Search

MM, characterized by the progressive accumulation of clonal plasma cells in bone marrow, remains a severe medical problem globally. Currently, almost all MM patients who have received standard treatments will eventually relapse. Autologous anti-BCMA CAR-T cells are one of the FDA-approved immunotherapy cell-based products for treating adults with relapsed or refractory (r/r) multiple myeloma. However, this type of CAR-T cell product has several limitations, including high costs, long manufacturing times, and possible manufacturing failure, which significantly hinder its wider application for more patients. In this review, we summarized the current development stage of applying other types of immune cells to bring the anti-BCMA CAR-T therapy from autologous to allogeneic. In general, anti-BCMA CAR gene-edited αβ T cells and CAR-Natural Killer (NK) cells are at the forefront, with multiple clinical trials ongoing, while CAR-γδ T cells and CAR-invariant Natural Killer T (iNKT) cells are still in pre-clinical studies. Other immune cells such as macrophages, B cells, and dendritic cells have been mainly developed to target other antigens and have the potential to be used to target BCMA. Nevertheless, additional regulatory requirements might need to be taken into account in developing these non-conventional allogenic anti-BCMA CAR-based cell products.

BackgroundIn the past, surgical resection was the only treatment available for esophageal diverticulum. Minimally invasive endoscopic treatment of esophageal diverticulum has become more and more popular in recent years. We reported a case of transoral endoscopic resection of esophageal diverticulum and crestectomy, which had a similar effect to surgery and retained the physiological function of the esophagus. It has the advantages of short procedure time, short hospital stay, and good long-term prognosis.Case presentationA 67-year-old gentleman presented with persistent dysphagia and repeated nausea and vomiting for 2 years. Combined with chest CT, barium esophagography and esophagogastroduodenoscopy, the diagnosis was a mid-esophageal diverticulum. After discussion and communication, the patient underwent oral endoscopic esophageal diverticulectomy. During the operation, the weak area of the bottom muscle layer of the diverticulum was completely removed, and the crest of the diverticulum was cut off, and the kiss suture was performed with titanium clips to reduce tension. After the operation, the right pleural effusion occurred and the lung infection was aggravated, and the right pleural drainage tube was placed to relieve the symptoms. An 18*100mm fully covered metal stent was placed under a gastroscope. Place the duodenal nutrition tube and the gastric tube drainage tube for vacuum suction. After a long period of fasting, enteral nutrition support, adequate postoperative drainage treatment and antibiotic treatment eventually l resulted in full recovery without recurrence.ConclusionThe selection of treatment for esophageal diverticulum needs to refer to many factors. For the middle esophageal diverticulum, especially those with large diverticulum sac and small mouth, and those who have indications for surgery, in addition to selective surgery and conventional endoscopic surgery, you can also try endoscopic diverticulectomy and crestectomy.

Ancestry informative markers (AIMs), which are distributed throughout the human genome, harbor significant allele frequency differences among diverse ethnic groups. The use of sets of AIMs to reconstruct population history and genetic relationships is attracting interest in the forensic community, because biogeographic ancestry information for a casework sample can potentially be predicted and used to guide the investigative process. However, subpopulation ancestry inference within East Asia remains in its infancy due to a lack of population reference data collection and incomplete validation work on newly developed or commercial AIM sets. In the present study, 316 Chinese persons, including 85 Sinitic-speaking Haikou Han, 120 Qiongzhong Hlai and 111 Daozhen Gelao individuals belonging to Tai-Kadai-speaking populations, were analyzed using the Precision ID Ancestry Panel (165 AISNPs). Combined with our previous 165-AISNP data (375 individuals from 6 populations), the 1000 Genomes Project and forensic literature, comprehensive population genetic comparisons and ancestry inference were further performed via ADMIXTURE, TreeMix, PCA, f-statistics and N-J tree. Although several nonpolymorphic loci were identified in the three southern Chinese populations, the forensic parameters of this ancestry inference panel were better than those for the 23 STR-based Huaxia Platinum System, which is suitable for use as a robust tool in forensic individual identification and parentage testing. The results based on the ancestry assignment and admixture proportion evaluation revealed that this panel could be used successfully to assign individuals at a continental scale but also possessed obvious limitations in discriminatory power in intercontinental individuals, especially for European-Asian admixed Uyghurs or in populations lacking reference databases. Population genetic analyses further revealed five continental population clusters and three East Asian-focused population subgroups, which is consistent with linguistic affiliations. Ancestry composition and multiple phylogenetic analysis further demonstrated that the geographically isolated Qiongzhong Hlai harbored a close phylogenetic relationship with Austronesian speakers and possessed a homogenous Tai-Kadai-dominant ancestry, which could be used as the ancestral source proxy in population history reconstruction of Tai-Kadai-speaking populations and as one of the representatives for forensic database establishment. In summary, more population-specific AIM sets focused on East Asian subpopulations, comprehensive algorithms and high-coverage population reference data should be developed and validated in the next step.

