Evolution of catalyst design for controlled synthesis of chiral single-walled carbon nanotubes.

Single-walled carbon nanotubes (SWCNTs) possess superb properties originating from their unique chiral structures. However, accurately controlling the structure of SWCNTs remains challenging due to the structural similarities of their chiral structures, which hinders their widespread application in various fields, particularly in electronics. In recent years, much effort has been devoted to preparing single chiral SWCNTs by adopting three constructive strategies, including growth condition control for structurally unstable liquid catalysts, employing stable solid catalyst design, and pre-synthesis of carbon seeds with a well-defined shape. This review comprehensively discusses the state-of-the-art developments in these approaches as well as their advantages and disadvantages. Moreover, insights into the key challenges and future directions are provided for acquiring chirally pure SWCNTs.

Antibiotic prophylaxis with piperacillin-tazobactam reduces organ/space surgical site infection after pancreaticoduodenectomy: a retrospective and propensity score-matched analysis.

BACKGROUND: The occurrence of surgical site infection (SSI) after pancreaticoduodenectomy (PD) is still relatively high. The aim of this retrospective study is to evaluate the efficacy of piperacillin-tazobactam as perioperative prophylactic antibiotic on organ/space SSI for patients underwent PD. METHODS: Four hundred seven consecutive patients who underwent PD between January 2018 and December 2022 were enrolled and analyzed retrospectively. The univariate and multivariate analysis were used to identify independent risk factors of organ/space SSI. Postoperative complications were compared between the two groups according to the use of prophylactic antibiotics by a ratio of 1:1 propensity score-matched (PSM) analysis. RESULTS: Based on perioperative prophylactic antibiotic use, all 407 patients were divided into the ceftriaxone group (n = 192, 47.2%) and piperacillin-tazobactam group (n = 215, 52.8%). The rate of organ/space SSI was 31.2% with the choice of perioperative antibiotics (OR = 2.837, 95%CI = 1.802-4.465, P < 0.01) as one of independent risk factors. After PSM, there were similar baseline characteristics among the groups. Meanwhile, the piperacillin-tazobactam group had a significant lower rate of organ/space SSI compared to the ceftriaxone group both before and after PSM(P < 0.05). CONCLUSIONS: The adoption of piperacillin-tazobactam as perioperative prophylaxis for patients underwent PD reduced organ/space SSI significantly.

Loss of Claudin-1 incurred by DNMT aberration promotes pancreatic cancer progression.

Pancreatic cancer (PC) is one of the most malignant and deadly tumors of digestive system with complex etiology and pathogenesis. Dysregulations of oncogenes and tumor suppressors due to epigenetic modifications causally affect tumorogenesis; however the key tumor suppressors and their regulations in PC are only partially defined. In this study, we found that Claudin-1 (encoded by CLDN1 gene) was significantly suppressed in PC that correlated with a poor clinical prognosis. Claudin-1 knockdown enhanced PC cell proliferation, migration, and stemness. Pancreatic specific Cldn1 knockout in KPC (LSLKrasG12D/Pdx1-Cre/Trp53R172H+) and KC (LSLKrasG12D/Pdx1-Cre) mice reduced mouse survival, promoted acinar-to-ductal metaplasia (ADM) process, and accelerated the development of pancreatic intraepithelial neoplasia (PanIN) and PC. Further investigation revealed that Claudin-1 suppression was mainly caused by aberrant DNA methylatransferase 1 (DNMT1) and DNMT3A elevations and the resultant CLDN1 promoter hypermethylation, as a DNMT specific inhibitor SGI-1027 effectively reversed the Claudin-1 suppression and inhibited PC progression both in vitro and in vivo in a Claudin-1 preservation-dependent manner. Together, our data suggest that Claudin-1 functions as a tumor suppressor in PC and its epigenetic suppression due to DNMT aberrations is a crucial event that promotes PC development and progression.

