[Analysis of the efficacy and safety of bone disease treatment in patients with newly diagnosed multiple myeloma treated with denosumab or zoledronic acid].

Objective: This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma. Methods: The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) . Results: Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration (P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum ß-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type Ⅰ N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups (P>0.05), and the median PFS and OS time were not reached (P>0.05) . Conclusions: In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.

[Daratumumab maintenance after autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma].

Objective: This study aimed to evaluate the efficacy and safety of daratumumab as a maintenance treatment after autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between May 1, 2022 and June 30, 2023 were retrospectively analyzed. Results: Fifteen patients (11 males and 4 females) with a median age of 58 (41-72) years were included. Thirteen patients did not receive daratumumab during induction therapy and auto-HSCT, 6 patients had renal impairment, and nine patients had high-risk cytogenetics. The median infusion of daratumumab was 12 (6-17) times, and the median duration of maintenance was 6 (1.5-12) months. The treatment efficacy was evaluated in all 15 patients, and daratumumab maintenance therapy increased the rate of stringent complete response from 40% to 60%. The renal response rate and median estimated glomerular filtration rate of six patients with RI-NDMM were also improved. During daratumumab maintenance therapy, the most common hematological grade 3 adverse event (AE) was lymphopenia [4 of 15 patients (26.67%) ], whereas the most common nonhematologic AEs were infusion-related reactions [7 of 15 patients (46.67%) ] and grade 3 pneumonia [5 of 15 patients (33.33%) ]. The five patients with pneumonia were daratumumab naive [5 of 13 patients (38.46%) ], with a median of 8 (6-10) infusions. Among them, the chest computed tomography of three patients showed interstitial infiltrates, and treatment with methylprednisolone was effective. With a median follow-up of 12 months, the 1-year overall survival rate was 93.33%, and only one patient died (which was not related to daratumumab treatment) . Conclusions: Daratumumab was safe and effective as a maintenance agent for post-auto-HSCT patients with NDMM, and AEs were controllable. The most common nonhematologic AE was grade 3 pneumonia, and a less dose-intense maintenance regimen for the first 8 weeks could reduce the incidence of pneumonia.

Platelet-activating factor and its structural analogues in the earthworm Eisenia foetida.

The earthworm Eisenia foetida was shown to contain large amounts of ether-containing phospholipids such as alkylacylglycerophosphocholine (61.3% of choline glycerophospholipids) and alkenylacylglycerophosphoethanolamine (66.0% of ethanolamine glycerophospholipids). We also found a substantial amount of ether-containing PAF-like lipid in this animal, its level being increased after the animal is injured. We showed evidence that this PAF-like lipid consists of PAF and PAF analogues containing short chain fatty acids other than acetic acid. Notably, a propionic acid-containing species but not PAF itself, is the most predominant species in this animal. We also confirmed that the earthworms contain enzyme activities involved in the synthesis of PAF and short chain fatty acid-containing PAF analogues. Interestingly, the acetyltransferase activity in earthworms is resistant to high concentrations of the substrate lysophospholipid. Thus, both the structure of the PAF-like lipid and the properties of the enzymes involved in the PAF-like lipid metabolism in the earthworms are somewhat different from those in mammalian tissues.

Control of cleavage spindle orientation in Caenorhabditis elegans: the role of the genes par-2 and par-3.

Polarized asymmetric divisions play important roles in the development of plants and animals. The first two embryonic cleavages of Caenorhabditis elegans provide an opportunity to study the mechanisms controlling polarized asymmetric divisions. The first cleavage is unequal, producing daughters with different sizes and fates. The daughter blastomeres divide with different orientations at the second cleavage; the anterior blastomere divides equally across the long axis of the egg, whereas the posterior blastomere divides unequally along the long axis. We report here the results of our analysis of the genes par-2 and par-3 with respect to their contribution to the polarity of these divisions. Strong loss-of-function mutations in both genes lead to an equal first cleavage and an altered second cleavage. Interestingly, the mutations exhibit striking gene-specific differences at the second cleavage. The par-2 mutations lead to transverse spindle orientations in both blastomeres, whereas par-3 mutations lead to longitudinal spindle orientations in both blastomeres. The spindle orientation defects correlate with defects in centrosome movements during both the first and the second cell cycle. Temperature shift experiments with par-2(it5ts) indicate that the par-2(+) activity is not required after the two-cell stage. Analysis of double mutants shows that par-3 is epistatic to par-2. We propose a model wherein par-2(+) and par-3(+) act in concert during the first cell cycle to affect asymmetric modification of the cytoskeleton. This polar modification leads to different behaviors of centrosomes in the anterior and posterior and leads ultimately to blastomere-specific spindle orientations at the second cleavage.

