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Background Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM). Methods This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m 2 . LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10 6 cells/kg [range, 0.07 to 2.1 × 10 6 ]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group. Results At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached. Conclusions LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM. Trial registration ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered

Many countries have undertaken large and high-profile payment-for-ecosystem-services (PES) programs to sustain the use of their natural resources. Nevertheless, few studies have comprehensively examined the impacts of existing PES programs. Grassland Ecological Compensation Policy (GECP) is one of the few pastorally focused PES programs with large investments and long duration, which aim to improve grassland quality and increase herder income. Here we present empirical evidence of the effects of GECP on grassland quality and herder income. Through a thorough and in-depth econometric analysis of remote sensing and household survey data, we find that, although GECP improves grassland quality (albeit to only a small extent) and has a large positive effect on income, it exacerbates existing income inequality among herders within their local communities. The analysis demonstrates that the program has induced herders to change their livestock production behavior. Heterogeneity analysis emphasizes the importance of making sure the programs are flexible and are adapted to local resource circumstances. China has introduced a payment-for-ecosytsem-services program called GECP which is focused on pastoral communities in grassland areas. Here, the authors combine remote sensing and household survey data to find small improvement in grassland quality and a significant positive effects on the income of herders.

Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 10 6 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

Calcium is an important integrative component of the human body and critical for human health. It has been well established that calcium intake is helpful in the prevention and treatment of osteoporosis, which has become one of the most serious public health problems across the world. However, community-dwelling adults with and without osteoporosis are rarely concerned or even not aware of the potential side effects of high or inappropriate doses of calcium intake. Some recent studies have revealed that excessive calcium intake might increase the risks of cardiovascular diseases. The purpose of this article was to review the health benefits, costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures, cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In the end, we suggest that calcium supplementation should be prescribed and taken cautiously, accounting for individual patients' risks and benefits. Clearly, further studies are needed to examine the health effects of calcium supplementation to make any solid recommendations for people of different genders, ages, and ethnicities.

Background There was much evidence suggesting that the serum lactate dehydrogenase (LDH) levels reflect the extent of various pathophysiological processes. However, the current information about dynamic change of LDH in COVID-19 pneumonia has not been well investigated. Methods Study was performed in 87 cases confirmed by COVID-19 infection. The serum LDH levels were determined at diagnosis and follow-up visits. The evaluation of clinical response to therapy was based on chest CT scan. We selected the value of LDH around the data of chest CT scan (− 1 ~ + 1 day). Results At diagnosis, significant differences in LDH levels were found between non-severe and severe group ( P  < 0.05). It was demonstrated that increase or decrease of LDH was indicative of radiographic progress or improvement ( P  < 0.05). The time to LDH normalization (5.67 ± 0.55, days) was positively correlated with the time to radiographic absorption (5.57 ± 0.65 days, r = 0.53, P  < 0.05). Applying the cut-off value of the increase in LDH has good specificity to predict disease progression. Conclusions Serum LDH was validated for its potential usefulness as markers for evaluating clinical severity and monitoring treatment response in COVID-19 pneumonia.

Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.

Increasing studies approach translation from alternative aspects, either borrowing different methodologies or concepts from other disciplines. These various attempts have expanded the field of translation studies to a broader area with a focus on either intercultural studies or the translator’s studies. Howard Goldblatt, as a respected translator in China, has provided limitless insights into Chinese literature in translation. Recent studies are moving closer to the specific traits of the translator, and this study thus focuses on Goldblatt’s translation of Red Sorghum, as the original work boasts plenty of cultural words, regional dialects, and colloquialisms. The purpose of this study is to determine Goldblatt’s translation tendency, the corresponding translation methods he adopted, as well as the reasons behind correspondent behaviors and choices. To answer the above inquiries, quantitative and qualitative methods will be jointly adopted. Multiple factors leading to the translator’s visibility and invisibility are also analyzed with reference to the quantitative results. Plain language summary This research demonstrates a renewed interest in “translator’s invisibility”, a concept proposed by Lawrence Venuti in 2001, through heightening its long neglected opposing aspect of “translator’s visibility”. This article has reexamined disputed viewpoints on Goldblatt’s translation tendency with solid evidence and extended the discussion on foreignization and domestication by substantiating them with specific instructive translation methods. This article has also discussed in greater detail how the translator grapples with fidelity and readability, the author and the market while making compromises when the two aspects conflict. It is hoped that this research may shed insights into trending research on translator’s studies and the ongoing discussion on Venuti’s domestication and foreignization in the particular area of literary translation. It is also hoped to benefit the production of translation in literature and help promote effective cultural exchange and cross-cultural communication.

