[Bendamustine combined with pomalidomide and dexamethasone in relapsed multiple myeloma with extramedullary disease: a multicenter study].

Objective: To evaluate the efficacy and safety of bendamustine combined with pomalidomide and dexamethasone (BPD regimen) in the treatment of relapsed multiple myeloma (MM) with extramedullary disease. Methods: This open, single-arm, multicenter prospective cohort study included 30 relapsed MM patients with extramedullary disease diagnosed in seven hospitals including Qingdao Municipal Hospital. The patients were treated with BPD regimen from February 2021 to November 2022. This study analyzed the efficacy and adverse reactions of the BPD regimen. Results: The median age of the 30 patients was 62 (47-72) years, of which 18 (60% ) had first-time recurrence. The overall response rate (ORR) of the 18 patients with first-time recurrence was 100%, of which three (16.7% ) achieved complete remission, 10 (55.5% ) achieved very good partial remission (VGPR), and five (27.8% ) achieved partial remission (PR). The ORR of 12 patients with recurrence after second-line or above treatment was 50%, including zero patients with ≥VGPR and six patients (50% ) with PR. Three cases (25% ) had stable disease, and three cases (25% ) had disease progression. The one-year progression free survival rate of all patients was 65.2% (95% CI 37.2% -83.1% ), and the 1-year overall survival rate was 90.0% (95% CI 76.2% -95.4% ). The common grade 3-4 hematology adverse reactions included two cases (6.7% ) of neutropenia and one case (3.3% ) of thrombocytopenia. The overall adverse reactions are controllable. Conclusions: The BPD regimen has good efficacy and tolerance in relapsed MM patients with extramedullary disease.

[Efficacy and safety of bendamustine-rituximab combination therapy for newly diagnosed indolent B-cell non-Hodgkin's lymphoma and elderly mantle cell lymphoma: a multi-center prospective phase II clinical trial in China].

Objectives: This study aimed to assess the efficacy and safety of bendamustine in combination with rituximab (BR regimen) for the treatment of newly diagnosed indolent B-cell non-Hodgkin's lymphoma (B-iNHL) and elderly mantle cell lymphoma (eMCL) . Methods: From December 1, 2020 to September 10, 2022, a multi-center prospective study was conducted across ten Grade A tertiary hospitals in Shandong Province, China. The BR regimen was administered to evaluate its efficacy and safety in newly diagnosed B-iNHL and eMCL patients, and all completed at least four cycles of induction therapy. Results: The 72 enrolled patients with B-iNHL or MCL were aged 24-74 years, with a median age of 55 years. Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1 were observed in 76.4% of patients, while 23.6% had scores of 2. Disease distribution included follicular lymphoma (FL) (51.4% ), marginal zone lymphoma (MZL) (33.3% ), eMCL (11.1% ), and the unknown subtype (4.2% ). According to the Ann Arbor staging system, 16.7% and 65.3% of patients were diagnosed with stage Ⅲ and stage Ⅳ lymphomas, respectively. Following four cycles of BR induction therapy, the overall response rate was 98.6%, with a complete response (CR) rate of 83.3% and a partial response (PR) rate of 15.3%. Only one eMCL patient experienced disease progression during treatment, and only one FL patient experienced a relapse. Even when evaluated using CT alone, the CR rate was 63.9%, considering the differences between PET/CT and CT assessments. The median follow-up duration was 11 months (range: 4-22), with a PFS rate of 96.8% and an OS rate of 100.0%. The main hematologic adverse reactions included grade 3-4 leukopenia (27.8%, with febrile neutropenia observed in 8.3% of patients), grade 3-4 lymphopenia (23.6% ), grade 3-4 anemia (5.6% ), and grade 3-4 thrombocytopenia (4.2% ). The main non-hematologic adverse reactions such as fatigue, nausea/vomiting, rash, and infections occurred in less than 20.0% of patients. Conclusion: Within the scope of this clinical trial conducted in China, the BR regimen demonstrated efficacy and safety in treating newly diagnosed B-iNHL and eMCL patients.

Preclinical pharmacokinetic study of a novel lipid-lowering agent, IMM-H007.