High endothelial venule is a prognostic immune-related biomarker in patients with resected intrahepatic cholangiocarcinoma.

Having been reported to be a crucial prognostic factor in solid tumours, the role of high endothelial venule (HEV) in intrahepatic cholangiocarcinoma (ICC) remains unclear, however. The data of ICC and healthy individuals were downloaded from the Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases. Meanwhile, a cutting-edge ICC high-resolution spatial transcriptome was also acquired before these data were comprehensively analysed using bioinformatics approaches. Moreover, 95 individuals with ICC who had undergone resection surgery were enrolled in this study to investigate the relationship between HEV and tumour microenvironment (TME) applying immunohistochemistry and multiple immunofluorescence techniques. The high-HEV subtype contains rich immune infiltrates including tertiary lymphoid structure (TLS), CD8+ T cells, and CD20+ B cells. Furthermore, HEV and TLS exhibited a strong relationship of spatial colocalization. Correlated with improved prognostic outcomes in ICC, the high-HEV subtype could be an independent prognostic indicator for individuals with ICC. This study revealed the association of HEV with immune function and observed a strong spatial colocalization correlation between HEV and TLS. Moreover, correlated with immunotherapeutic response, HEV could improve prognostic outcomes, which may be a potential indicator of immunotherapy pathology in ICC.

The role of preoperative biliary drainage on postoperative outcome after pancreaticoduodenectomy in patients with obstructive jaundice.

Background: The role of preoperative biliary drainage (PBD) on obstructive jaundice patients is still controversial. The aim of this retrospective study is to clarify the effect of PBD on postoperative outcomes of pancreaticoduodenectomy (PD) and explore a reasonable PBD strategy for periampullary carcinomas (PAC) patients with obstructive jaundice before surgery. Methods: A total of 148 patients with obstructive jaundice who underwent PD were enrolled in this research and divided into drainage group and no-drainage group according to whether they received PBD. Patients who received PBD were classified into long-term group (>2 weeks) and short-term group (≤2 weeks) according to PBD duration. The clinical data of patients were statistically compared between groups to explore the influence of PBD and its duration. Analysis of pathogens in bile and peritoneal fluid was performed to probe the role of bile pathogens in opportunistic pathogenic bacterial infection after PD. Results: Of all, 98 patients underwent PBD. The mean duration between drainage and surgery was 13 days. Regarding postoperative outcomes, the incidence of postoperative intra-abdominal infection was significantly higher in the drainage group than the no-drainage group (P=0.026). In patients with total bilirubin (TB) less than 250 µmol/L, postoperative intra-abdominal infection was more frequently observed in the drainage group compared to the no-drainage group (P=0.022). Compared to the short-term drainage group, the proportion of positive ascites culture was significantly higher in the long-term drainage group (P=0.022). There were no statistically significant differences in postoperative complications between short-term group and no-drainage group. The most frequent pathogens detected in bile were Klebsiella pneumoniae, hemolytic Streptococcus and Enterococcus faecalis. The most commonly detected pathogens in peritoneal fluid were Klebsiella pneumoniae, Enterococcus faecalis and Staphylococcus epidermidis which appeared to have a high agreement with pathogens in preoperative bile cultures. Conclusions: Routine PBD should not be performed in obstructive jaundice PAC patients with TB less than 250 µmol/L. For patients with indications for PBD, the drainage duration should be controlled within 2 weeks. Bile bacteria may represent a major source of opportunistic pathogenic bacteria infection after PD.

Bifidobacterium and Lactobacillus improve inflammatory bowel disease in zebrafish of different ages by regulating the intestinal mucosal barrier and microbiota.

