Regulating Size and Charge of Liposomes in Microneedles to Enhance Intracellular Drug Delivery Efficiency in Skin for Psoriasis Therapy.

The stratum corneum (SC) and cell membrane are two major barriers that hinder the therapeutic outcomes of transdermal drug delivery for the treatment of skin diseases. While microneedles (MNs) can efficiently penetrate the SC to deliver nanomedicines, the optimization of physicochemical properties of nanomedicines in MNs to enhance their in vivo cellular delivery efficiency remains unclear. Here, how the size and surface charge of drug-loaded liposomes in MNs influence the retention time and cellular delivery in psoriatic skin is systematically investigated. The results indicate that while 100 nm negatively-charged liposomes in MNs show higher cellular uptake in vitro, 250 and 450 nm liposomes could enhance skin retention and the long-term in vivo cellular delivery efficiency of drugs. Moreover, 250 nm cationic liposomes with a stronger positive charge show an extraordinarily long skin retention time of 132 h and significantly higher in vivo cellular internalization. In the treatment study, dexamethasone (dex)-loaded cationic liposomes-integrated MNs show better therapeutic outcomes than dex-loaded anionic liposomes-integrated MNs in a psoriasis-like animal model. The design principles of liposomes in MN drug delivery systems explored in the study hold the potential for enhancing the therapeutic outcomes of psoriasis and are instrumental for successful translation.

Clinical efficacy and long-term immunogenicity of an early triple dose regimen of SARS-CoV-2 mRNA vaccination in cancer patients.

INTRODUCTION: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. METHOD: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. RESULTS: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P<0.05) and chemotherapy (92.8%±18.1, P<0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection. CONCLUSION: This study demonstrates the benefit of early administration of the third dose among cancer patients.

Booster doses of COVID-19 vaccines for patients with haematological and solid cancer: a systematic review and individual patient data meta-analysis.

IMPORTANCE: Patients with cancer have an increased risk of severe disease and mortality from COVID-19, as the disease and antineoplastic therapy cause reduced vaccine immunogenicity. Booster doses have been proposed to enhance protection, and efficacy data are emerging from several studies. OBJECTIVE: To evaluate the proportion of COVID-19 primary vaccination non-responders with cancer who seroconvert after a booster dose. METHODS: PubMed, EMBASE, CENTRAL and medRxiv were searched from 1st January 2021 to 10th March 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal checklist. RESULTS: After the eligibility assessment, 22 studies were included in this systematic review and 17 for meta-analysis of seroconversion in non-responders, pooling a total of 849 patients with haematological cancer and 82 patients with solid cancer. Haematological cancer non-responders exhibited lower seroconversion at 44% (95% CI 36-53%) than solid cancer at 80% (95% CI 69-87%). Individual patient data meta-analysis found the odds of having a meaningful rise in antibody titres to be significantly associated with increased duration between the second and third dose (OR 1.02, 95% CI 1.00-1.03, P ≤ 0.05), age of patient (OR 0.960, 95% CI 0.934-0.987, P ≤ 0.05) and cancer type. With patients with haematological cancer as a reference, patients with lung cancer had 16.8 times the odds of achieving a meaningful increase in antibody titres (OR 16.8, 95% CI 2.95-318, P ≤ 0.05) and gastrointestinal cancer patients had 25.4 times the odds of achieving a meaningful increase in antibody titres (OR 25.4, 95% CI 5.26-492.21, P ≤ 0.05). CONCLUSIONS: administration of a COVID-19 vaccine booster dose is effective in improving seroconversion and antibody levels. Patients with haematological cancer consistently demonstrate poorer response to booster vaccines than patients with solid cancer.

