Anti-BCMA CAR-T therapy for multiple myeloma with extramedullary disease: A case report and review of the literature.

INTRODUCTION: Multiple myeloma (MM) with extramedullary disease (EMD) is rare in clinical practice, and B cell maturation antigen (BCMA) CAR-T cell therapy is a novel therapy for hematologic malignancies. Very few reports have been published on the effect of CAR-T-cell therapy in MM with EMD. Here, we report a case of MM with extramedullary lesions treated with BCMA CAR-T therapy. CASE PRESENTATION: A 66-year-old female patient presented to our hospital with an enlarged left maxillary gingiva. DIAGNOSIS: Diagnosis of indolent MM stage III (DS staging) and stage III (ISS and R ISS) with extramedullary lesions. INTERVENTION: The patient underwent a clinical trial of humanized anti-BCMA CAR T cell therapy. RESULTS: Symptoms improved; left gingival hyperplasia and swelling resolved; left buccal mass resolved; and neck and submandibular masses resolved. Pathological examination of the exfoliated masses showed necrotic tissue. CONCLUSION: MM with extramedullary lesions often has limited treatment options, and traditional chemotherapy methods are ineffective; however, BCMA CAR-T cell therapy can significantly improve the symptoms of extramedullary lesions in MM.

Evaluation of three scoring systems for predicting renal prognosis in antineutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) is characterized by rapidly progressive glomerulonephritis, and timely initiation of treatment and evaluation is critical to prevent the progression of renal disease to end-stage renal disease (ESRD). The aim of this study was to evaluate predictive value of the renal risk score (RRS), Birmingham vasculitis activity score (BVAS), and renal vascular lesions (RVLs) score for renal prognosis in AAGN. METHODS: A retrospective analysis of ninety-four patients diagnosed with AAGN after renal biopsy was performed. The RRS, BVAS, and RVLs score were evaluated in relation to clinicopathologic features and renal prognosis. A receiver operating characteristic curve (ROC) was used to evaluate their renal prognostic value. RESULTS: The median follow-up time was 36 months. Thirty-eight patients progressed to ESRD. Survival analysis showed that renal prognosis worsened in the RRS group in order of low, medium, and high RRS (P < 0.05). Within the RVLs group, the renal prognosis of the groups with severe and moderate RVLs was worse than that of the group without RVLs (P = 0.012, P < 0.001), and the group with mild RVLs was close to that of the group without RVLs. ROC analysis showed that the AUC of RRS, BVAS, RVLs score, RVLs score combined with RRS (RVLs score & RRS, RR), RVLs score, and RRS combined with BVAS (RVLs score & RRS & BVAS, RRB) were 0.865, 0.624, 0.763, 0.910, and 0.942, respectively. The predictive power of RRB and RR was comparable and significantly better than the RRS, BVAS, and RVLs score. Based on simplicity and validity, RR was selected as the best predictor, and the relationship between RRS, RVLs score, and RR was calculated using a linear fit, resulting in the linear equation RR = -0.4766 + 0.1231 × RVLs score + 0.395 × RRS (P < 0.001). CONCLUSIONS: In AAGN, the predictive power of RR for renal prognosis was superior to that of RRS, BVAS, and RVLs score. RR may serve as a new predictor of renal prognosis in AAGN.

The role of APTX4870 peptide in reducing cellular inflammatory responses by inhibiting Mycobacterium tuberculosis-derived mycolic acid-induced cytotoxicity.

Tuberculosis is a serious zoonotic disease caused by Mycobacterium tuberculosis (M.tb) and the M.tb complex. Mycolic acid is an extracellular carbohydrate polymer produced, secreted, and accumulated outside the cells of various Mycobacterium tuberculosis strains. Mycolic acid produced by Mycobacterium plays an important role in infection. However, there have been few reports on drugs that inhibit mycolic acid-induced cytotoxicity. The purpose of this study was to investigate the role of the panned peptide in Mycobacterium-derived mycolic acid (M.tb-MA)-induced cell injury. The heptapeptide (APTX4870) was isolated from various phage libraries using phage display (Ph.D-7, Ph.D-12, and Ph.D-C7C). The efficacy of APTX4870 against mycolic acid was demonstrated by evaluating clinical samples and conducting in vitro and Vivo. APTX4870 inhibited apoptosis, increased autophagy to decrease inflammation, and reduced M.tb-MA-induced lung damage. These findings suggest that this heptapeptide, which selectively targets M.tb-MA, might be exploited as a potential novel M.tb therapeutic treatment.