AIMS: Inflammatory bowel disease (IBD) patients are accompanied by impaired intestinal barrier integrity and gut microbiota dysbiosis. Strategies targeting the gut microbiota are potential therapies for preventing and ameliorating IBD. MAIN METHODS: The potential roles of two probiotic stains, Bifidobacterium longum BL986 (BL986) and Lactobacillus casei LC122 (LC122), on intestinal mucosal barrier function and microbiota in IBD zebrafish of different ages were investigated. KEY FINDINGS: BL986 and LC122 treatment promoted the development and increased the microbiota diversity in larval zebrafish. Both probiotic treatment ameliorated mortality, promoted intestinal mucus secretion, and reduced the expression of inflammatory markers, thereby improving intestinal mucosal barrier function in dextran sulfate sodium salt (DSS)-induced ulcerative colitis (UC) and 2,4,6-trinitro-benzenesulfonicacid (TNBS)-induced Crohn's disease (CD) models in zebrafish. Moreover, the composition and function of microbiota were altered in IBD zebrafish, and probiotics treatment displayed prominent microbiota features. BL986 was more potent in the DSS-induced UC model, and increased the abundance of Faecalibaculum and butyric acid levels. LC122 exerted better protection against TNBS-induced CD, and increased the abundance of Enhydrobacter and acetic acid levels. Furthermore, the effect of probiotics was stronger in larval and aged zebrafish. CONCLUSION: The impact of probiotics on IBD might differ from the subtypes of IBD and the age of the zebrafish, suggesting the types of disease and age should be taken into full consideration during the practical usage of probiotics.

Therapeutic effect and safety of individualized chemotherapy combined with sequential immunotherapy based on BRCA1 mRNA expression level in unresectable pancreatic cancer.

Aim: We aimed to evaluate the efficacy and safety of individualized chemotherapy combined with sequential immunotherapy based on BRCA1 mRNA expression in unresectable pancreatic cancer. Methods: The expression of BRCA1 mRNA in tumor tissues of 25 patients with pancreatic cancer was detected in this retrospective study. Patients in the medium and high expression groups were treated with paclitaxel-based chemotherapy: albumin paclitaxel 125mg/m2, gemcitabine 1g/m2, day 1. Patients in the low expression group were treated with oxaliplatin-based chemotherapy: oxaliplatin 85mg/m2, gemcitabine 1g/m2, day 1. Sequential GM-CSF and IL-2 immunotherapy were applied. Patient condition, treatment efficacy and safety were assessed every 4 cycles. Results: A total of 25 patients were enrolled in the study. All of them were observed for toxic side effects and 24 of them were evaluated for efficacy. The median overall survival and median progression-free survival were 11.9 months and 6.3 months. The disease control rate was 91.7%, of which 37.5% (9/24) patients achieved partial remission (PR), 54.2% (13/24) patients achieved stable disease (SD) and 8.3% (2/24) patients were assessed as progressive disease(PD). Of the 15 patients with medium or high expression in BRCA1 mRNA, 7 achieved PR and 8 achieved SD. Of the 9 patients with low BRCA1 mRNA expression, 2 achieved PR, 5 achieved SD and 2 had PD. The proportion of eosinophils in the blood of some patients with good therapeutic effects was significantly higher than that before treatment. Hematological and non-hematological toxicity during the treatment were mostly grade 1~2. The two most common grade 3 to 4 adverse events were fever and thrombocytopenia. Conclusion: Our results suggest that individualized selection of chemotherapy combined with sequential immunotherapy according to BRCA1 mRNA expression level in unresectable pancreatic cancer could control the disease and have controllable adverse reactions.