Mesenchymal stromal cells (MSCs) are viewed as immune-privileged cells and have been broadly applied in allogeneic adoptive cell transfer for regenerative medicine or immune-suppressing purpose. However, the surface expression of human leukocyte antigen (HLA) class I molecules on MSCs could still possibly induce the rejection of allogeneic MSCs from the recipients. Here, we disrupted the β2 microglobulin ( B2M) gene in human peripheral blood mononuclear cell-derived induced pluripotent stem cells (iPSCs) with two clustered regulatory interspaced short palindromic repeat (CRISPR)-associated Cas9 endonuclease-based methods. The B2M knockout iPSCs did not express HLA class I molecules but maintained their pluripotency and genome stability. Subsequently, MSCs were derived from the HLA-negative iPSCs (iMSCs). We demonstrated that B2M knockout did not affect iMSC phenotype, multipotency, and immune suppressive characteristics and, most importantly, reduced iMSC immunogenicity to allogeneic peripheral blood mononuclear cells. Thus, B2M knockout iPSCs could serve as unlimited off-the-shelf cell resources in adoptive cell transfer, while the derived iMSCs hold great potential as universal grafts in allogeneic MSC transplantation.

Supplemental Material, Generation_of_mesenchymal_stromal_cells_with_low_immunogenicity_from_human_PBMC for Generation of Mesenchymal Stromal Cells with Low Immunogenicity from Human PBMC-Derived β2 Microglobulin Knockout Induced Pluripotent Stem Cells by Shijun Zha, Johan Chin-Kang Tay, Sumin Zhu, Zhendong Li, Zhicheng Du and Shu Wang in Cell Transplantation

A cyanine-derivative photosensitizer, CYBF2, was synthesized for photodynamic therapy of cancer. The photosensitizer can be activated by red-light with enhanced photostability compared to traditional cyanine photosensitizers. CYBF2 was able to generate singlet oxygen inside the cell mitochondria, which efficiently resulted in apoptosis of cancer cells.

Ancestry informative markers (AIMs), which are distributed throughout the human genome, harbor significant allele frequency differences among diverse ethnic groups. The use of sets of AIMs to reconstruct population history and genetic relationships is attracting interest in the forensic community, because biogeographic ancestry information for a casework sample can potentially be predicted and used to guide the investigative process. However, subpopulation ancestry inference within East Asia remains in its infancy due to a lack of population reference data collection and incomplete validation work on newly developed or commercial AIM sets. In the present study, 316 Chinese persons, including 85 Sinitic-speaking Haikou Han, 120 Qiongzhong Hlai and 111 Daozhen Gelao individuals belonging to Tai-Kadai-speaking populations, were analyzed using the Precision ID Ancestry Panel (165 AISNPs). Combined with our previous 165-AISNP data (375 individuals from 6 populations), the 1000 Genomes Project and forensic literature, comprehensive population genetic comparisons and ancestry inference were further performed via ADMIXTURE, TreeMix, PCA, f-statistics and N-J tree. Although several nonpolymorphic loci were identified in the three southern Chinese populations, the forensic parameters of this ancestry inference panel were better than those for the 23 STR-based Huaxia Platinum System, which is suitable for use as a robust tool in forensic individual identification and parentage testing. The results based on the ancestry assignment and admixture proportion evaluation revealed that this panel could be used successfully to assign individuals at a continental scale but also possessed obvious limitations in discriminatory power in intercontinental individuals, especially for European-Asian admixed Uyghurs or in populations lacking reference databases. Population genetic analyses further revealed five continental population clusters and three East Asian-focused population subgroups, which is consistent with linguistic affiliations. Ancestry composition and multiple phylogenetic analysis further demonstrated that the geographically isolated Qiongzhong Hlai harbored a close phylogenetic relationship with Austronesian speakers and possessed a homogenous Tai-Kadai-dominant ancestry, which could be used as the ancestral source proxy in population history reconstruction of Tai-Kadai-speaking populations and as one of the representatives for forensic database establishment. In summary, more population-specific AIM sets focused on East Asian subpopulations, comprehensive algorithms and high-coverage population reference data should be developed and validated in the next step.