Geospatial epidemiology of Toxoplasma gondii infection in livestock, pets, and humans in China, 1984-2020.

Undercooked or raw meat containing cyst-stage bradyzoites and oocyst-contaminated pets are presumed to constitute a major source of human toxoplasmosis. As the geospatial epidemiology of Toxoplasma gondii (T. gondii) infection in livestock, pets, and humans is rarely studied in China, we undertook a geospatial analysis using GIS visualization techniques. The present study retrieved information from the PubMed, China National Knowledge Infrastructure, and Baidu Scholar databases from 1984 up to 2020. All the data about the seroprevalence of T. gondii in livestock (sheep and goats, pigs, cattle and yaks), pets (cats, dogs), and humans in China were collected. Geospatial epidemiology of T. gondii infection in these hosts was performed using GIS. Results revealed that the estimated pooled seroprevalence of T. gondii was ranged from 3.98 to 43.02% in sheep and goats in China, 0.75 to 30.34% in cattle and yaks, 10.45 to 66.47% in pigs, 2.50 to 60.00% in cats, 0.56 to 27.65% in dogs, and 0.72 to 23.41% in humans. The higher seroprevalences of T. gondii were observed in sheep and goats in the districts of Chongqing, Zhejiang, and Beijing. The infection rates of T. gondii in cattle and yaks were higher in Guizhou, Zhejiang, and Chongqing. Also, the pigs from Chongqing and Guizhou were most severely infected with T. gondii. For cats, the districts of Shanxi, Hebei, and Yunnan had higher seroprevalences of T. gondii and, the infections among dogs were higher in Yunnan and Hebei as well. Furthermore, higher infection pressure of T. gondii exists in the districts of Taiwan and Tibet in humans. The geographical and spatial distribution of toxoplasmosis indicated that infection with T. gondii was widely spread in China, with a wide range of variations among the different hosts and regions in the country. Our results suggested that livestock and pets are not only a reservoir for the parasite but also a direct source of T. gondii infection for humans. It is important to control T. gondii infections in these animals that would reduce the risk of toxoplasmosis in humans.

[Effects of curcumin on liver injury induced by chronic alcohol addiction].

Objective: To investigate the intervention effects of curcumin (Curc) on liver injury induced by chronic alcohol addiction in mice. Methods: Thirty Balb/c mice were randomly divided into normal control group (Control), model group (Model), low-dose Curc group (5 mg/kg, Curc-L), medium dose Curc group (10 mg/kg, Curc-M) and high-dose Curc group (15 mg/kg, Curc-H), with 6 mice in each group. The chronic alcohol addiction liver injury model was prepared with 20% liquor. The mice in control group were given 2 ml of normal saline every day. The mice in model group were given 5 ml/kg of 20% liquor every day, and the mice in Curc treatment group were treated with Curc at the doses of 5, 10, 15 mg/kg in 2 ml saline every day for 35 days. The weight of liver was measured and the health status of mice was observed. Serum ALT, AST, ALP and liver TG, TC, HDL-C, LDL-C, MDA, SOD, GSH-Px and NO were measured. The pathological changes of liver tissues stained with hematoxylin and eosin were observed. Results: Compared with the control group, the liver mass and serum levels of ALT, AST, ALP, MDA, NO, TC, TG, HDL-C, LDL-C in the model group were increased significantly (P＜0.05, P＜0.01), the activities of SOD and GSH-Px were decreased significantly (P＜0.05, P＜0.01), the liver cells were vacuolated and infiltrated with inflammatory cells, and the expression levels of NF-κB and MAPK protein in liver tissues were increased significantly (P＜0.01). Compared with the model group, the levels of ALT, AST, ALP, MDA, NO, TC, TG, HDL-C, LDL-C in Curc group were decreased significantly nd the activities of SOD and GSH-Px were increased significantly (P＜0.05, P＜0.01). Conclusion: Curc can effectively reduce liver tissue damage by regulating NF-κB/MAPK signal pathway.