Study protocol for a prospective, open-label, single-arm, phase II study on the combination of tislelizumab, nab-paclitaxel, gemcitabine, and concurrent radiotherapy as the induction therapy for patients with locally advanced and borderline resectable pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with a low resection rate. Chemotherapy and radiotherapy (RT) are the main treatment approaches for patients with advanced pancreatic cancer, and neoadjuvant chemoradiotherapy is considered a promising strategy to increase the resection rate. Recently, immune checkpoint inhibitor (ICI) therapy has shown remarkable efficacy in several cancers. Therefore, the combination of ICI, chemotherapy, and concurrent radiotherapy is promising for patients with potentially resectable pancreatic cancer, mainly referring to locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC), to increase the chances of conversion to surgical resectability and prolong survival. This study aims to introduce the design of a clinical trial. Methods: This is an open-label, single-arm, and single-center phase II trial. Patients with pathologically and radiographically confirmed LAPC or BRPC without prior anti-cancer treatment or severe morbidities will be enrolled. All patients will receive induction therapy and will be further evaluated by the Multiple Disciplinary Team (MDT) for the possibility of surgery. The induction therapy consists of up to four cycles of gemcitabine 1,000 mg/m2 and nab-paclitaxel 125 mg/m2 via intravenous (IV) infusion on days 1 and 8, along with tislelizumab (a PD-1 monoclonal antibody) 200 mg administered through IV infusion on day 1 every 3 weeks, concurrently with stereotactic body radiation therapy (SBRT) during the third cycle of treatment. After surgery, patients without progression will receive another two to four cycles of adjuvant therapy with gemcitabine, nab-paclitaxel, and tislelizumab. The primary objectives are objective response rate (ORR) and the R0 resection rate. The secondary objectives are median overall survival (mOS), median progression free survival (mPFS), disease control rate (DCR), pathological grade of tumor tissue after therapy, and adverse reactions. Besides, we expect to explore the value of circulating tumor DNA (ctDNA) in predicting tumor response to induction therapy and survival outcome of patients. Discussion: This is a protocol for a clinical trial that attempts to evaluate the safety and efficacy of the combination of anti-PD-1 antibody plus chemotherapy and radiotherapy as the induction therapy for LAPC and BRPC. The results of this phase II study will provide evidence for the clinical practice of this modality. Clinical Trial Registration: http://www.chictr.org.cn/edit.aspx?pid=53720&htm=4, identifier ChiCTR2000032955.

Development and validation of a nomogram for predicting post-operative abdominal infection in patients undergoing pancreaticoduodenectomy.

AIM: The aim of this retrospective study is to develop and validate a predictive nomogram for predicting the risk of post-operative abdominal infection (PAI) in patients undergoing pancreaticoduodenectomy (PD). METHODS: A total of 360 patients who underwent PD were enrolled into this research and randomly divided into the development and validation group. The clinical data of patients were statistically compared and the nomogram was constructed based on the results of multivariate logistic regression analysis and stepwise (stepAIC) selection. The nomogram was internally and crossly validated by the development and validation cohort. The discriminatory ability of the nomogram was estimated by AUC (Area Under the receiver operating characteristic Curve), calibration curve and decision curve analysis. RESULTS: After PD, post-operative abdominal infection occurred in 33.89% (n = 122) of patients. The nomogram showed that preoperative biliary drainage and C-reactive protein (CRP), direct bilirubin (DB), alkaline phosphatase (AKP) levels on the 3rd postoperative day (POD3) were independent prognostic factors for abdominal infection after PD. The internal and cross validation of Receiver Operating Characteristic (ROC) curve was statistically significant (AUC = 0.723 and 0.786, respectively). The calibration curves showed good agreement between nomogram predictions and actual observations. The decision curves showed that the nomogram was of great clinical value. CONCLUSION: A nomogram based on perioperative risk factors such as preoperative biliary drainage, CRP, DB and AKP could simply and accurately predict the risk degree of PAI in patients undergoing PD.

Case Report: Pathologic Complete Response to Induction Therapy in a Patient With Potentially Resectable Pancreatic Cancer.