The article "Preclinical pharmacokinetic study of a novel lipid-lowering agent, IMM-H007, by Z.-L. Zhang, W.-Q. Liu, X.-Z. Deng, published in Eur Rev Med Pharmacol Sci 2018; 22 (24): 8939-8950-DOI: 10.26355/eurrev_201812_16664-PMID: 30575938" has been withdrawn from the authors stating that "after our article was published, we received a conflict of interest from the Chinese Academy of Sciences. They declared that they developed IMM-H007 for the first time and they had already applied for the patent. We had already cited in the references that IMM-H007 came from the Chinese Academy of Sciences. But they still insisted that we had violated their rights. We had to withdraw our paper in order to avoid greater conflicts and disputes". The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/16664.

Preclinical pharmacokinetic study of a novel lipid-lowering agent, IMM-H007.

OBJECTIVE: To investigate the pharmacokinetic characteristics of absorption, distribution, metabolism, and excretion in vivo after oral administration and sublingual venous injection of the small molecule IMM-H007 in hamsters. MATERIALS AND  METHODS: Pharmacokinetic characteristics, including absorption, distribution, metabolism, and excretion, were studied in vivo by LC-MS/MS after oral administration and sublingual venous injection of IMM-H007 in hamsters. Furthermore, IMM-H007 stability in artificial gastric juices, artificial intestinal juices, and Tris-HCl buffer was also analyzed. RESULTS: There was no significant matrix or impurity interference in golden hamster whole blood as shown using MS/MS analysis to detect the existence of these substances. IMM-H007, Ml, and MP exhibited good linearity in the range of 1-500 ng/mL, 2-1000 ng/mL, and 10-5000 ng/mL, respectively. The matrix effect was 71.93-105.49%, and IMM-H007, M1, and MP were stable during the process of sample disposal. These results illustrate that the HPLC MS/MS analytic method is simple, reliable, and sensitive and exhibits high specificity and which meets the clinical pharmacokinetic requirements of IMM-H007. IMM-H007 is rapidly absorbed through the oral route in hamsters. The Cmax and AUC(0-t) of the Ml and MP metabolites in male and female hamsters were increased with increasing dosage and were proportional to the dose. In addition, T1/2 and MRT(0-t) were significantly prolonged with increasing dosage, exhibiting linear dynamic characteristics and no significant gender differences. Bioavailability in male and female golden hamsters after oral administration of IMM-H007 was calculated using the sum of Ml and MP, resulting in 6.97% and 8.95%, respectively. IMM-H007 and its metabolites were stable in Tris-HCl buffer, artificial gastric juices, and artificial intestinal juices. CONCLUSIONS: We provide an experimental basis for elucidating the material pharmacodynamics actions of IMM-H007 and predicting its potential drug interactions.

The relevance of Tim-3 polymorphisms and F protein to the outcomes of HCV infection.

Hepatitis C virus (HCV) is one of the major causes of liver inflammation. The aim of this study was to investigate the associations of T-cell immunoglobulin and mucin domain-3 (Tim-3) polymorphisms and the alternate reading frame protein (F protein) with the outcomes of HCV infection. Three single-nucleotide polymorphisms (SNPs; rs10053538, rs12186731, and rs13170556) of Tim-3 were genotyped in this study, which included 203 healthy controls, 558 hepatitis C anti-F-positive patients, and 163 hepatitis C anti-F-negative patients. The results revealed that the rs12186731 CT and rs13170556 TC and CC genotypes were significantly less frequent in the anti-F-positive patients [odds ratio (OR) = 0.54, 95 % confidence interval (CI) = 0.35-0.83, p = 0.005; OR = 0.26, 95 % CI = 0.18-0.39, p < 0.001; and OR = 0.19, 95 % CI = 0.10-0.35, p < 0.001, respectively), and the rs13170556 TC genotype was more frequent in the chronic HCV (CHC) patients (OR = 1.70, 95 % CI = 1.20-2.40, p = 0.002). The combined analysis of the rs12186731 CT and rs13170556 TC/CC genotypes revealed a locus-dosage protective effect in the anti-F-positive patients (OR = 0.22, 95 % CI = 0.14-0.33, p trend < 0.001). Stratified analyses revealed that the frequencies of the rs12186731 (CT + TT) genotypes were significantly lower in the older (OR = 0.31, 95 % CI = 0.15-0.65, p = 0.002) and female (OR = 0.30, 95 % CI = 0.17-0.52, p < 0.001) subgroups, and rs13170556 (TC + CC) genotypes exhibited the same effect in all subgroups (all p < 0.001) in the anti-F antibody generations. Moreover, the rs13170556 (TC + CC) genotypes were significantly more frequent in the younger (OR = 1.86, 95 % CI = 1.18-2.94, p = 0.007) and female (OR = 2.38, 95 % CI = 1.48-3.83, p < 0.001) subgroups of CHC patients. These findings suggest that the rs12186731 CT and rs13170556 TC/CC genotypes of Tim-3 provide potential protective effects with the F protein in the outcomes of HCV infection and that these effects are related to sex and age.