[Efficacy of high dose glucocorticoid in the salvage treatment of sudden deafness].

Objective:To observe the efficacy and safety of high dose dexamethasone injection in the tympanic cavity in the patients with sudden and severe deafness who failed conventional treatment. Method:A total of 43 patients with unilateral sudden and severe deafness were recruited in this study. All patients were not cured with conventional comprehensive treatment in the department of otology. They were divided into two groups: 21cases were treated with high dose dexamethasone injection into the tympanic cavity by ventilation tube （dexamethasone group）, while routine treatment was continued in 22 cases （conventional control group）. Each patient underwent a hearing test before treatment, the hearing thresholds of 6 frequencies （0.25, 0.5, 1.0, 2.0, 4.0, 8.0 kHz） were recorded. After one week of treatment, the above-mentioned six frequencies were re-recorded. A decrease of the pure tone threshold average （PTA） more than 15 dB was set for effective. Result:After 1 week treatment, comparison of the PTA value before and after treatment in dexamethasone group（t=11.749） and in conventional control group （t=7.364），comparison of the PTA value of the two groups （t=-2.628），comparison of the PTA value of hearing improvement between the two groups （t=2.717）,the differences were statistically significant（P<0.01 or 0.05）. Sixteen cases in dexamethasone group were effective, the effective rate was 76.2%;10 cases in conventional control group was effective, the effective rate was 45.5%,the difference of the two curative effects was statistically significant（χ²=3.058,P<0.05）. Eighteen patients in dexamethasone group had vertigo before treatment. The patients were followed up for 6 months after treatment. The vertigo disappeared or decreased in 14 cases, the improve rate is 77.8%.17 patients in the conventional control group had vertigo before treatment, the patients were followed up for 6 months after treatment, the vertigo disappeared or decreased in 6 cases, the improve rate is 35.3%,the difference was statistically significant（P=0.018）. Conclusion:High dose dexamethasone injection into the tympanic cavity is more effective than conventional therapy in the salvage treatment of sudden and severe deafness, and it is helpful to improve vertigo.

Rutin inhibits amylin-induced neurocytotoxicity and oxidative stress.

Recent evidence showed that amylin deposition is not only found in the pancreas in type 2 diabetes mellitus (T2DM) patients, but also in other peripheral organs, such as kidneys, heart and brain. Circulating amylin oligomers that cross the blood-brain barrier and accumulate in the brain may be an important contributor to diabetic cerebral injury and neurodegeneration. Moreover, increasing epidemiological studies indicate that there is a significant association between T2DM and Alzheimer's disease (AD). Amylin and ß-amyloid (Aß) may share common pathophysiology and show strikingly similar neurotoxicity profiles in the brain. To explore the potential effects of rutin on AD, we here investigated the effect of rutin on amylin aggregation by thioflavin T dyeing, evaluated the effect of rutin on amylin-induced neurocytotoxicity by the MTT assay, and assessed oxidative stress, as well as the generation of nitric oxide (NO) and pro-inflammatory cytokines in neuronal cells. Our results showed that the flavonoid antioxidant rutin inhibited amylin-induced neurocytotoxicity, decreased the production of reactive oxygen species (ROS), NO, glutathione disulfide (GSSG), malondialdehyde (MDA) and pro-inflammatory cytokines TNF-α and IL-1ß, attenuated mitochondrial damage and increased the GSH/GSSG ratio. These protective effects of rutin may have resulted from its ability to inhibit amylin aggregation, enhance the antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and reduce inducible nitric oxide synthase (iNOS) activity. These in vitro results indicate that rutin is a promising natural product for protecting neuronal cells from amylin-induced neurotoxicity and oxidative stress, and rutin administration could be a feasible therapeutic strategy for preventing AD development and protecting the aging brain or slowing neurodegenerative processes.

Decreasing oxidative stress and neuroinflammation with a multifunctional peptide rescues memory deficits in mice with Alzheimer disease.