Interactions of polyhomeotic with Polycomb group genes of Drosophila melanogaster.

The Polycomb (Pc) group genes of Drosophila are negative regulators of homeotic genes, but individual loci have pleiotropic phenotypes. It has been suggested that Pc group genes might form a regulatory hierarchy, or might be members of a multimeric complex that obeys the law of mass action. Recently, it was shown that polyhomeotic (ph) immunoprecipitates in a multimeric complex that includes Pc. Here, we show that duplications of ph suppress homeotic transformations of Pc and Pcl, supporting a mass-action model for Pc group function. We crossed ph alleles to all members of the Polycomb group, and to E(Pc) and Su(z)2 to look for synergistic effects. We observed extragenic noncomplementation between ph503 and Pc, Psc1 and Su(z)2(1) in females, and between ph409 and Sce1, ScmD1 and E(z)1 mutations in males, suggesting that these gene products might interact directly with ph. Males hemizygous for a temperature-sensitive allele, ph2, are lethal when heterozygous with mutants in Asx, Pc, Pcl, Psc, Sce and Scm, and with E(Pc) and Su(z)2. Mutations in trithorax group genes were not able to suppress the lethality of ph2/Y; Psc1/+ males. ph2 was not lethal with extra sex combs, E(z), super sex combs (sxc) or l(4)102EFc heterozygotes, but did cause earlier lethality in embryos homozygous for E(z), sxc and l(4)102EFc. However, ph503 did not enhance homeotic phenotypes of esc heterozygotes derived from homozygous esc- mothers. We examined the embryonic phenotypes of ph2 embryos that were lethal when heterozygous or homozygous for other mutations. Based on this phenotypic analysis, we suggest that ph may perform different functions in conjunction with differing subsets of Pc group genes.

The polyhomeotic locus of Drosophila melanogaster is transcriptionally and post-transcriptionally regulated during embryogenesis.

The polyhomeotic (ph) locus of Drosophila is a complex locus essential for the maintenance of segmental identity. Genetic analysis suggested that two independent units contribute to ph function. Comparison of genomic sequence shows that the ph locus has been duplicated, and that it contains proximal and distal transcription units. The proximal transcription unit encodes two embryonic mRNAs of 6.4 and 6.1 kb, and the distal unit encodes a 6.4-kb embryonic mRNA. The proximal and distal transcription units are differentially regulated at the mRNA level during development as shown by developmental Northern analysis. The distal protein is very similar to the proximal product, except for the absence of an amino terminal region, and a small region near the carboxy terminus. The long open reading frame in the distal cDNA does not begin with an ATG codon, and an internal ATG is used for a start codon. We show that the proximal protein occurs in two forms that are developmentally regulated, and that probably arise from use of two different initiator methionine codons. We find no evidence for differential binding of proximal and distal products to polytene chromosomes. Nevertheless, we show that mutations in the proximal and distal proteins have differing effects on regulation of a reporter under the control of a regulatory region from bithoraxoid, suggesting that ph proximal and distal proteins have different functions. These results show that the ph locus undergoes complex developmental regulation, and suggest that Polycomb group regulation may be more dynamic than anticipated.

Aspirin induces non-enzymatic formation of platelet-activating factor from lyso platelet-activating factor.

Substantial amounts of platelet-activating factor (PAF) were formed when lysoPAF was mixed with aspirin (e.g. 0.04% of added lysoPAF (200 nmol) was converted to PAF when mixed with aspirin (2 mumol) for 1 h). Non-enzymatic formation of PAF from aspirin and lysoPAF also occurs in the aqueous solution or in organic solvents in time-dependent and dose-dependent manners. Possible meanings of the non-enzymatic formation of PAF are discussed.

A multicentre study on eradication of Helicobacter pylori using four 1-week triple therapies in China.