Prevention of Oxaliplatin-Induced Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) has significant clinical impact on the quality of life for cancer patients and is a dose limiting toxicity. Trials studying preventive measures have been inconclusive. A systematic review and meta-analysis were conducted to evaluate the existing pharmacological and non-pharmacological interventions to prevent chronic OIPN. METHODS: Literature databases PubMed-MEDLINE, Embase and Scopus, were searched from 1 Jan 2005 to 08 Aug 2020 and major conferences' abstracts were reviewed for randomized controlled trials that examined the efficacy of any preventive measure for OIPN. The primary outcome measure was the incidence of chronic OIPN with a preventive intervention as compared to placebo or no intervention. The pooled risk ratio and its 95% confidence interval were calculated using a random effects model. A network meta-analysis was conducted to derive indirect evidence of any preventive effect of an intervention against placebo when original trials compared one intervention against another. RESULTS: Forty-four trials were analyzed describing 29 chemoprotective interventions, including combinations, and 1 non-pharmacological intervention. Ratings were assessed via a combination of outcomes with quality assessment using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Of the 30 interventions examined, there were six interventions supporting potential efficacy, 11 interventions with insufficient evidence and 13 interventions not recommended. CONCLUSION: Currently, there is insufficient certainty to support any intervention as effective in preventing OIPN. Of note is that most of these studies have focused on pharmacological interventions; non-pharmacological interventions are underexplored. Further research on ways to limit OIPN is needed. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=225095, Prospero Registration Number: CRD42021225095.

Personalised, Rational, Efficacy-Driven Cancer Drug Dosing via an Artificial Intelligence SystEm (PRECISE): A Protocol for the PRECISE CURATE.AI Pilot Clinical Trial.

Introduction: Oncologists have traditionally administered the maximum tolerated doses of drugs in chemotherapy. However, these toxicity-guided doses may lead to suboptimal efficacy. CURATE.AI is an indication-agnostic, mechanism-independent and efficacy-driven personalised dosing platform that may offer a more optimal solution. While CURATE.AI has already been applied in a variety of clinical settings, there are no prior randomised controlled trials (RCTs) on CURATE.AI-guided chemotherapy dosing for solid tumours. Therefore, we aim to assess the technical and logistical feasibility of a future RCT for CURATE.AI-guided solid tumour chemotherapy dosing. We will also collect exploratory data on efficacy and toxicity, which will inform RCT power calculations. Methods and analysis: This is an open-label, single-arm, two-centre, prospective pilot clinical trial, recruiting adults with metastatic solid tumours and raised baseline tumour marker levels who are planned for palliative-intent, capecitabine-based chemotherapy. As CURATE.AI is a small data platform, it will guide drug dosing for each participant based only on their own tumour marker levels and drug doses as input data. The primary outcome is the proportion of participants in whom CURATE.AI is successfully applied to provide efficacy-driven personalised dosing, as judged based on predefined considerations. Secondary outcomes include the timeliness of dose recommendations, participant and physician adherence to CURATE.AI-recommended doses, and the proportion of clinically significant dose changes. We aim to initially enrol 10 participants from two hospitals in Singapore, perform an interim analysis, and consider either cohort expansion or an RCT. Recruitment began in August 2020. This pilot clinical trial will provide key data for a future RCT of CURATE.AI-guided personalised dosing for precision oncology. Ethics and dissemination: The National Healthcare Group (NHG) Domain Specific Review Board has granted ethical approval for this study (DSRB 2020/00334). We will distribute our findings at scientific conferences and publish them in peer-reviewed journals. Trial registration number: NCT04522284.

A Surface-Confined Gradient Conductive Network Strategy for Transparent Strain Sensors toward Full-Range Monitoring.

The development of transparent and flexible sensors suitable for the full-range monitoring of human activities is highly desirable, yet presents a daunting challenge due to the need for a combination of properties such as high stretchability, high sensitivity, and good linearity. Gradient structures are commonly found in many biological systems and exhibit excellent mechanical properties. Here, we report a novel surface-confined gradient conductive network (SGN) strategy to construct conductive polymer hydrogel-based stain sensors (CHSS). This CHSS showed an ultrahigh stretchability of 4000% strain, transparency above 90% at a wavelength of 600 nm, as well as skin-like Young's modulus of 40 kPa. Impressively, the sensitivity was improved to 3.0 and outstanding linear sensing performance was achieved simultaneously in the ultrawide range of 0% to 4000% strain with a high R-square value of 0.994. With the help of SGN strategy, this CHSS was able to monitor both large-scale and small-scale human motions and activities. This SGN strategy can open a new avenue for the development of novel flexible strain sensors with excellent mechanical, transparent, and sensing performance for full-range monitoring of human activities.