Immune monotherapy does not appear to work in patients with pancreatic cancer so far. We are conducting a clinical trial that combines programmed cell death protein-1 (PD-1) inhibitor with chemotherapy and concurrent radiotherapy as induction therapy for patients with locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC). Here, we report a case with a pathologic complete response (pCR) and no postoperative complications after the induction therapy. The patient received four cycles of induction therapy and achieved a partial response (PR) with a significant decline of tumor marker carbohydrate antigen 19-9 (CA19-9). Also, peripheral blood samples were collected during the treatment to investigate serial circulating tumor DNA (ctDNA) dynamic changes in predicting the tumor response and outcomes in patients. Our result suggested that PD-1 blockade plus chemotherapy and concurrent radiotherapy is a promising mode as induction therapy for patients with potentially resectable pancreatic cancer. In this case, serial ctDNA alterations accurately provide a comprehensive outlook of the tumor status and monitor the response to the therapy, as validated by standard imaging.

Challenges and opportunities in metastatic breast cancer treatments: Nano-drug combinations delivered preferentially to metastatic cells may enhance therapeutic response.

Despite advances in breast cancer treatments and related 5-year survival outcomes, metastatic breast cancer cures remain elusive. The current standard of care includes a combination of surgery, radiation therapy and drug therapy. However, even the most advanced procedures and treatments do not prevent breast cancer recurrence and metastasis. Once metastasis occurs, patient prognosis is poor. Recent elucidation of the spatiotemporal transit of metastatic cancer cells from primary tumor sites to distant sites provide an opportunity to integrate knowledge of drug disposition in our effort to enhance drug localization and exposure in cancer laden tissues . Novel technologies have been developed, but could be further refined to facilitate the distribution of drugs to target cancer cells and tissues. The purpose of this review is to highlight the challenges in metastatic breast cancer treatment and focus on novel drug combination and nanotechnology approaches to overcome the challenges. With improved definition of metastatic tissue target, directed localization and retention of multiple, pharmacologically active drugs to tissues and cells of interest may overcome the limitations in breast cancer treatment that may lead to a cure for breast cancer.

ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models.

Despite the availability of molecularly targeted treatments such as antibodies and small molecules for human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and programmed death-ligand 1 (PD-L1), limited treatment options are available for advanced metastatic breast cancer (MBC), which constitutes ~90% mortality. Many of these monotherapies often lead to drug resistance. Novel MBC-targeted drug-combination therapeutic approaches that may reduce resistance are urgently needed. We investigated intercellular adhesion molecule-1 (ICAM-1), which is abundant in MBC, as a potential target to co-localize two current drug combinations, gemcitabine (G) and paclitaxel (T), assembled in a novel drug-combination nanoparticle (GT DcNP) form. With an ICAM-1-binding peptide (referred to as LFA1-P) coated on GT DcNPs, we evaluated the role of the LFA1-P density in breast cancer cell localization in vitro and in vivo. We found that 1-2% LFA1-P peptide incorporated on GT DcNPs provided optimal cancer cell binding in vitro with ~4× enhancement compared to non-peptide GT DcNPs. The in vivo probing of GT DcNPs labeled with a near-infrared marker, indocyanine green, in mice by bio-imaging and G and T analyses indicated LFA1-P enhanced drug and GT DcNP localization in breast cancer cells. The target/healthy tissue (lung/gastrointestinal (GI)) ratio of particles increased by ~60× compared to the non-ligand control. Collectively, these data indicated that LFA1 on GT DcNPs may provide ICAM-1-targeted G and T drug combination delivery to advancing MBC cells found in lung tissues. As ICAM-1 is generally expressed even in breast cancers that are triple-negative phenotypes, which are unresponsive to inhibitors of nuclear receptors or HER2/estrogen receptor (ER) agents, ICAM-1-targeted LFA1-P-coated GT DcNPs should be considered for clinical development to improve therapeutic outcomes of MBCs.

Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective.

