Complete remission of gallbladder neuroendocrine carcinoma with liver metastasis by tislelizumab plus chemotherapy: a case report.

Background: Gallbladder neuroendocrine carcinoma (GB-NEC) is an extremely rare cancer with a poor prognosis in the clinic. Although surgical resection remains the primary and preferred therapeutics, many patients are in a late stage and lose the opportunity for surgery. However, due to the extremely low morbidity, the specific treatment guidelines for GB-NEC have not been established. Case presentation: A 52-year-old woman was admitted to our hospital with the chief complaint of "almost 1 month after palliative surgery for metastatic gallbladder carcinoma." According to the results of pathological findings and imaging manifestations, the patient was diagnosed with GB-NEC with a clinical stage of pT3N1M1 (IVB). The patient then received tislelizumab plus EP chemotherapy (etoposide 100 mg + cisplatin 30 mg, d1-3) every 3 weeks for 8 cycles from 12 November, 2021, followed by maintenance therapy (tislelizumab alone) every 3 weeks until now. The tumor response was evaluated as complete remission since 13 February, 2023. As of the last follow-up, the patient remains alive, with no complaints of discomfort. Conclusions: Gallbladder NEC has no specific symptoms, and the diagnosis is based on pathological and immunohistochemical results. The therapeutic course and efficacy of the case in this study indicates that the application of PD-1 inhibitor might be a feasible therapeutic option for GB-NEC. However, this potential strategy needs validation by further clinical studies in the future.

Efficacy of a WeChat-Based Multimodal Digital Transformation Management Model in New-Onset Mild to Moderate Hypertension: Randomized Clinical Trial.

BACKGROUND: The advantages of multimodal digitally transformed mobile health management for patients diagnosed with mild to moderate hypertension are not yet established. OBJECTIVE: We aim to evaluate the therapeutic benefits of a novel WeChat-based multimodal digital transforming management model in mobile health blood pressure (BP) management. METHODS: This randomized controlled clinical trial included 175 individuals with new-onset mild to moderate hypertension who were admitted to our center between September and October 2022. The patients were randomly assigned to either the multimodal intervention group (n=88) or the usual care group (n=87). The primary composite outcome was home and office BP differences after 6 months. The major secondary outcomes were 6-month quality-of-life scores, including the self-rating anxiety scale, self-rating depression scale, and Pittsburgh Sleep Quality Index. RESULTS: The mean home BP decreased from 151.74 (SD 8.02)/94.22 (SD 9.32) to 126.19 (SD 8.45)/82.28 (SD 9.26) mm Hg in the multimodal intervention group and from 150.78 (SD 7.87)/91.53 (SD 9.78) to 133.48 (SD 10.86)/84.45 (SD 9.19) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -8.25 mm Hg (95% CI -11.71 to -4.78 mm Hg; P<.001) and -4.85 mm Hg (95% CI -8.41 to -1.30 mm Hg; P=.008), respectively. The mean office BP decreased from 153.64 (SD 8.39)/93.56 (SD 8.45) to 127.81 (SD 8.04)/ 82.16 (SD 8.06) mm Hg in the multimodal intervention group and from 151.48 (SD 7.14)/(91.31 (SD 9.61) to 134.92 (SD 10.11)/85.09 (SD 8.26) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -9.27 mm Hg (95% CI -12.62 to -5.91 mm Hg; P<.001) and -5.18 mm Hg (95% CI -8.47 to -1.89 mm Hg; P=.002), respectively. From baseline to 6 months, home BP control <140/90 mm Hg was achieved in 64 (72.7%) patients in the multimodal intervention group and 46 (52.9%) patients in the usual care group (P=.007). Meanwhile, home BP control <130/80 mm Hg was achieved in 32 (36.4%) patients in the multimodal intervention group and 16 (18.4%) patients in the usual care group (P=.008). After 6 months, there were significant differences in the quality-of-life total and graded scores, including self-rating anxiety scale scores (P=.04), self-rating depression scale scores (P=.03), and Pittsburgh Sleep Quality Index scores (P<.001), in the multimodal intervention group compared with the usual care group. CONCLUSIONS: The WeChat-based multimodal intervention model improved the BP control rates and lowered the BP levels more than the usual care approach. The multimodal digital transforming management model for hypertension represents an emerging medical practice that utilizes the individual's various risk factor profiles for primary care and personalized therapy decision-making in patients with hypertension. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200063550; https://www.chictr.org.cn/showproj.html?proj=175816.

Targeted delivery of Dbait by an artificial extracellular vesicle for improved radiotherapy sensitivity of esophageal cancer.