Alzheimer disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and memory loss. Aggregated amyloid-ß (Aß), oxidative stress, and inflammation have pivotal roles in the pathogenesis of AD. Therefore, the inhibition of Aß-induced neurotoxicity, oxidative stress, and inflammation is a potential therapeutic strategy for the treatment of AD. In this study, a heptapeptide, isolated from a Ph.D.-C7C library by phage display, attenuated Aß42-induced cytotoxicity in SH-SY5Y neuroblastoma cells and reduced Aß42-induced oxidative stress by decreasing the production of reactive oxygen species and glutathione disulfide. As a result, glutathione level increased and superoxide dismutase and glutathione peroxidase activities were enhanced in vitro and in vivo. This peptide also suppressed the inflammatory response by decreasing the release of proinflammatory cytokines, such as tumor necrosis factor α and interleukin 1ß, in microglia and by reducing microgliosis and astrogliosis in AD transgenic mice. This peptide was intracerebroventricularly administered to APPswe/PS1dE9 transgenic mice. We found that this peptide significantly improved spatial memory and reduced the amyloid plaque burden and soluble and insoluble Aß levels. Our findings suggest that this multifunctional peptide has therapeutic potential for an Aß-targeted treatment of AD.

Activated scavenger receptor A promotes glial internalization of aß.

Beta-amyloid (Aß) aggregates have a pivotal role in pathological processing of Alzheimer's disease (AD). The clearance of Aß monomer or aggregates is a causal strategy for AD treatment. Microglia and astrocytes are the main macrophages that exert critical neuroprotective roles in the brain. They may effectively clear the toxic accumulation of Aß at the initial stage of AD, however, their functions are attenuated because of glial overactivation. In this study, we first showed that heptapeptide XD4 activates the class A scavenger receptor (SR-A) on the glia by increasing the binding of Aß to SR-A, thereby promoting glial phagocytosis of Aß oligomer in microglia and astrocytes and triggering intracellular mitogen-activated protein kinase (MAPK) signaling cascades. Moreover, XD4 enhances the internalization of Aß monomers to microglia and astrocytes through macropinocytosis or SR-A-mediated phagocytosis. Furthermore, XD4 significantly inhibits Aß oligomer-induced cytotoxicity to glial cells and decreases the production of proinflammatory cytokines, such as TNF-α and IL-1ß, in vitro and in vivo. Our findings may provide a novel strategy for AD treatment by activating SR-A.

Rutin improves spatial memory in Alzheimer's disease transgenic mice by reducing Aß oligomer level and attenuating oxidative stress and neuroinflammation.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by extracellular ß-amyloid (Aß) plaques and intracellular neurofibrillary tangles in the brain. Aß aggregation is closely associated with neurotoxicity, oxidative stress, and neuronal inflammation. The soluble Aß oligomers are believed to be the most neurotoxic form among all forms of Aß aggregates. We have previously reported a polyphenol compound rutin that could inhibit Aß aggregation and cytotoxicity, attenuate oxidative stress, and decrease the production of nitric oxide and proinflammatory cytokines in vitro. In the current study, we investigated the effect of rutin on APPswe/PS1dE9 transgenic mice. Results demonstrated that orally administered rutin significantly attenuated memory deficits in AD transgenic mice, decreased oligomeric Aß level, increased super oxide dismutase (SOD) activity and glutathione (GSH)/glutathione disulfide (GSSG) ratio, reduced GSSG and malondialdehyde (MDA) levels, downregulated microgliosis and astrocytosis, and decreased interleukin (IL)-1ß and IL-6 levels in the brain. These results indicated that rutin is a promising agent for AD treatment because of its antioxidant, anti-inflammatory, and reducing Aß oligomer activities.

Pan-amyloid oligomer specific scFv antibody attenuates memory deficits and brain amyloid burden in mice with Alzheimer's disease.

