11 subfamilies and 15 of 17 tribes of modern Histeridae); (ii) partitioned alignment of 6030 bp from downloaded nucleotide sequences (28S, CAD, COI, 18S) of 50 taxa (representing 10 subfamilies and 15 of 17 tribes of modern Histeridae); and (iii) a combined morphological and molecular dataset for 75 taxa. Phylogenetic analyses of the morphology and combined matrices recovered the new Lower Cretaceous taxon as a sister group to remaining Histeridae and it is placed in †Antigracilinae subfam. n. †Antigracilinae constitutes the earliest record of Histeridae from the Lower Cretaceous Yixian Formation (∼125 Myr), backdating the minimum age of the family by 25 Myr from the earliest Cenomanian (~99 Myr) to the Barremian of the Cretaceous Period. Our molecular phylogeny supports Histeridae to be divided into seven different clades, with currently recognised subfamilies Abraeinae (sensu lato), Saprininae, Chlamydopsinae, and Histerinae (sensu lato) recovered as monophyletic, while Dendrophilinae, Onthophilinae, and Tribalinae are polyphyletic taxa. The Burmese amber species †Pantostictus burmanicus Poinar & Brown is placed as a sister group to the tribe Plegaderini (Abraeinae) and was assigned as a new tribe Pantostictini trib. n. Both molecular and combined phylogenies recovered the subfamilies Trypanaeinae and Trypeticinae deeply within the subfamily Abraeinae (sensu lato), and they are downgraded into Trypanaeini stat. n. and Trypeticini stat. n.

Congruence of morphological and molecular phylogenies of the rove beetle subfamily Staphylininae (Coleoptera: Staphylinidae).

Staphylininae is the third largest subfamily of the enormous family Staphylinidae. Monophyly of Staphylininae and its sister relationship to the subfamily Paederinae have been broadly accepted according to both conventional morphology- and molecular-based phylogenies until the last three years. Recent molecular phylogenies rejected monophyly of Staphylininae and regarded Paederinae as a clade within it. This paper re-evaluates the recent molecular work, aiming to clarify the relationship between Staphylininae and Paederinae and resolve intertribal relationships within Staphylininae. Based on a new six-gene data set (5707 bp) for 92 taxa including Oxyporinae (outgroup), representatives of Paederinae, and members of all extant tribes of Staphylininae from published DNA data in GenBank, we generated a well-resolved phylogeny of Staphylininae with all deep nodes (intertribal relationships) strongly supported, and reassert the hypothesis that Staphylininae is monophyletic and indeed the sister group to Paederinae using both Bayesian and maximum likelihood inference. Additionally, our study is a case-study to show that both outgroup selection and completeness of nucleotide data can influence the outcome of a molecular phylogeny. With an increasing number of staphylinid fossils being discovered, the robust phylogeny of Staphylininae inferred by our research will provide a good framework for understanding the early evolution of this group.

A Mesozoic clown beetle myrmecophile (Coleoptera: Histeridae).

Complex interspecies relationships are widespread among metazoans, but the evolutionary history of these lifestyles is poorly understood. We describe a fossil beetle in 99-million-year-old Burmese amber that we infer to have been a social impostor of the earliest-known ant colonies. Promyrmister kistneri gen. et sp. nov. belongs to the haeteriine clown beetles (Coleoptera: Histeridae), a major clade of 'myrmecophiles'-specialized nest intruders with dramatic anatomical, chemical and behavioral adaptations for colony infiltration. Promyrmister reveals that myrmecophiles evolved close to the emergence of ant eusociality, in colonies of stem-group ants that predominate Burmese amber, or with cryptic crown-group ants that remain largely unknown at this time. The clown beetle-ant relationship has been maintained ever since by the beetles host-switching to numerous modern ant genera, ultimately diversifying into one of the largest radiations of symbiotic animals. We infer that obligate behavioral symbioses can evolve relatively rapidly, and be sustained over deep time.

Taxonomy of the genus Diochus Erichson, 1839 (Coleoptera: Staphylinidae, Staphylininae, Diochini) in China with descriptions of four new species.