TBX21 polymorphisms are associated with virus persistence in hepatitis C virus infection patients from a high-risk Chinese population.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and the varied outcomes of the infection depend on both viral and host factors. We have demonstrated that the HCV alternate reading frame protein (F protein) is related to Th1/Th2 bias which is involved in virus persistence in chronic hepatitis C (CHC) patients. The purpose of this study was to test the hypothesis that genetic variants of TBX21 (T cell specific T-box transcription factor) were associated with the outcomes of HCV infection and F protein generation. Three single nucleotide polymorphisms (SNPs) (rs17250932, rs2074190, rs4794067) in the TBX21 gene were genotyped in a case-control study in a cohort of a high-risk group, including 354 healthy controls and 747 CHC patients (190 anti-F protein antibody seronegative patients and 557 anti-F protein antibody seropositive patients). Results showed that the rs4794067 C allele in the TBX21 promoter was significantly more common in CHC patients (OR = 1.335, 95% CI = 1.058-1.684, P = 0.015), exceptionally in anti-F protein seropositive patients (OR = 1.547, 95% CI = 1.140-2.101, P = 0.005), compared with healthy controls. And the risk effect was also significantly high in patients with HCV 1b genotype and mild fibrosis (P = 0.021, P = 0.010, respectively). Compared with the most frequent haplotype TAT, haplotype analysis showed that the distribution of TAC was significantly different between the chronic HCV carrier group and the healthy group, and so was the anti-F antibody seronegativity group and the anti-F antibody seronegativity group (all P < 0.001). Our results suggested that TBX21 variants may be involved in the etiology of this disease.

A stereological study of the effects of experimental inguinal cryptorchidism and subsequent orchiopexy on spermatogenesis in adult monkeys.

Our previous study demonstrated that experimental intra-abdominal cryptorchidism in adult rabbits for 13 weeks resulted in severe spermatogenic arrest: type A spermatogonia was the only germ cell type seen in the seminiferous epithelium and its number per testis was reduced by 84%. Seven weeks following orchiopexy, the type A spermatogonial number returned to the near-normal range in most animals and spermatogenesis partially recovered (Reproduction 2002, 124, 95-105). This study aimed to determine whether inguinal cryptorchidism would produce less-severe damage to spermatogenesis and whether subsequent orchiopexy would better restore spermatogenesis. Five normal adult male rhesus monkeys (Macaca mulatta) underwent bilateral artificial inguinal cryptorchidism. Half a year later, one testis together with the ipsilateral epididymis were removed from each animal and then unilateral orchiopexy was performed on the contralateral side, with the remaining testis and epididymis being removed another half a year later. A contemporary unbiased and efficient stereological tool, the optical disector, was used to estimate numbers of all types of spermatogenic cells in the testis and spermatozoa in the epididymis. Spermatogenic arrest was induced by cryptorchidism at the stage of spermatogonia (n = 1), spermatocytes (n = 2) or early spermatids (n = 1), with the type A spermatogonial numbers per testis being reduced to 14.8-57.2% of the control average; in one of the five cryptorchid animals, however, spermatogenesis remained normal. Subsequent orchiopexy, which was successfully performed on two animals with cryptorchidism-induced spermatogenic arrest, brought on a full or partial recovery of spermatogenesis. In conclusion, inguinal cryptorchidism induces less severe (in comparison with an intra-abdominal one) and variable damage to spermatogenesis, which is restored, at least in part, by subsequent orchiopexy.