Intensification of radiotherapy has been shown to be an effective way for improving the therapeutic efficacy of radiation sensitive malignancies such as esophageal cancer (EC). The application of DNA Bait (Dbait), a type of DNA repair inhibitor, is an emerging strategy for radiosensitization. In this study, a Eca-109 cancerous cytomembrane-cloaked biomimetic drug delivery system (DDS), CMEC-Dbait, was designed and successfully fabricated, for targeted delivery of Dbait. Our systematic evaluation demonstrated that the ingenious artificial gastrointestinal extracellular vesicle owns neat spherical structure, proper particle size (154.6±5.5 nm) and surface charge (2.6±0.3 mV), favourable biocompatibility and immunocompatibility, being conducive to in vivo drug delivery. Besides, Eca-109 cytomembrane coating endowed CMEC-Dbait with effective targeting ability to homologous EC cells. Owing to these advantages, the biomimetic DDS was proved to be a potent radiosensitizer in vitro, indicated by remarkably reduced cell viability and enhanced cellular apoptosis by the combination therapy of radiation and CMEC-Dbait. The result was validated in vivo using mouse xenograft models of EC, the results illustrated that radiotherapy plus CMEC-Dbait significantly suppressed tumor growth and prolonged survival of tumor bearing mice. Western blotting results showed that CMEC-Dbait can significantly inhibit DNA damage repair signaling pathways by simulating DNA double-strand breaks both in and ex vivo. In conclusion, the versatile biomimetic CMEC-Dbait was characterized of low toxicity, excellent biocompatibility and satisfactory drug delivery efficiency, which is confirmed to be an ideal radiosensitizer for homologous cancer and merits further investigation in both pre-clinical and clinical studies.

Targeted delivery of a PROTAC induced PDEδ degrader by a biomimetic drug delivery system for enhanced cytotoxicity against pancreatic cancer cells.

Pancreatic carcinoma (PC) has one of the highest mortality-to-incidence ratios of any solid tumor worldwide. Although KRAS mutation is commonly found in 95% of PCs, directly targeting KRAS remains to be a highly challenging task because of its lacking catalytic pockets where molecule inhibitors can bind with. Proteolysis-targeting chimeric (PROTAC) represents an effective approach for specific degradation of disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system (UPS). Previously, we designed a first-in-class PROTAC induced PDEδ degrader (PIPD), which demonstrated improved anti-tumor efficacy against KRAS mutant malignancies. However, translating cellular degradative effects from bench to beside remains a highly challenging task because of PROTAC's poor penetration efficiency across target cytomembranes and non-targeting delivery induced undesired "off target" side-effects. Herein, a smart nano-drug delivery system (CM8988-PIPD) was successfully constructed by biomimetic strategy for targeted delivery of PIPD. The biomimetic nanoparticle showed well-defined regular spherical structure with an average particle size of approximately 124.8 nm. Cancer cytomembrane camouflage endows CM8988-PIPD with excellent in vivo serum stability, controlled drug release profile, favorable biocompatibility & immunocompatibility, and prominent targeting ability to homologous PC cells. Owing to these advantages, the smart DDS significantly enhanced PDEδ degrading efficacy, resulting in induced cellular apoptosis (more than 50% for both PC cells) and suppressed cell proliferation via the inhibition of RAS signaling. In vitro studies illustrated that CM8988-PIPD hold great potential for the treatment of PC, which merits further investigation in both pre-clinical and clinical investigations in the future.

Association between metabolic syndrome and endometrial cancer risk: a systematic review and meta-analysis of observational studies.

Existing evidence has revealed inconsistent results on the association between metabolic syndrome (MetS) and endometrial cancer (EC) risk. Herein, we aim to better understand this association. Systematic searches of PubMed, EMBASE, and Web of Science through 12 December 2019 were conducted. Observational studies that provided risk estimates of MetS and EC risk were eligible. The quality of the included studies was judged based on the Newcastle-Ottawa scale. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Six studies, comprising 17,772 EC cases and 150,371 participants were included. MetS, diagnosed according to the criteria of the National Cholesterol Education Program-Third Adult Treatment Panel, was associated with an increased risk of EC (OR: 1.62; 95% CI = 1.26-2.07) with substantial heterogeneity (I2 = 78.3%). Furthermore, we found that women with MetS, diagnosed according to the criteria of the International Diabetes Federation, had a significantly higher risk of EC compared to healthy controls (OR: 1.45; 95% CI = 1.16-1.81; I2 = 64.6%). Our findings were generally consistent with the main results in the majority of prespecified subgroups, as well as in sensitivity analyses. In conclusion, MetS is associated with EC risk.

