This article reports two cases of children with B-cell acute lymphoblastic leukemia (B-ALL) complicated by invasive fungal disease (IFD) who received bridging treatment using blinatumomab. Case 1 was a 4-month-old female infant who experienced recurrent high fever and limb weakness during chemotherapy. Blood culture was negative, and next-generation sequencing (NGS) of peripheral blood, bronchoalveolar lavage fluid, and cerebrospinal fluid were all negative. Chest CT and cranial MRI revealed obvious infection foci. Case 2 was a 2-year-old male patient who experienced recurrent high fever with multiple inflammatory masses during chemotherapy. Candida tropicalis was detected in peripheral blood and abscess fluid using NGS, while blood culture and imaging examinations showed no obvious abnormalities. After antifungal and blinatumomab therapy, both cases showed significant improvement in symptoms, signs, and imaging, and B-ALL remained in continuous remission. The report indicates that bridging treatment with blinatumomab in children with B-ALL complicated by IFD can rebuild the immune system and control the underlying disease in the presence of immunosuppression and severe fungal infection.
Child, Preschool ; Female ; Humans ; Infant ; Male ; Antibodies, Bispecific/therapeutic use* ; Invasive Fungal Infections/drug therapy* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Remission Induction

OBJECTIVE: To explore the possible effects and mechanism of Zhizhu Decoction (ZZD) on the pathophysiology of slow transit constipation (STC). METHODS: A total of 54 C57BL/6 mice was randomly divided into the following 6 groups by a random number table, including control, STC model (model), positive control, and low-, medium- and high-doses ZZD treatment groups (5, 10, 20 g/kg, namely L, M-, and H-ZZD, respectively), 9 mice in each group. Following 2-week treatment, intestinal transport rate (ITR) and fecal water content were determined, and blood and colon tissue samples were collected. Hematoxylin-eosin and periodic acid-Schiff staining were performed to evaluate the morphology of colon tissues and calculate the number of goblet cells. To determine intestinal permeability, serum levels of lipopolysaccharide (LPS), low-density lipoprotein (LDL) and mannose were measured using enzyme-linked immunosorbent assay (ELISA). Western blot analysis was carried out to detect the expression levels of intestinal tight junction proteins zona-occludens-1 (ZO-1), claudin-1, occludin and recombinant mucin 2 (MUC2). The mRNA expression levels of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-4, IL-10 and IL-22 were determined using reverse transcription-quantitative reverse transcription reaction. Colon indexes of oxidative stress were measured by ELISA, and protein expression levels of colon silent information regulator 1/forkhead box O transcription factor 1 (SIRT1/FoxO1) antioxidant signaling pathway were detected by Western blot. RESULTS: Compared with the model group, ITR and fecal moisture were significantly enhanced in STC mice in the M-ZZD and H-ZZD groups (P<0.01). Additionally, ZZD treatment notably increased the thickness of mucosal and muscular tissue, elevated the number of goblet cells in the colon of STC mice, reduced the secretion levels of LPS, LDL and mannose, and upregulated ZO-1, claudin-1, occludin and MUC2 expressions in the colon in a dose-dependent manner, compared with the model group (P<0.05 or P<0.01). In addition, ZZD significantly attenuated intestinal inflammation and oxidative stress and activated the SIRT1/FoxO1 signaling pathway (P<0.05 or P<0.01). CONCLUSION ZZD exhibited beneficial effects on the intestinal system of STC mice and alleviated intestinal inflammation and oxidative stress via activating SIRT1/FoxO1 antioxidant signaling pathway in the colon.
Mice ; Animals ; Sirtuin 1/genetics* ; Antioxidants ; Occludin ; Lipopolysaccharides ; Claudin-1 ; Mannose ; Mice, Inbred C57BL ; Constipation/drug therapy* ; Inflammation ; Signal Transduction

Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

Humans ; Mutation ; NAV1.5 Voltage-Gated Sodium Channel/genetics*

Objective: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. Methods: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. Results: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). Conclusion An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.
Aged ; Asian Continental Ancestry Group ; Blood Glucose/analysis* ; China/epidemiology* ; Cohort Studies ; Diabetes Mellitus/blood* ; Female ; Glucose Tolerance Test ; Glycated Hemoglobin A/analysis* ; Glycemic Index ; Humans ; Male ; Middle Aged ; Uric Acid/blood*