A meta-analysis on immune checkpoint inhibitor efficacy for advanced non-small cell lung cancer between East Asians versus non-East Asians.

BACKGROUND: We conducted a meta-analysis to assess the efficacy of immune checkpoint inhibitors (ICIs) (PD-1/L1 and CTLA-4 inhibitors) in first and subsequent lines in East Asians and non-East Asians. METHODS: We searched PubMed-MEDLINE, Embase and Scopus, from inception to 20 Sep 2019, and reviewed major conferences' abstracts, for randomised controlled trials of ICI in advanced-stage NSCLC (Stage IIIB or IV) without EGFR mutation that reported hazard ratios (HRs) stratified by geographical region including the region "Asia" or "East Asia". The primary outcome measures were overall survival (OS) and progression-free survival (PFS). The pooled HR and its 95% confidence interval (CI) for OS and PFS in East Asians and non-East Asians were calculated using a random effect model and the difference compared using an interaction test. RESULTS: A total of 5,465 patients from 7 randomised controlled trials involving CTLA-4 and/or PD-1/L1 inhibitors were included, with 1,740 (32%) East Asians and 3,725 (68%) non-East Asians. ICI was associated with an improvement in OS and PFS for both East Asian (OS HR, 0.74; 95% CI, 0.65-0.85; PFS HR, 0.56; 95% CI, 0.40-0.79) and non-East Asian patients (OS HR, 0.78; 95% CI, 0.72-0.85; PFS HR, 0.69; 95% CI, 0.56-0.85), with no significant difference between the two groups (Pinteraction=0.55 for OS; Pinteraction=0.33 for PFS). Subgroup analyses showed a statistically significant superior PFS (but not OS) for East Asians than non-East Asians in trials that used immune checkpoint inhibitor in the first-line treatment (Pinteraction=0.02). No significant regional difference was found in further subgroups of pure ICI and combination of ICI with chemotherapy. CONCLUSIONS: There is no significant difference in response to ICI between East Asians and non-East Asians with advanced stage NSCLC, and the statistically significant subgroup difference in PFS in the first line use of ICI may not be clinically significant.

Predictive Biomarkers of Immune Checkpoint Inhibition in Gastroesophageal Cancers.

Immune checkpoint inhibition has transformed cancer treatment. For gastroesophageal cancer, this class of drugs have demonstrated durable responses and survival benefit in a subgroup of patients, resulting in regulatory approval. However, several recent randomized phase III studies in gastroesophageal cancer have reported negative results, blunting initial enthusiasm. Identification and validation of predictive biomarkers with appropriate patient selection for benefit from immunotherapy is an area of intense research with novel concepts rapidly emerging. In this review we describe the latest immune checkpoint inhibitor trials which have been reported in gastroesophageal cancers with a focus on predictive biomarkers. We also explore novel biomarkers being developed to improve precision oncology for immunotherapy in gastroesophageal cancers.

Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression.

PURPOSE: Metformin may have a role in reducing the incidence of colorectal cancer (CRC) and improving survival outcome. This meta-analysis explored the effect of metformin use on colorectal adenoma and cancer incidence, and colorectal oncological outcomes. METHODS: A database search was conducted on Medline, Embase and CNKI for studies comparing metformin vs. non-metformin users, metformin users vs. non-diabetics and metformin users vs. diabetics with diet-only treatment. Meta-analysis was done with DerSimonian and Laird with risk ratios (RR), and hazard ratios (HR) for survival outcomes. RESULTS: We included 58 studies and summarized incidences of colorectal adenoma and cancer, as well as cancer survival outcomes. Metformin users had a significant lower incidence of colorectal adenoma (RR 0.77, CI 0.67-0.88, p < 0.001), advanced adenoma (0.61, CI 0.42-0.88, p = 0.008) and CRC (RR 0.76, CI 0.69-0.84, p < 0.001) respectively compared with non-metformin users. Overall survival (HR 0.6, CI 0.53-0.67, p < 0.001) and CRC-specific survival (HR 0.66, CI 0.59-0.74, p < 0.001) were higher among metformin users compared with non-metformin users. Further analysis on overall survival of metastatic CRC patients revealed significantly higher survival rates in metformin users (HR 0.77, CI 0.68-0.87, p < 0.001). CONCLUSION: This meta-analysis showed that metformin use significantly reduces colorectal adenoma and cancer incidence and improves colorectal cancer outcomes.

