Probiotics for the Treatment of Docetaxel-Related Weight Gain of Breast Cancer Patients—A Single-Center, Randomized, Double-Blind, and Placebo-Controlled Trial

Background: Docetaxel is an important chemotherapy-agent for breast cancer treatment. One of its side-effects is weight gain, which increases the all-cause mortality rate. Considering gut microbiota is one important factor for weight regulation, we hypothesized that probiotics could be potentially used to reduce the docetaxel-related weight gain in breast cancer patients.Methods: From 10/8/2018 to 10/17/2019, 100 breast cancer (Stage I-III) patients underwent four cycles of docetaxel-based chemotherapy were enrolled and randomly assigned to receive probiotics (Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis) or placebo (supplementary material of the probiotics capsule) treatment for 84 days with three capsules per time, twice/day. The primary outcome: the changes in body weight and body-fat percentage of the patients were measured by a designated physician using a fat analyzer, and the secondary outcomes: the fasting insulin, plasma glucose, and lipids were directly obtained from the Hospital Information System (HIS); The metabolites were measured using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS); The fecal microbiome was analyzed using bacterial 16S ribosomal RNA (rRNA) gene sequence. All indicators were measured 1 day before the first cycle of docetaxel-based chemotherapy and 21 days after the last cycle of docetaxel-based chemotherapy.Results: Compared with the placebo group, the probiotic group showed significantly smaller changes in body weight (Mean [SD] 0.77 [2.58] vs. 2.70 [3.08], P = 0.03), body-fat percentage (Mean [SD] 0.04 [1.14] vs. 3.86 [11.09], P = 0.02), and low density lipoprotein (LDL) (Mean [SD]−0.05[0.68] vs. 0.39 [0.58], P = 0.002). Moreover, five of the 340 detected plasma metabolites showed significant differences between the two groups. The change of biliverdin dihydrochloride (B = −0.724, P = 0.02) was inverse correlated with weight gain. One strain of the phylum and three strains of the genus were detected to be significantly different between the two groups. Also, the changes of Bacteroides (B = −0.917, P < 0.001) and Anaerostipes (B = −0.894, P < 0.001) were inverse correlated with the change of LDL.Conclusions: Probiotics supplement during docetaxel-based chemotherapy for breast cancer treatment may help to reduce the increase in body weight, body-fat percentage, plasma LDL, and minimize the metabolic changes and gut dysbacteriosis.Clinical Trial Registration:http://www.chictr.org.cn/showproj.aspx?proj=24294, ChiCTR-INQ-17014181

Early Exposure to Paraquat Sensitizes Dopaminergic Neurons to Subsequent Silencing of PINK1 Gene Expression in Mice

Environmental exposure, genetic modification, and aging are considered risky for Parkinson's disease (PD). How these risk factors cooperate to induce progressive neurodegeneration in PD remains largely unknown. Paraquat is an herbicide commonly used for weed and grass control. Exposure to paraquat is associated with the increased incidence of PD. In contrast to familial PD, most sporadic PD cases do not have genetic mutation, but may suffer from partial dysfunction of neuron-protective genes as aging. Using conditional transgenic RNAi, we showed that temporal silencing of PINK1 expression in adult mice increased striatal dopamine, the phenotype that could not be induced by constitutive gene silencing. Moreover, early exposure to paraquat sensitized dopaminergic neurons to subsequent silencing of PINK1 gene expression, leading to a significant loss of dopaminergic neurons. Our findings suggest a novel pathogenesis of PD: exposure to environmental toxicants early in the life reduces the threshold of developing PD and partial dysfunction of neuron-protective genes later in the life initiates a process of progressive neurodegeneration to cross the reduced threshold of disease onset