Objective:To explore the clinical efficacy of modified Zhizhutang in treating senile primary constipation due to Qi-Yin deficiency and its influences on gastrointestinal neurotransmitters and gastrointestinal motility. Method:One hundred and twenty-one eligible patients were randomly divided into a control group （n=60） and an observation group （n=61）. On the basis of lifestyle adjustments， patients in the control group further received oral Qihuang Tongmi soft capsule，three capsules per time，three times per day， whereas those in the observation group were further treated with modified Zhizhutang，one bag per day， for eight successive weeks. The number of complete spontaneous bowel movements （CSBM， normal defecation was considered if CSBM ≥ three times per week） before and after treatment was recorded. The main symptoms of constipation，the patient assessment of constipation quality of life （PAC-QOL）， and the traditional Chinese medicine （TCM） syndrome before and after treatment were scored， followed by the anorectal pressure measurement and colonic transit test before and after treatment. The levels of somatostatin （SS），motilin （MTL），substance P （SP） and vasoactive intestinal peptide （VIP） before and after treatment were detected. Result:The weekly average number of CSBM in the observation group was greater than that of the control group （P<0.01）， but the TCM syndrome score was lower than that of the control group （P<0.01）. The normal defecation rate in the observation group was 57.38% （35/61），which was higher than 35% （21/60） of the control group （χ²=6.092，P<0.05）. The scores of the main symptoms of constipation in the observation group were significantly lower than those in the control group （P<0.01）. The PAC-QOL subscale scores and the total score of the observation group significantly declined as compared with those of the control group （P<0.01）. The anal resting pressure and anal maximum systolic pressure of the observation group were higher than those of the control group （P<0.01），while the first sensation volume， urge sensation volume and maximum tolerable volume were lower （P<0.01）. The excretion rates of markers in the observation group at 24 h，48 h and 72 h were significantly elevated in comparison with those in the control group （P<0.01）. Compared with the control group， the observation group also exhibited increased serum MTL and SP （P<0.01） and decreased SS and VIP （P<0.01）. The recurrence rate in the observation group was 34.29% （12/35），obviously lower than 61.90% （13/21） in the control group （χ²=5.051，P<0.05）. The total effective rates in the observation group and the control group were 95.08% （58/61） and 81.67% （49/60） ， implying a significant difference （χ²=5.321，P<0.01）. Conclusion:For the elderly with primary constipation due to Qi-Yin deficiency， oral administration of modified Zhizhutang helps to regulate gastrointestinal neurotransmitters，improve gastrointestinal motility and gastrointestinal emptying rate， alleviate the symptoms of constipation， restore spontaneous bowel movements， improve their quality of life， and lower the recurrence rate. Its clinical effects were better than those of Qihuang Tongmi soft capsule.

Objective::To observe effect of addition and subtraction therapy of Huaihuasan combined with Taohuatang to ulcerative colitis with cold-heat complicated syndrome at active stage, and to study regulation effect to immune function and inflammatory response. Method::One hundred and twelve patients were randomly divided into control group and observation group by random number table. Patients with light and middle symptoms in control group got mesalazine slow release tablets, 1.0 g/time, 3 times/days, patients with severe symptoms or whose symptoms were not changed after getting for 4 weeks in control group got prednisone acetate tablets, 0.75 mg·kg^-1·d^-1 for 3 times. Based on the treatment in control group, patients in observation group added Huaihuasan combined with Taohuatang, 1 dose/day. The course of treatment was 4 weeks. At remission period, mesalazine slow release tablets were used for maintain long-term maintenance therapy, 0.5 g/times, 3 times/days. Scores of disease activities were graded by improvement mayo, and clinical remission and clinical efficacy were recorded, scores of cold-heat complicated syndrome, mucous membrane under enteroscopy and histology of mucosa belongs to Geboes were graded. And levels of tumor necrosis factor-α(TNF-α) in peripheral blood, interleukin-8 (IL-8), IL-10, T lymphocyte subsets (CD4⁺, CD8⁺), and adverse reactions, 6 months' follow-up and recurrence were also be recorded. Result::Therapeutic effect of traditional Chinese medicine syndromes were analyzed by rank sum test, which in observation group was better than that in control group (Z=1.915, P<0.05). Clinical effect in observation group was 98.04%(50/51) higher than 84.00%(42/50) in control group, clinical remission rate was 94.12%(48/51) higher than 78.00%(39/50) in control group, and mucosal healing rate was 96.08%(49/51) higher than 82.00%(41/50) in control group (P<0.05). Scores of mayo, cold-heat complicated syndrome, colonic mucosa and index scores of Geboes were all lower than those in control group (P<0.01). And levels of TNF-α, IL-8 and CD8⁺ were lower than those in control group (P<0.01), and levels of IL-10, CD4⁺ and CD4⁺ /CD8⁺ were higher than those in control group (P<0.01). Recurrence rate during 6 months in observation group was 10.42%(5/48) lower than 30.77%(12/39) in control group (χ²=5.669, P<0.05), as for adverse reactions, there was no significant difference between two groups. Conclusion::Huaihuasan combined with Taohuatang can induce UC to remission period, inhibit the activity of disease, alleviate clinical symptoms, regulate immune function and expression of inflammatory factors, alleviate inflammatory reaction, promote intestinal mucosal healing, and can maintain clinical remission and reduce recurrence. The clinical efficacy is superior to that of 5-ASA/glucocorticoid in Western medicine.