BACKGROUND: Short-term proton pump inhibitor-based triple therapies for the eradication of Helicobacter pylori are used widely. The eradication rates vary greatly from country to country and from region to region. AIM: To assess the efficacy at eradicating H. pylori of 1-week regimens containing three medications: omeprazole (O) or colloidal bismuth subcitrate (B), furazolidone (F) or metronidazole (M), and amoxicillin (A) or clarithromycin (C). METHODS: A multicentre study involving 20 hospitals in different regions of China. A total of 892 patients with H. pylori-positive non-ulcer dyspepsia or healed duodenal ulcer confirmed by endoscopy were recruited to receive, randomly, one of four regimens: OMC, OFC, OFA, and BFC, b.d. for 7 days. 13C-urea breath test was performed 4-8 weeks after completion of treatment. RESULTS: The eradication rates with per protocol/intention-to-treat analyses were: OMC (n=217/219) 66%/65%; OFC (n=227/229) 69%/69%; OFA (n=223/225) 87%/86%; and BFC (n=214/219) 80%/78%. The eradication rate (per protocol analysis) in duodenal ulcer (79%) was higher than that in non-ulcer dyspepsia (73%, P=0.033). Patient compliance was good. The adverse events of the four regimens were mild, and mainly gastrointestinal. CONCLUSIONS: The omeprazole, furazolidine and amoxicillin regimen achieves a high H. pylori eradication rate in different geographical regions of China.

Transient activation of 1-O-alkyl-sn-glycero-3-phosphocholine: acetyl-CoA acetyltransferase during the incubation of macrophages.

The activity of the platelet-activating factor (PAF)-synthesizing enzyme, 1-O-alkyl-sn-glycero-3-phosphocholine (lysoPAF):acetyl-CoA acetyltransferase (EC 2.3.1.67) in alveolar macrophage lysate was found to be elevated after warming the cells to 37 degrees C. Such an increase in enzyme activity was detectable only when intact cells were warmed. The stimulation was transient, reaching a peak at 2 min, and then gradually decreased to the control level. We could not find increased PAF formation in warmed cells which had increased acetyltransferase activity, even though substantial amounts of lysoPAF were shown to be present within cells. In contrast, considerable amounts of PAF were formed after treatment of the cells with exogenous lysoPAF. These results suggest that the activation of acetyltransferase is not sufficient to induce PAF formation and that the increased availability of substrates, especially lysoPAF, in the cells is indispensable for triggering PAF biosynthesis in this type of cells.

Efficacy and safety of telmisartan vs. losartan in control of mild-to-moderate hypertension: a multicentre, randomised, double-blind study.

This multicentre, randomised, double-blind, double-dummy, parallel-group study compared the efficacy and safety of telmisartan with those of losartan after 8 weeks' treatment. In total, 330 patients with mild-to-moderate hypertension (systolic blood pressure [SBP] <180 mmHg; diastolic blood pressure [DBP] 95-109 mmHg) were randomly assigned to receive once-daily treatment with telmisartan 40 mg (n = 164) or losartan 50 mg (n = 166). After 4 weeks' treatment, if a patient's DBP was > or = 90 mmHg, the dose was increased to telmisartan 80 mg or losartan 100 mg, respectively. The results show that mean trough seated blood pressure was reduced significantly more in the telmisartan group than that in the losartan group (SBP 12.5 mmHg vs. 9.4 mmHg, p = 0.037; DBP 10.9 mmHg vs. 9.3 mmHg, p = 0.030). The overall DBP response rate (reduction from baseline in mean seated DBP > or = 10 mmHg and/or a mean seated DBP <90 mmHg) at the end of the study in the telmisartan group was higher than that in losartan group (70.1% vs. 58.7%, p = 0.020). At both the low and high doses, the DBP response rates for telmisartan were significantly higher than those for losartan (telmisartan 40 mg vs. losartan 50 mg: 46.3% vs. 32.5%, p = 0.010; telmisartan 80 mg vs. losartan 100 mg: 79.3% vs. 65.3%, p = 0.008). Adverse events with the two treatments were comparable (telmisartan vs. losartan 23.2% vs. 22.9%, p = 0.952). Most events were mild in intensity and abated within 72 h. Thus, telmisartan 40 mg or 80 mg administered once daily can reduce SBP and DBP effectively and safely.

[The composition of phospholipid and biosynthesis of platelet-activating factor in earthworm (Eisenia foetida)].