The sensibility of the new blood lipid indicator--atherogenic index of plasma (AIP) in menopausal women with coronary artery disease.

BACKGROUND: Dyslipidemia is a key driver of coronary artery disease (CAD) development. This study aimed to determine whether the atherogenic index of plasma (AIP), a novel comprehensive lipid index, is an independent and reliable predictor of CAD risk in postmenopausal women. METHODS: A cohort of consecutive 4644 postmenopausal women (aged 50 or above) undergoing coronary angiography (CAG) in Anzhen Hospital (Beijing, China) from January-December 2014 was included in the analysis. Of them, 3039 women were CAD patients, and 1605 were non-CAD subjects. RESULTS: Relative to control subjects, TG levels in CAD patients were higher and HDL-C levels were lower. In CAD patients, non-traditional lipid profile values (TC/HDL-C, AI, and AIP) were significantly elevated relative to controls. AIP was positively correlated with TC (r = 0.157), TG (r = 0.835), LDL-C (r = 0.058), non-HDL-C (r = 0.337), TC/HDL-C (r = 0.683), LDL-C/HDL-C (r = 0.437), LCI (r = 0.662), and AI (r = 0.684), and negatively correlated with HDL-C (r = - 0.682) (all P < 0.001), but was independent of age (r = - 0.022; P = 0.130) and BMI (r = 0.020, P = 0.168). Aunivariate logistic regression analysis revealed AIP to be the measured lipid parameter most closely related to CAD, and its unadjusted odds ratio was 1.824 (95% CI: 1.467-2.267, P < 0.001). After adjusting for several CAD risk factors (age, BMI, smoking, drinking, EH, DM, hyperlipidemia, and family history of CVD, AIP was still found to represent a significant CAD risk factor (OR 1.553, 95% CI: 1.234-1.955, P < 0. 001). CONCLUSION: AIP may be a powerful independent predictor of CAD risk in Chinese Han postmenopausal women, and may be superior to the traditional lipid indices.

Characterization of native-like HIV-1 gp140 glycoprotein expressed in insect cells.

The trimeric HIV-1 envelope glycoprotein (Env) is critical for vaccine development aimed at achieving broadly-neutralizing antibody responses. The use of various recombinant expression systems and construct designs are associated with the resultant nature of produced proteins, especially in terms of glycosylation, antigenicity, and immunogenicity of the glycoprotein. Here, we explored an otherwise baculovirus cassette than classical one designed to express HIV-1 Env protein, including SOSIP mutation and Foldon moiety involvement. This improved design increased the ratio of the Env trimer fraction from ∼40% to ∼60% with respect to that of prototypical design, as indicated by high-performance size-exclusion chromatography and sedimentation velocity analysis. In addition, the design prolonged cell viability and enhanced the final yield (approximately 13-15 mg/L) after affinity purification. gp140 produced from insect cells mimicked the native-like trimer and mainly adopted glycosylation pattern of oligomannose glycans. The native-like Env proteins conferred cross-clade neutralizing antibody production in BALB/c mice. In summary, the expression of Env in insect cells by optimizing the baculovirus vector provides an alternative strategy for HIV-1 immunogen production and may benefit future Env-based HIV vaccine design.

[Expression and self-assembly of HIV-1 CAP2NC protein].

We constructed the CAP2NC prokaryotic expression vector of HIV-1 NL4-3 strain and obtained relatively pure CAP2NC protein by optimizing its purification conditions to explore its in vitro self-assembly conditions. Primers were designed according to the CAP2NC DNA sequence of HIV-1 NL4-3 strain. The target gene was amplified by PCR and cloned into prokaryotic expression vector pTO-T7. Then the recombinant strain was transformed into Escherichia coli BL21 (DE3). IPTG induced protein expression, then the protein was purified by hydrophobic chromatography. SDS-PAGE and Western blotting were performed to analyze the target protein, and the biological activity of the antigen was identified through ELISA. The self-assembly of CAP2NC protein was analyzed by transmission electron microscopy and gel filtration chromatography. The protein had good reaction with the specific antibodies of p24 and formed different structures in various conditions. When 10% yeast RNA was added to the protein complex, the recombinant protein only formed into a tubular structure, which was similar to the self-assembled structure of the HIV-1 virus capsid. The results showed that the HIV-1 CAP2NC protein had in vitro self-assembly activity, and the RNA affected the structure of CAP2NC protein assembly. The protein can be used as a simple and effective molecular model to study its structure, and then it can provide a reference for the study of HIV immature virus particles.