This paper studies the taxonomy of the genus Diochus Erichson, 1839 (Coleoptera: Staphylinidae, Staphylininae, Diochini) from China. Four new species are described: Diochus bicornutus sp. nov. from Fujian, Hainan, Zhejiang, Guangxi and Yunnan, D. ampullaceus sp. nov. from Guangxi, D. bisegmentatus sp. nov. from Hainan and Yunnan, and D. membranaceus sp. nov. from Fujian. All other species previously reported from China are redescribed based on the examination of the holotypes, except the holotype of D. antennatus (Motschulsky, 1858), which was missing. Line drawings of the now missing holotype of D. antennatus (Motschulsky, 1858) are provided. A lectotype is designated for D. conicollis (Motschulsky, 1858). The Chinese fauna of the genus Diochus is now represented by eight species (four doubtfully recorded) and a key to all the Chinese species is provided. The type specimens of the new species are deposited in the Institute of Zoology, Chinese Academy of Sciences (IZ-CAS).

Taxonomy of the genus Erymus Bordoni (Coleoptera: Staphylinidae, Staphylininae, Xantholinini) in China with descriptions of two new species.

This paper studies the taxonomy of the genus Erymus Bordoni, 2002 (Coleoptera: Staphylinidae, Staphylininae, Xantholinini) from China. Two new species are described: Erymus wufengensis sp. n. from Hubei, and E. gilvus sp. n. from Hainan, Guangxi, and Guangdong provinces of China. The previously known four species of this genus are redescribed, and the identification key to all six Chinese species of the genus is provided. The type specimens of the new species are deposited in the Institute of Zoology, Chinese Academy of Sciences (IZ-CAS).

Taxonomy of the genus Megalinus Mulsant & Rey (Coleoptera: Staphylinidae, Xantholinini) and seven new species from China.

This paper studies the taxonomy of the genus Megalinus Mulsant & Rey, 1877 (Coleoptera: Staphylinidae, Xantholinini)and offers a comprehensive revision of the Chinese fauna. Seven new species are described: Megalinus ailaoshanensis Zhou & Zhou sp. nov. from Yunnan, M. hailuogouensis Bordoni sp. nov. from Sichuan, M. liupanshanensis Zhou & Zhou sp. nov. from Ningxia, M. ningxiaensis Bordoni sp. nov. from Ningxia, M. nonvaricosus Zhou & Zhou sp. nov.from Ningxia, M. solidus Zhou & Zhou sp. nov. from Hainan and Yunnan, and M. tangi Bordoni sp. nov. from Xizang. The taxonomic status of M. leishanensis (Bordoni, 2007) is reinstated and treated as a valid species here. The following new synonym is proposed: M. suffusus (Sharp, 1874) = L. flavoelytratus (Bordoni, 2007) syn. nov. Three species originally described in Chinese are redescribed here: M. cinnamomeus (Zheng, 1994), M. coracinus (Zheng, 1994) andM. zhenyuanensis (Zheng, 1994). Therefore the Chinese fauna of the genus Megalinus is now represented by a total of 33 species. A key to all Chinese species is provided.

Two new species of Xanthophius Motschulsky (Coleoptera: Staphylinidae, Staphylininae, Xantholinini) from China with notes on X. filum (Kraatz).

This paper studies the taxonomy of the genus Xanthophius Motschulsky, 1860 (Coleoptera: Staphylinidae, Staphylininae, Xantholinini). Two new species are described from China: Xanthophius unicidentatus sp. n. from Yunnan, Zhejiang, Guangxi and Hainan, and X. gutianshanensis sp. n. from Zhejiang. The number of species of Xanthophius therefore increased to eight. The elaborate structures of the everted endophallus of X. filum (Kraatz, 1859) is described for the first time and illustrated with a color plate. A key to eight species and their geographical distribution map are provided. The type specimens of the new species are deposited in the Institute of Zoology, Chinese Academy of Sciences (IZ-CAS).

Taxonomy of the genus Metolinus Cameron (Coleoptera, Staphylinidae, Staphylininae, Xantholinini) from China with description of three new species.

This paper studies the taxonomy of the genus Metolinus Cameron, 1920 (Coleoptera: Staphylinidae, Staphylininae, Xantholinini) from China and describes three new species: Metolinus xizangensissp. n. from Xizang (Tibet), Metolinus emarginatussp. n. fromSichuan, and Metolinus binariussp. n. from Yunnan. The Chinese fauna of the genus is thus increased to 8 species in total. A key to eight Chinese species is provided. Female genital segments and other important morphological characters are illustrated in line drawings for the new species as well as Metolinus shanicus Bordoni, 2002 and Metolinus gardneri (Cameron, 1945). The text also provides color plates with habitus photographs and a map to show the species' geographical distribution pattern. The type specimens of the new species are deposited in Institute of Zoology, the Chinese Academy of Sciences (IZ-CAS).