Serious complications due to perforation restrict the development of duodenal endoscopic treatment. The key stage for remediation is the successful endoscopic closure to prevent peritonitis and the need for surgical intervention. This report aimed to present a new simple method for the closure of large iatrogenic duodenal perforations with purse-string sutures using the novel endoloops and repositionable clips through a single-channel endoscope. A total of 23 patients with iatrogenic duodenal perforations ≥ 1 cm were retrospectively studied who were presently treated by purse-string sutures using the novel endoloops and the repositionable hemostasis clips with the single-channel endoscope at four institutes. During and after the procedure, a 20-gauge needle was used to relieve the pneumoperitoneum or subcutaneous emphysema. Finally, a gastroduodenal decompression tube was placed. The median maximum diameter of iatrogenic duodenal perforations was 1.65 cm (range 1.0–3.0 cm). Complete endoscopic closure of all 23 perforations was achieved. No patient had severe complications such as peritonitis. The wounds were healed and no obvious duodenal stricture was observed in all cases after 3 months. Purse-string sutures using the novel endoloops and repositionable endoclips through single-channel endoscope were feasible, effective and easy methods for the closure of large duodenal iatrogenic perforations.

Background Esophageal leiomyomas, the most common benign primary tumors of the esophagus, are esophageal subepithelial lesions treated by surgery traditionally. In recent years, endoscopic submucosal dissection and related endoscopic treatment techniques are adopted by endoscopists to resect gastrointestinal submucosal tumors. But if a giant esophageal leiomyoma approaches the esophagus entrance and originates from the deep layer of muscularis propria, it will be difficult for both endoscopic resection and surgical treatment. Especially, endoscopic resection has a high risk of huge perforation difficult to be sutured. Case presentation A 72-year-old man with dysphagia underwent gastroscopy examination which indicated a large submucous eminence lesion, about 18–24 cm from the incisors. Endoscopic ultrasonography revealed the lesion was hypoechoic and originated from the muscularis propria with a clear boundary. The patient refused invasive surgical resection. Then, an en bloc endoscopic full-thickness resection was performed, which perforation was successfully closed with purse-string sutures using a novel endoloop device through standard single-channel endoscopy. Histopathologic examination showed an esophageal leiomyoma. Conclusion This endoscopic procedure may be an alternative to avoid surgery for the removal of a giant upper esophagus tumor from muscularis propria layer.

Vγ9Vδ2 T cells are a minor subset of lymphocytes in the peripheral blood that has been extensively investigated for their tolerability, safety and anticancer efficacy. A hindrance to the broad application of these cells for adoptive cellular immunotherapy has been attaining clinically appropriate numbers of Vγ9Vδ2 T cells. Furthermore, Vγ9Vδ2 T cells exist at low frequencies among cancer patients. We, therefore, sought to conceive an economical method that allows for a quick and robust large-scale expansion of Vγ9Vδ2 T cells. A two-step protocol was developed, in which peripheral blood mononuclear cells (PBMCs) from healthy donors or cancer patients were activated with Zometa and interleukin (IL)-2, followed by co-culturing with gamma-irradiated, CD64-, CD86- and CD137L-expressing K562 artificial antigen-presenting cells (aAPCs) in the presence of the anti-CD3 antibody OKT3. We optimized the co-culture ratio of K562 aAPCs to immune cells, and migrated this method to a G-Rex cell growth platform to derive clinically relevant cell numbers in a Good Manufacturing Practice (GMP)-compliant manner. We further include a depletion step to selectively remove αβ T lymphocytes. The method exhibited high expansion folds and a specific enrichment of Vγ9Vδ2 T cells. Expanded Vγ9Vδ2 T cells displayed an effector memory phenotype with a concomitant down-regulated expression of inhibitory immune checkpoint receptors. Finally, we ascertained the cytotoxic activity of these expanded cells by using nonmodified and chimeric antigen receptor (CAR)-engrafted Vγ9Vδ2 T cells against a panel of solid tumor cells. Overall, we report an efficient approach to generate highly functional Vγ9Vδ2 T cells in massive numbers suitable for clinical application in an allogeneic setting.