Platelet-activating factor (PAF) was for the first time confirmed to exist in a lower animal, earthworm (Eisenia foetida). It amounts to 10.7 +/- 6.1 pmol/g wet body weight, and varied seasonally. Phospholipid analysis revealed that 1-O-alkyl-2-acyl-sn-glycerophosphocholine, a stored form of PAF precursor, accounted for 61.4% of the choline glycerophospholipids. Two kinds of enzyme activities operating in PAF generation in mammalian cells were also detected from this species. The PAF level increased markedly under some injurious stimuli such as cutting and pricking. The results suggest that PAF may be a primary mediator involved in pathological and physiological reactions even in lower animal like earthworm. The findings also cast a new light on the mechanisms underlying the antihypertensive and other effects of the Chinese medicinal earthworm, pheretima.

[Effect of enterogastric circulation of diazepam on its CNS inhibitory action in mice].

The present study was designed to examine whether disturbance of the enterogastric circulation of diazepam would obviously affect its inhibitory action on CNS. Intragastric administration of acidic liquid (pH 1) elicited a marked increase in the amount of diazepam in the gastric juice of mice 1 h after i.v. diazepam, as measured by HPLC method. The effects of ig acidic charcoal (2 g.kg-1, pH 1), neutral charcoal and normal saline on diazepam-induced CNS depression were compared by studying the duration of hypnotic action, inhibition of spontaneous activity, dropping rate in rotating rod test and mortality after i.v. diazepam (10-40 mg.kg-1) in mice. The results showed that the animals receiving ig acidic charcoal recovered more rapidly from CNS depression and exhibited lower mortality than the animals in neutral charcoal group and normal saline group.

[A hypotensive analog of platelet-activating factor (PAF) in pheretima].

Experiments showed that intravenous administration of pheretima decoction elicited pronounced decrease of hypotension in rats. Pretreatment with CV6209, a specific PAF antagonist, significantly inhibited the hypotensive activity of pheretima. Furthermore, an analog of PAF was separated from the total lipids of pheretima and its content was measured to be around 90-130 ng/g.

Operons as a common form of chromosomal organization in C. elegans.

Although eukaryotic genes are usually transcribed individually, at least a few Caenorhabditis elegans genes appear to be transcribed polycistronically in clusters resembling bacterial operons. The spliced leader SL2 (ref. 2) is specific for trans-splicing to downstream genes in these operons. In addition, many C. elegans pre-mRNAs are trans-spliced to SL1 (ref. 3) near the 5' ends of pre-mRNAs. Because operons have not previously been found in higher eukaryotes, we have investigated how widespread they are in the C. elegans genome. We identified gene clusters using the extensive data generated by the genome project and tested seven for trans-splicing specificity. All were found to fit expectations for polycistronic transcription. In addition, we surveyed reported C. elegans genes for trans-splicing specificity. Both methods indicate that the pre-mRNAs of about 70% of C. elegans genes are trans-spliced and as many as a quarter are transcribed in operons.

Synthesis and action of PAF in human eosinophils.

We compared the level of PAF precursor as well as the synthesis and the catabolism of PAF in eosinophils with those in neutrophils. The modes of action of PAf on these two types of cells were also compared.

Locust ion transport peptide (ITP): primary structure, cDNA and expression in a baculovirus system.

Ion transport peptide (ITP) purified from locust nervous corpus cardiacum (CC) has previously been shown to stimulate salt and water reabsorption and inhibit acid secretion in the ileum of Schistocerca gregaria. We used the partial amino acid sequence of purified ITP to derive degenerate primers. These were used to amplify a cDNA from brain RNA using reverse transcription and the polymerase chain reaction (RtPCR). This sequence was extended using anchored PCR to yield a partial, 517bp cDNA clone. This cDNA encodes a putative ITP prohormone which could be cleaved at two dibasic amino acid sites to yield a 72 residue active amidated peptide. The deduced amino acid sequence from the cDNA agrees completely with the amino acid sequence and molecular mass (8564Da) derived from analysis of purified ITP. Relative to a family of crustacean hyperglycaemic hormones (CHH), all six cysteine residues and many other amino acid residues are conserved in ITP, establishing that ITP is a homologue. However, CHH, crab eyestalk and CC extracts from distantly related insects have no action, whereas CC extracts from closely related insects are active on the locust ITP assay, showing that the bioassay is selective. Insect Sf9 cells transfected with a baculovirus containing our partial cDNA secreted a potent stimulant of locust ileal transport, confirming that the peptide encoded by our ITP clone has biological activity. The mRNA for ITP is restricted to the brain and CC. Interestingly, a related mRNA is observed in other tissues which are not active on the ITP bioassay.