AI Assistant in Online Pharmacy

Artificial intelligence (AI) has been increasingly popular in diagnosing diseases and recommending drugs in digital healthcare platforms. Leveraging the introduction of an AI-powered medical assistant to one drug category in an online pharmacy platform, we investigate how the adoption of AI affects users’ purchase behaviors using a difference-in-differences design. We find that the adoption of the AI assistant significantly increases users’ purchases in the platform, even for drugs not recommended by the AI assistant. Furthermore, we find that the positive effect of the AI assistant adoption is stronger for early technology adopters, inexperienced users, and users with higher privacy concerns, likely because these users tend to perceive higher value from AI. Finally, our mediation analysis shows that the AI feature increases users’ purchases by increasing their engagement levels in the platform. Our results have important implications for designing and evaluating AI features in online platforms

TDP-43 Potentiates Alpha-synuclein Toxicity to Dopaminergic Neurons in Transgenic Mice

TDP-43 and α-synuclein are two disease proteins involved in a wide range of neurodegenerative diseases. While TDP-43 proteinopathy is considered a pathologic hallmark of sporadic amyotrophic lateral sclerosis and frontotemporal lobe degeneration, α-synuclein is a major component of Lewy body characteristic of Parkinson's disease. Intriguingly, TDP-43 proteinopathy also coexists with Lewy body and with synucleinopathy in certain disease conditions. Here we reported the effects of TDP-43 on α-synuclein neurotoxicity in transgenic mice. Overexpression of mutant TDP-43 (M337V substitution) in mice caused early death in transgenic founders, but overexpression of normal TDP-43 only induced a moderate loss of cortical neurons in the transgenic mice at advanced ages. Interestingly, concomitant overexpression of normal TDP-43 and mutant α-synuclein caused a more severe loss of dopaminergic neurons in the double transgenic mice as compared to single-gene transgenic mice. TDP-43 potentiated α-synuclein toxicity to dopaminergic neurons in living animals. Our finding provides in vivo evidence suggesting that disease proteins such as TDP-43 and α-synuclein may play a synergistic role in disease induction in neurodegenerative diseases

Temporal Expression of Mutant LRRK2 in Adult Rats Impairs Dopamine Reuptake

Parkinson's disease (PD) results from progressive degeneration of dopaminergic neurons. Most PD cases are sporadic, but some have pathogenic mutation in the individual genes. Mutation of the leucine-rich repeat kinase-2 (LRRK2) gene is associated with familial and sporadic PD, as exemplified by G2019S substitution. While constitutive expression of mutant LRRK2 in transgenic mice fails to induce neuron death, transient expression of the disease gene by viral delivery causes a substantial loss of dopaminergic neurons in mice. To further assess LRRK2 pathogenesis, we created inducible transgenic rats expressing human LRRK2 with G2019S substitution. Temporal overexpression of LRRK2G2019S in adult rats impaired dopamine reuptake by dopamine transporter (DAT) and thus enhanced locomotor activity, the phenotypes that were not observed in transgenic rats constitutively expressing the gene throughout life time. Reduced DAT binding activity is an early sign of dopaminergic dysfunction in asymptomatic subjects carrying pathogenic mutation in LRRK2. Our transgenic rats recapitulated the initiation process of dopaminergic dysfunction caused by pathogenic mutation in LRRK2. Inducible transgenic approach uncovered phenotypes that may be obscured by developmental compensation in constitutive transgenic rats. Finding in inducible LRRK2 transgenic rats would guide developing effective strategy in transgenic studies: Inducible expression of transgene may induce greater phenotypes than constitutive gene expression, particularly in rodents with short life time

Perioperative probiotics attenuates postoperative cognitive dysfunction in elderly patients undergoing hip or knee arthroplasty: A randomized, double-blind, and placebo-controlled trial