The oxidation behavior and surface properties of hot-pressed ZrB 2 -SiC ultrahigh-temperature ceramic composites are investigated under aerothermal heating conditions in the high-temperature, low-pressure partially dissociated airstream of the 1.2 MW Plasmatron facility at the von Karman Institute for Fluid Dynamics. Samples are oxidized at different flow enthalpies for exposure times of up to 20 min at surface temperatures ranging from 1250 to 1575°C. The microstructure and composition of the resulting oxide layers are characterized using electron and optical microscopies, x-ray diffraction, and energy-dispersive x-ray analysis. Comparisons are made with samples oxidized under similar temperature and pressure conditions in a furnace test environment in which atomic oxygen concentrations are negligible. Changes in surface optical properties are documented using spectral reflectance measurements, and effective catalytic efficiencies are estimated using computational fluid dynamics calculations together with measured surface temperatures and heat fluxes.

Optical emission spectroscopy is used to investigate the oxidation of a hot-pressed ZrB 2 -SiC ultrahigh-temperature ceramic composite tested in the 1.2 MW Plasmatron facility at the von Karman Institute for Fluid Dynamics. Time-resolved spectra enable the in situ detection and temporal characterization of electronically excited B, BO, and BO 2 species concentrations directly adjacent to the oxidizing sample surface. The evolution of these boron species correlates well with the transient formation of a complex multilayer oxide scale containing a silica-rich glassy outer layer that limits oxide growth.

Friction stir spot welding is performed on 5083 Al alloy using tools with a conventional cylindrical pin and the proposed triangular pin. Partial metallurgical bond (called as ‘hook’) is formed in the weld region between the overlapped metal sheets. The tool-pin geometry significantly affects the hook shape. Under the same process condition, welds made with the cylindrical pin have a continuous hook which bypasses the stir zone and points downward towards the weld bottom. By contrast, for welds made with the triangular pin, the hook is directed upwards and then arrested at the periphery of the stir zone. The difference in the hook shape could be attributed to the asymmetric rotation of the triangular pin that may cause the material in the vicinity of the pin to move back and forth in the radial direction resulting in the hook being broken-up (dispersed) in the stir zone. In addition, the triangular pin results in a finer grain structure in the stir zone compared to the cylindrical pin. Static strength of welds made with the triangular pin is twice that of welds made with the cylindrical pin, which is attributed to the finer grain size as well as tensile failure mode as a result of the arrested hook.

Dense ZrB2–SiC ultra-high temperature ceramics were prepared by a novel pressureless sintering process. The relative density of sintered ceramics increased from 62.5% for ZrB2 to 96.7% by coating the starting ZrB2 powder with polycarbosilane, which was converted to C and SiC by pyrolysis. The mechanism of enhanced densification and the mechanical properties of the sintered ZrB2–SiC ceramics were investigated.

Zirconium diboride (ZrB 2 ) was densified by pressureless sintering using

A two phase particulate ceramic composite containing ZrB 2 and B 4 C was densified by microwave sintering a mixture of ZrB 2 and 4 wt% B 4 C powders. The particulate composite reached >98% relative density at processing temperatures as low as 1720 °C. In comparison to conventional sintering, microwave sintering promoted densification of the composite at lower temperatures without promoting rapid grain growth. Vickers’ hardness and fracture toughness of the microwave sintered specimens were as high as 17.5 GPa and 3.8 MPa m 1/2 , respectively.