A quantitative (stereological) study of the effects of experimental unilateral cryptorchidism and subsequent orchiopexy on spermatogenesis in adult rabbit testis.

The aim of this study was to examine the controversial effects of experimental unilateral cryptorchidism and subsequent orchiopexy on the number of germ cells and other morphometric characteristics of testicular and epididymal structures in adult rabbits. Unilateral cryptorchidism was induced in 11 mature male New Zealand white rabbits by returning one testis, together with the ipsilateral epididymis, to the abdominal cavity via a surgical procedure. After 3 months, testes and epididymides were removed from six animals (and from six age-matched control animals that did not undergo the surgery). Orchiopexy was performed on the five remaining animals and the testes and epididymides of these animals (and an additional six age-matched control animals) were removed 7 weeks later. A contemporary, unbiased and efficient stereological tool, the optical disector, was used to estimate the number of nuclei in the testis and epididymis using methacrylate-embedded sections of 25 micron in thickness. Cryptorchidism resulted in severe testicular atrophy and spermatogenic arrest: type A spermatogonia and Sertoli cells only were seen in the seminiferous epithelium, and the number of type A spermatogonia per testis was reduced by 84%. After orchiopexy, the testis remained atrophied and the number of type A spermatogonia returned to the near-normal range in four of five animals, but spermatogenesis was recovered only partially at the stage of early primary spermatocytes (one animal), late primary spermatocytes (two animals) or spermatids (one animal). In conclusion, cryptorchidism caused severe spermatogenic arrest that was potentially recoverable (in view of the restoration of the number of type A spermatogonia), but orchiopexy failed to induce full recovery of spermatogenesis.

Quantitative (stereological) study of the effects of vasectomy on spermatogenesis in rhesus monkeys (Macaca mulatta).

Vasectomy reversal by vasovasostomy after long-term vasectomy in men results in lower sperm counts and pregnancy rates compared with controls, and severe damage to spermatogenesis has been observed in some animal models such as mice. The primary aim of this study was to evaluate, using sophisticated stereological methods, whether vasectomy of 6 and 12 months in a non-human primate would lead to, among other morphometric changes, reduced numbers of germ cells in testes and spermatozoa in epididymides. Five normal adult male rhesus monkeys (Macaca mulatta) underwent bilateral vasectomy, with another three aged-matched normal monkeys not undergoing vasectomy. One testis together with the ipsilateral epididymis was removed from each animal at 6 months, and the other testis and epididymis, the prostate gland and seminal vesicles were removed at 12 months. Various morphometric data were obtained using stereological methods and an unbiased and efficient stereological tool, the optical disector, was used to estimate nuclear numbers of all types of spermatogenic cells in testes and spermatozoa in epididymides using methacrylate-embedded sections 25 microm in thickness. As shown by a two-way repeated measures analysis of variance, vasectomy or hemicastration (removal of the organs at 6 months) had no significant effects on all quantitative parameters of stereology obtained from the testis, epididymis, prostate gland and seminal vesicle, except that (i) sperm granuloma was observed from three of five vasectomized animals both at 6 and 12 months, and (ii) hemicastration significantly reduced the diameter of the seminiferous tubules and increased the number of type A spermatogonia per testis. In conclusion, vasectomy in the non-human primate is a safe procedure in terms of effects on the structures of the reproductive organs.

[A new method prepared gene probe].

Plasmid pNZ8802 containing K88ac gene was digested by EcoRI, and the small fragment was cloned to vector plasmid pUB110. One of the hybrid plasmids was named as pNZ8803 which was used to gene probe for detecting varity of strains. Strains containing K88ac or K88ab gene were all positive hybridization, and strains which did not containing K88ac gene were all negative hybridization. The result indicated that the gene probe was highly specificity and sensitivity.