BackgroundPostoperative cognitive dysfunction (POCD) is a common complication in elderly patients following surgery. The preventive and/or treatment strategies for the incidence remain limited.ObjectiveThis study aimed to investigate the preventive effect of perioperative probiotic treatment on POCD in elderly patients undergoing hip or knee arthroplasty.MethodsAfter obtaining ethical approval and written informed consent, 106 patients (age ≥60 years) were recruited, who scheduled elective hip or knee arthroplasty, from 16 March 2021 to 25 February 2022 for this randomized, double-blind, and placebo-controlled trial. They were randomly assigned with a 1:1 ratio to receive either probiotics or placebo treatment (four capsules, twice/day) from hospital admission until discharge. Cognitive function was assessed with a battery of 11 neuropsychological tests on the admission day and the seventh day after surgery, respectively.ResultsA total of 96 of 106 patients completed the study, and their data were finally analyzed. POCD occurred in 12 (26.7%) of 45 patients in the probiotic group and 29 (56.9%) of 51 patients in the placebo group (relative risk [RR], 0.47 [95% confidence interval [CI], 0.27 to 0.81]; P = 0.003). Among them, mild POCD occurred in 11 (24.4%) in the probiotic group and 24 (47.1%) in the placebo group (RR, 0.52 [95% CI, 0.29 to 0.94]; P = 0.022). No significant difference in severe POCD incidence was found between the two groups (P = 0.209). Compared with the placebo group, the verbal memory domain cognitive function was mainly improved in the probiotic group.ConclusionProbiotics may be used perioperatively to prevent POCD development and improve verbal memory performance in elderly patients receiving hip or knee arthroplasty.Clinical trial registrationwww.chictr.org.cn, identifier: ChiCTR2100045620

Adjunctive granisetron therapy in patients with sepsis or septic shock (GRANTISS): A single-center, single-blinded, randomized, controlled clinical trial

Background: In preclinical experiments, we demonstrated that the 5-HT3 receptor antagonist granisetron results in reduced inflammation and improved survival in septic mice. This randomized controlled trial was designed to assess the efficacy and safety of granisetron in patients with sepsis.Methods: Adult patients with sepsis and procalcitonin ≥ 2 ng/ml were randomized in a 1:1 ratio to receive intravenous granisetron (3 mg every 8 h) or normal saline at the same volume and frequency for 4 days or until intensive care unit discharge. The primary outcome was 28-day all-cause mortality. Secondary outcomes included the duration of supportive therapies for organ function, changes in sequential organ failure assessment scores over 96 h, procalcitonin reduction rate over 96 h, the incidence of new organ dysfunction, and changes in laboratory variable over 96 h. Adverse events were monitored as the safety outcome.Results: The modified intention-to-treat analysis included 150 septic patients. The 28-day all-cause mortalities in the granisetron and placebo groups were 34.7% and 35.6%, respectively (odds ratio, 0.96; 95% CI, 0.49–1.89). No differences were observed in secondary outcomes. In the subgroup analysis of patients without abdominal or digestive tract infections, the 28-day mortality in the granisetron group was 10.9% lower than mortality in the placebo group. Adverse events were not statistically different between the groups.Conclusion: Granisetron did not improve 28-day mortality in patients with sepsis. However, a further clinical trial targeted to septic patients without abdominal/digestive tract infections perhaps is worthy of consideration

FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and glial reaction. While transgenic rats that overexpressed the wild-type human FUS were asymptomatic at young ages, they showed a deficit in spatial learning and memory and a significant loss of cortical and hippocampal neurons at advanced ages. These results suggest that mutant FUS is more toxic to neurons than normal FUS and that increased expression of normal FUS is sufficient to induce neuron death. Our FUS transgenic rats reproduced some phenotypes of ALS and FTLD and will provide a useful model for mechanistic studies of FUS–related diseases

Structural Basis for Specific Binding of Human MPP8 Chromodomain to Histone H3 Methylated at Lysine 9

. MPP8 binding to methylated H3K9 is suggested to recruit the H3K9 methyltransferases GLP and ESET, and DNA methyltransferase 3A to the promoter of the E-cadherin gene, mediating the E-cadherin gene silencing and promote tumor cell motility and invasion. MPP8 contains a chromodomain in its N-terminus, which is used to bind the methylated H3K9. HP1, a chromodomain containing protein that binds to methylated H3K9 as well. The structure also reveals that the human MPP8 chromodomain forms homodimer, which is mediated via an unexpected domain swapping interaction through two β strands from the two protomer subunits.Our findings reveal the molecular mechanism of selective binding of human MPP8 chromodomain to methylated histone H3K9. The observation of human MPP8 chromodomain in both solution and crystal lattice may provide clues to study MPP8-mediated gene regulation furthermore