The synergistic roles of boron carbide and carbon additions in the enhanced densification of zirconium diboride (ZrB2) by pressureless sintering have been studied. ZrB2 was sintered to >99% relative density at 1900°C. The combination of 2 wt% boron carbide and 1 wt% carbon promoted densification by removing surface oxide impurities (ZrO2 and B2O3) and inhibiting grain growth. Four-point bending strength (473±43 MPa), Vickers' microhardness (19.6±0.4 GPa), fracture toughness (3.5±0.6 MPa·m1/2), and Young's modulus (507 GPa) were measured. Thermal gravimetry showed that the combination of additives did not have an adverse effect on the oxidation behavior.

Carbon-coated zirconium diboride powders were sintered to near theoretical density at temperatures as low as 1900 °C without an external pressure. Relative density increased from ∼70% for uncoated ZrB2 to >99% for ZrB2 coated with at least 1.0 wt% carbon. Thermodynamic analysis indicated that carbon reacted with and removed oxide impurities (ZrO2 and B2O3) that were present on the particle surfaces, which promoted densification by minimizing grain coarsening. The effects of initial particle size and carbon content on densification, microstructure, and properties were investigated.

SiC/cordierite composite porous ceramics were prepared by a reactive process, in which clay, talc and alumina were mixed with SiC powder and graphite was used as the pore former. The mixture was heated in air so that graphite was burned out and SiC particles were bonded by reaction-derived cordierite. The sintering temperature was chosen as 1360 °C according to DTA and XRD studies. The volume fraction of graphite had a strong influence on porosity and strength. A three-point bending strength of 54.6 MPa was achieved at a porosity of 27.6%, while the strength of 9.3 MPa was corresponding to a porosity of 59.6%. Moreover, as-prepared composite porous ceramics exhibited excellent resistance to cyclic thermal shock.

The influence of silicon carbide (SiC) particle size on the microstructure and mechanical properties of zirconium diboride–silicon carbide (ZrB2–SiC) ceramics was investigated. ZrB2-based ceramics containing 30 vol.% SiC particles were prepared from four different α-SiC precursor powders with average particle sizes ranging from 0.45 to 10 μm. Examination of the dense ceramics showed that smaller starting SiC particle sizes led to improved densification, finer grain sizes, and higher strength. For example, ceramics prepared from SiC with the particle size of 10 μm had a strength of 389 MPa, but the strength increased to 909 MPa for ceramics prepared from SiC with a starting particle size of 0.45 μm. Analysis indicates that SiC particle size controls the strength of ZrB2–SiC.

An in situ reaction bonding technique was developed to fabricate mullite-bonded porous silicon carbide (SiC) ceramics in air from SiC and α-Al 2 O 3 , using graphite as the pore-former. Graphite is burned out to produce pores and the surface of SiC is oxidized to SiO 2 at high temperature. With further increasing the temperature, the amorphous SiO 2 converts into cristobalite and reacts with α-Al 2 O 3 to form mullite (3Al 2 O 3 ·2SiO 2 ). SiC particles are bonded by the mullite and oxidation-derived SiO 2 to obtain porous SiC ceramics. The reaction bonding behavior, open porosity, pore size distribution and mechanical strength of porous SiC ceramics were investigated as a function of the sintering temperature, forming pressure and graphite content. In addition, the phase composition and microstructure were also studied.

A series of chemically modified ordered mesoporous carbon materials (FC- x , x = 0, 0.5, 1.0, 1.5, 2.0, and 3.0) were prepared by an easy oxidation method in nitric acid aqueous solution. Fourier transform infrared spectroscopy study indicated that the content of the functional groups, such as –COOH and C–OH, increased as a function of oxidation treatment time. Both small-angle X-ray diffraction patterns and transmission electron micrographs confirmed that the ordered mesostructures were preserved after surface oxidation. Nitrogen adsorption measurement showed that the specific surface area and pore size of the carbon materials first increased and then decreased when the oxidation time was longer. The chemically modified ordered mesoporous carbon materials showed better capacitance performance than that of the CMK-3 without acid treatment. The introduced functional groups produced pseudo-capacitance, which resulted in an increase in specific capacitance. The carbon materials treated for 1.5 h showed the highest high-rate capacity. The specific capacitance reached ∼250 F g −1 at a scan rate of 1 mV s −1 .