This research presents bending responses of FG-GPLRC plates based upon higher order shear deformation theory (HSDT) for various sets of boundary conditions. The rule of the mixture and modified Halpin–Tsai model are engaged to provide the effective material constant of the composite layers. By employing Hamilton’s principle, the governing equations of the structure are derived and solved with the aid of the differential quadrature method (DQM). Afterward, a parametric study is done to present the effects of three kinds of FG patterns, weight fraction of the GPLs, radius ratio, and thickness to inner radius ratio on the bending characteristics of the FG-GPLRC disk. Numerical results reveal that in the initial value of the Zt/h, using more GPLs for reinforcing the structure provides an increase in the normal stresses but this matter is inverse for the higher value of the Zt/h. The results show that considering the smaller radius ratio is a reason for boosting the shear stresses of the structure for each Zt/h. Another consequence is that for the negative value of Zt/h, it is true that by increasing h/Ri , the normal stresses increases but if there is positive value for Zt/h, the radial and circumferential stresses fall down by having an increase in the h/Ri.

Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We performed integrative analyses in a Chinese cohort of peri-/post-menopausal women with metagenomics/targeted metabolomics/whole-genome sequencing to identify novel microbiome-related biomarkers for bone health. Bacteroides vulgatus was found to be negatively associated with bone mineral density (BMD), which was validated in US white people. Serum valeric acid (VA), a microbiota derived metabolite, was positively associated with BMD and causally downregulated by B. vulgatus . Ovariectomized mice fed B. vulgatus demonstrated increased bone resorption and poorer bone micro-structure, while those fed VA demonstrated reduced bone resorption and better bone micro-structure. VA suppressed RELA protein production (pro-inflammatory), and enhanced IL10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells and enhanced maturation of osteoblasts in vitro. The findings suggest that B. vulgatus and VA may represent promising targets for osteoporosis prevention/treatment. Gut microbiota has been reported to influence osteoporosis risk, but the individual species, and underlying mechanisms, remain largely unknown. Here, the authors identify Bacteroides vulgatus and serum valeric acid as potential targets for osteoporosis prevention/treatment.

Diabetes mellitus (DM) is a global epidemic with increasing incidence, which results in diverse complications, seriously affects the patient quality of life, and brings huge economic burdens to society. Diabetic neuropathy is the most common chronic complication of DM, resulting in neuropathic pain and chronic itch. The precise mechanisms of diabetic neuropathy have not been fully clarified, hindering the exploration of novel therapies for diabetic neuropathy and its terrible symptoms such as diabetic pain and itch. Accumulating evidence suggests that neuroinflammation plays a critical role in the pathophysiologic process of neuropathic pain and chronic itch. Indeed, researchers have currently made significant progress in knowing the role of glial cells and the pro-inflammatory mediators produced from glial cells in the modulation of chronic pain and itch signal processing. Here, we provide an overview of the current understanding of neuroinflammation in contributing to the sensitization of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, we also summarize the inflammation mechanisms that contribute to the pathogenesis of diabetic itch, including activation of glial cells, oxidative stress, and pro-inflammatory factors. Targeting excessive neuroinflammation may provide potential and effective therapies for the treatment of chronic neuropathic pain and itch in DM.