Over 50 million people have been infected with the SARS-CoV-2 virus, while around 1 million have died due to COVID-19 disease progression. COVID-19 presents flu-like symptoms that can escalate, in about 7-10 days from onset, into a cytokine storm causing respiratory failure and death. Although social distancing reduces transmissibility, COVID-19 vaccines and therapeutics are essential to regain socioeconomic normalcy. Even if effective and safe vaccines are found, pharmacological interventions are still needed to limit disease severity and mortality. Integrating current knowledge and drug candidates (approved drugs for repositioning among >35 candidates) undergoing clinical studies (>3000 registered in ClinicalTrials.gov), we employed Systems Pharmacology approaches to project how antivirals and immunoregulatory agents could be optimally evaluated for use. Antivirals are likely to be effective only at the early stage of infection, soon after exposure and before hospitalization, while immunomodulatory agents should be effective in the later-stage cytokine storm. As current antiviral candidates are administered in hospitals over 5-7 days, a long-acting combination that targets multiple SARS-CoV-2 lifecycle steps may provide a long-lasting, single-dose treatment in outpatient settings. Long-acting therapeutics may still be needed even when vaccines become available as vaccines are likely to be approved based on a 50% efficacy target.

Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules.

PURPOSE: To develop drug-combination nanoparticles (DcNPs) composed of hydrophilic gemcitabine (G) and hydrophobic paclitaxel (T) and deliver both drugs to metastatic cancer cells. METHODS: GT DcNPs were evaluated based on particle size and drug association efficiency (AE%). The effect of DcNP on GT plasma time-course and tissue distribution was characterized in mice and a pharmacokinetic model was developed. A GT distribution study into cancer nodules (derived from 4 T1 cells) was performed. RESULTS: An optimized GT DcNP composition (d = 59.2 nm ±9.2 nm) was found to be suitable for IV formulation. Plasma exposure of G and T were enhanced 61-fold and 3.8-fold when given in DcNP form compared to the conventional formulation, respectively. Mechanism based pharmacokinetic modeling and simulation show that both G and T remain highly associated to DcNPs in vivo (G: 98%, T:75%). GT DcNPs have minimal distribution to healthy organs with selective distribution and retention in tumor burdened tissue. Tumor bearing lungs had a 5-fold higher tissue-to-plasma ratio of gemcitabine in GT DcNPs compared to healthy lungs. CONCLUSIONS: DcNPs can deliver hydrophilic G and hydrophobic T together to cancer nodules and produce long acting exposure, likely due to stable GT association to DcNPs in vivo.

Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.

Early diagnosis along with new drugs targeted to cancer receptors and immunocheckpoints have improved breast cancer survival. However, full remission remains elusive for metastatic breast cancer due to dose-limiting toxicities of heavily used, highly potent drug combinations such as gemcitabine and paclitaxel. Therefore, novel strategies that lower the effective dose and improve safety margins could enhance the effect of these drug combinations. To this end, we developed and evaluated a novel drug combination of gemcitabine and paclitaxel (GT). Leveraging a simple and scalable drug-combination nanoparticle platform (DcNP), we successfully prepared an injectable GT combination in DcNP (GT DcNP). Compared to a Cremophor EL/ethanol assisted drug suspension in buffer (CrEL), GT DcNP exhibits about 56-fold and 8.6-fold increases in plasma drug exposure (area under the curve, AUC) and apparent half-life of gemcitabine respectively, and a 2.9-fold increase of AUC for paclitaxel. Using 4T1 as a syngeneic model for breast cancer metastasis, we found that a single GT (20/2 mg/kg) dose in DcNP nearly eliminated colonization in the lungs. This effect was not achievable by a CrEL drug combination at a 5-fold higher dose (i.e., 100/10 mg/kg GT). A dose-response study indicates that GT DcNP provided a therapeutic index of ~15.8. Collectively, these data suggest that GT DcNP could be effective against advancing metastatic breast cancer with a margin of safety. As the DcNP formulation is intentionally designed to be simple, scalable, and long-acting, it may be suitable for clinical development to find effective treatment against metastatic breast cancer.