Amyloid oligomers have a critical function in the pathologic processes of various amyloidoses, such as Alzheimer's disease (AD), Parkinson disease (PD), Huntington's disease, prion-related diseases, type 2 diabetes, and hereditary renal amyloidosis. Our previous reports demonstrated that a conformation-dependent oligomer-specific single-chain variable fragment (scFv) antibody, W20, isolated from a naïve human scFv library, can recognize oligomers assembled from α-synuclein, amylin, insulin, Aß40/42, prion peptide 106-126, and lysozyme, inhibit the aggregation of various amyloid, and attenuate amyloid oligomer-induced cytotoxicity In vitro. Furthermore, W20 recognized the amyloid oligomers in all types of plaques, Lewy bodies, and amylin deposits in the brain tissues of AD and PD patients and in the pancreas of type 2 diabetes patients. In the current study, we showed that W20 blocked the binding of Aß oligomers to SH-SY5Y cells, did not bind to heat shock protein, rescued cognitive impairments in APP/PS1 transgenic mice, and interfered with Aß levels and deposits in mouse brain. These results suggest that W20 may be a promising therapeutic for the treatment of AD.

A peptide binding to the ß-site of APP improves spatial memory and attenuates Aß burden in Alzheimer's disease transgenic mice.

Amyloid precursor protein cleaving enzyme 1 (BACE1), an aspartyl protease, initiates processing of the amyloid precursor protein (APP) into ß-amyloid (Aß); the peptide likely contributes to development of Alzheimer's disease (AD). BACE1 is an attractive therapeutic target for AD treatment, but it exhibits other physiological activities and has many other substrates besides APP. Thus, inhibition of BACE1 function may cause adverse side effects. Here, we present a peptide, S1, isolated from a peptide library that selectively inhibits BACE1 hydrolytic activity by binding to the ß-proteolytic site on APP and Aß N-terminal. The S1 peptide significantly reduced Aß levels in vitro and in vivo and inhibited Aß cytotoxicity in SH-SY5Y cells. When applied to APPswe/PS1dE9 double transgenic mice by intracerebroventricular injection, S1 significantly improved the spatial memory as determined by the Morris Water Maze, and also attenuated their Aß burden. These results indicate that the dual-functional peptide S1 may have therapeutic potential for AD by both reducing Aß generation and inhibiting Aß cytotoxicity.

Rutin inhibits ß-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines.

Alzheimer's disease (AD) is a complex, multi-factorial neurodegenerative disease. The aggregation of soluble ß-amyloid (Aß) into fibrillar deposits is a pathological hallmark of AD. The Aß aggregate-induced neurotoxicity, inflammatory reactions, oxidative stress, and nitric oxide (NO) generation are strongly linked to the etiology of AD. Here, we show that the common dietary flavonoid, rutin, can dose-dependently inhibit Aß42 fibrillization and attenuate Aß42-induced cytotoxicity in SH-SY5Y neuroblastoma cells. Moreover, rutin decreases the formation of reactive oxygen species (ROS), NO, glutathione disulfide (GSSG), and malondialdehyde (MDA), reduces inducible nitric oxide synthase (iNOS) activity, attenuates mitochondrial damage, increases the glutathione (GSH)/GSSG ratio, enhances the activities of super oxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and modulates the production of proinflammatory cytokines by decreasing TNF-α and IL-1ß generation in microglia. Taken together, the actions of rutin on multiple pathogenic factors deserves further investigation for the prevention and treatment of AD.

[Expression of Survivin, Caspase-3 and p53 in surgical margin of laryngeal squamous cell carcinoma and their relationship].

OBJECTIVE: To study the expression of Survivin, Caspase-3 and p53 in surgical margin of laryngeal squamous cell carcinoma (LSCC), and their clinical significance and relationship. METHOD: Immunohistochemistry method was used to detect the expression of Survivin, Caspase-3 and p53 in 116 cases of surgical margin of LSCC. RESULT: According to the recurrence, the patients were divided into four group, recurrence within one year, between one year to three years, between three to five years, more than 5 years (include no recurrence). The expression rate of survivin were 92.9%, 85.0%, 50.0% and 21.1% (P < 0.01) in four groups, respectively. The expression rate of Caspase-3 were 50.0%, 50.0%, 66.7% and 89.5% (P < 0.01). The expression rate of p53 were 57.1%, 37.5%, 45.8% and 18.4% (P < 0.05). The expression rate of survivin, caspase-3 and p53 in four groups, respectively, there were significant differences (P < 0.05). CONCLUSION: Expression of Survivin, Caspase-3 and p53 in surgical margin of LSCC may play an important role in the tumorigenesis and development of laryngeal carcinoma. They are feasible for early diagnosis and prognosis estimation.