An ordered mesoporous nickel oxide/carbon (NiO/C) nanocomposite with NiO nanocrystallites uniformly embedded within the carbon wall has been synthesized. The resultant structures have been characterized by X-ray diffraction (XRD), nitrogen adsorption and transmission electron microscopy (TEM). In this nanocomposite, NiO nanocrystallites and carbon are combined to construct the backbone of the mesoporous structures. Since the NiO nanocrystallites are not incorporated in the mesochannels, the obtained nanocomposite has large surface area and high pore volume. When 12 wt.% NiO is loaded, the BET surface area and pore volume of the nanocomposite reach 1006 m 2 g − 1 and 0.91 cm 3 g − 1 , respectively.

Porous SiC ceramics were fabricated without and with Y 2 O 3 addition from SiC, Al 2 O 3 and graphite in air by the in situ reaction bonding process. This process is based on the oxidation of SiC and the mullitization between Al 2 O 3 and oxidation-derived SiO 2 . SiC particles are bonded by the mullite (3Al 2 O 3 ·2SiO 2 ) and SiO 2 . The pores are produced by both stacking SiC particles and burning out graphite. Comparison of phase composition, microstructure, flexural strength, open porosity and pore size distribution of reaction-bonded porous SiC ceramics without and with Y 2 O 3 addition was conducted. Moreover, the effect of Y 2 O 3 content was investigated. Due to the enhancement of neck formation (bonding part between SiC particles) by the addition of Y 2 O 3 , a high strength of 27.5 MPa was achieved at an open porosity of 44.4%.

Sol–gel bioglasses have many advantages comparing to melt-derived bioglasses. 3-D scaffold prepared by sol–gel method is a promising substrate material for bone tissue engineering. But, it is difficult to produce macroporous sol–gel bioglasses with pores larger than 100 μm. In this work, a series of macroporous bioglasses was produced by adding PEG particles into the sol as pore former. The mesoporous texture features of the samples were assessed through a nitrogen sorption technique. The macropore structure was collected by intrusion mercury porosimetry. In vitro tests showed that the samples had good bioactivity. Combining the sol–gel routine with the pore former might be a useful approach for preparation scaffolds with applications to the repair and reconstruction of damaged tissue.

This paper reports a new method to obtain macroporous bioactive glasses by sol–gel and pore former technologies. The in vitro tests showed that the samples had good apatite-forming ability. Noticeably, these bioglasses exhibit high specific surface areas and excellent mechanical performances. The compressive strength is as high as 34.4±5.7 MPa. This method may be a useful approach for preparation of scaffolds for tissue engineering.

Polycarbosilane (PCS) was used as a precursor to prepare porous silicon carbide (SiC) ceramics with in situ growth of β-SiC nanowires. The pore size of the as-prepared porous ceramics was 1.37 μm in average, and had a narrow distribution. The nanowires with diameters ranging from ∼10 to 50 nm existed in the channels of the porous body. Their morphology, microstructure, and composition were characterized by field emission scanning electron microscopy, transmission electron microscopy, and energy-dispersive X-ray spectroscopy, which confirmed that the nanowires had a single-crystal β-SiC structure with the 〈111〉 growth direction. A vapor–liquid–solid process was discussed as a possible growth mechanism of the β-SiC nanowires.

Preceramic polymer polycarbosilane (PCS) and silicon carbide (SiC) powders were adopted as the starting materials for the fabrication of porous SiC ceramics. During the heat treatment process, PCS experienced an organic–inorganic transformation and acted as the bonding material between SiC particles at a low temperature of 1100 °C. The particle size of starting SiC powders and PCS content can control the pore size distribution and porosity. Fracture strength increases with higher content of PCS. Moreover, the as-fabricated porous SiC ceramics exhibit a low average coefficient of thermal expansion (CTE) of 3.4×10−6/K from room temperature to 800 °C.