Characterization and epitope mapping of a panel of monoclonal antibodies against HIV-1 matrix protein.

The HIV-1 Gag precursor protein (p55) is the main structural protein comprising the matrix (MA/p17), capsid (CA/p24), and nucleocapsid (NC/p7) proteins, and is uniquely responsible for virion assembly within the virus life cycle. The MA protein plays a critical role in plasma membrane targeting and envelope glycoprotein (Env) uptake during virion assembly. Yet, when viral infection occurs, the MA protein may also be involved in virion uncoating, dissociating from the plasma membrane, and participating in the nuclear importation process. Thus, the MA protein contains a reversibly membrane-binding signal and varied conformation to govern its subcellular localization and biological functions. However, these purported different conformations of the MA protein during assembly are poorly understood, especially in terms of its function as a component of the precursor protein. In this study, we characterized a panel of monoclonal antibodies against MA that showed discrete reactivity to p55, an intermediate (p41), and the final p17 mature form. We suggest that these antibodies could be used to track the different conformations of MA during the HIV-1 life cycle, particularly during HIV-1 assembly and maturation, and contribute to structure determination of MA or MA precursors. These antibodies would also have clinical value, including serving for therapeutic strategy to interfere AIDS progression, reagent in diagnostic kit for the detection of virion-free p17 or p17 derived from virion lysate.

Expression, Purification and Characterization of Hiv-1 Capsid Precursor Protein p41.

Human immunodeficiency virus type 1 (HIV-1) has been a global epidemic since 1983; yet, the virology and immunology related to HIV-1 remain elusive. Furthermore, as there is still no effective chemoprophylaxis or vaccine to treat patients with HIV-1, most research focuses on strategies to prevent HIV-1 infection, such as with antiviral drugs, novel therapeutics, or improved diagnostic kits. The HIV-1 Gag precursor protein (p55)-comprising the matrix (MA/p17), capsid (CA/p24), and nucleocapsid (NC/p7) protein domains-is the main structural HIV-1 protein, and is uniquely responsible for virion assembly within the virus life cycle. Recently, the immature and mature capsid structures were solved; however, the precursor protein structure is still unknown. Here, we expressed two subtypes of HIV-1 MA-CA stretch of the Gag protein, referred to as p41, in a bacterial expression system. We characterized the purified p41 protein, and showed its superior antigenicity over that of p24, highlighting the potential influence of the p17 domain on p24 structure. We further showed that p41 has good immunogenicity to induce an antibody response in mice. These results will aid future investigations into the HIV-1 capsid precursor structure, and potentially contribute to improving the design of diagnostic kits.

Association between antidepressant medication use and epithelial ovarian cancer risk: a systematic review and meta-analysis of observational studies.

AIM: The aim of this paper is to clarify the inconsistent findings in the association between antidepressant use and the risk of epithelial ovarian cancer (EOC). METHODS: This study is a meta-analysis of observational studies retrieved from the PubMed, EMBASE, and Web of Science databases prior to August 15, 2017. Two researchers independently screened studies and extracted study characteristics and risk estimates. The odds ratios (OR) and 95% confidence intervals (CI) of EOC risk were summarized using an inverse variance weighted random-effects model. Heterogeneity between studies was assessed with the I2 statistic. RESULTS: Eight case-control studies involving 7878 EOC cases and 73 913 controls were identified. Compared with non-use, use of antidepressants was not significantly associated with EOC risk (summarized OR = 1.10, 95% CI: 0.91-1.32, I2  = 74.4%). Similar null results were also observed in the use of selective serotonin reuptake inhibitors (OR = 1.04, 95% CI = 0.80-1.35), tricyclic antidepressants (OR = 1.01, 95% CI = 0.79-1.30), and other antidepressant drugs (OR = 0.91, 95% CI = 0.74-1.12). Subgroup analyses of study characteristics, stratified by the type of control subjects, geographic location, exposure assessment, number of cases, and adjustment for potential confounders, showed that the ORs were broadly consistent across strata. The OR per 1 year-increment of duration was 0.99 (95% CI = 0.94-1.05, I2  = 40.0%, P = 0.154). Additionally, the OR for the greatest intensity of antidepressant use compared with never use was 0.82 (95% CI = 0.70-0.98, I2  = 0%, P = 0.489). Furthermore, no evidence of publication bias was detected through Funnel plots as well as Egger's and Begg's tests. CONCLUSIONS: There is no association between antidepressant use and EOC risk. Further prospective studies are warranted to confirm these findings.