Interactions between two-dimensional nanoclay and blood cells in hemostasis.

Uncontrolled bleeding following trauma is associated with a high risk of death. The two-dimensional (2D) nanoclay kaolinite as an effective hemostatic has been developed for early intervention to prevent blood loss. However, the interfacial interactions between kaolinite and blood cells in hemostasis, and the effects of the stacking structure or particle size of kaolinite on bleeding control are unclear. Here, the interactions between kaolinite and blood cells were analyzed qualitatively and quantitatively by using scanning electron microscopy, confocal laser-scanning microscopy, and flow cytometry. The results showed that kaolinite not only bonds with platelets but also induces platelets aggregation, and does not disturb red blood cells, which facilitates the formation of blood clotting in hemostasis. Further, kaolinite nanoclay with smaller nanosheets and looser aggregation showed higher hemostatic activity, which was attributed to the higher water absorption capacity, and the ability to activate the intrinsic coagulation pathway and platelets activation and aggregation. Accordingly, controlling the particle size or thickness and aggregate status of kaolinite or 2D nanoclay nanosheets could be an alternative strategy for enhancing the hemostatic activity of 2D nanoclay-based materials.

One-step microwave-assisted preparation of oxygen-rich multifunctional carbon quantum dots and their application for Cu2+-curcumin detection.

Carbon quantum dots (CQDs), owing to its unique optical properties, have achieved tremendous progress for the detection of different metal ions, organic small molecules, macromolecules, etc. Here we synthesized fluorescent CQDs by a simple one-step microwave-assisted method using 3,4-Dihydroxy-l-phenylalanine (levodopa) as the carbon resource. The CQDs proved to be a multifunctional probe which can be used for detection of various species including copper ion, biothiols and curcumin, via different mechanisms. The selective detection of copper ion was obtained by fluorescence quenching and the mechanism was proved to be static quenching by electrostatic interaction. The fluorescence of levoCQDs-Cu2+ system can be recovered by biothiols (GSH, Cys and Hcy), implying levoCQDs-Cu2+ system can also be applied for biothiols detection. The excitation spectrum of levoCQDs had a good overlap with the absorption peak of curcumin, making it as a suitable curcumin probe by fluorescence quenching via inner filter effect (IFE). Furthermore, the levoCQDs can also track the formation of Cu2+-Curcumin complexes by restoring the fluorescence of the CQDs in levoCQDs and Cu2+-Curcumin system, and this feature may be exploited in the mechanism study of Cu2+-Curcumin in the treatment of Alzheimer's disease. The fluorescent levoCQDs were finally used for Cu2+ and curcumin detection in some real samples including different types of environmental water samples and human serum samples, providing a convenient strategy to monitor Cu2+and curcumin in environmental and biological samples.

Streamlined asymmetric α-difunctionalization of ynones.

Ynones are a unique class of structural motifs that show remarkable chemical versatility. Chiral ynones, particularly those possessing an α-stereogenic center, are highly attractive templates for structural diversification. So far, only very limited examples have been reported for asymmetric α-functionalization of ynones. Asymmetric double α-functionalization of ynones remains elusive. Here we describe a streamlined strategy for asymmetric α-difunctionalization of ynones. We developed a gold-catalyzed multicomponent condensation reaction from a simple ynone, an amine, and an electrophilic alkynylating reagent to generate a 1,2-dialkynyl enamine, a key stable and isolable intermediate. This intermediate can undergo asymmetric fluorination catalyzed by a chiral phosphoric acid derivative. Chiral ynones with an α-quaternary carbon and containing a fluorine and an alkyne can be synthesized in high yield and high ee. The synthetic utility of this method is demonstrated by the synthesis of enantioenriched tri(hetero)arylmethyl fluorides.

Histopathological analysis of infiltrating T cell subsets in acute T cell-mediated rejection in the kidney transplant.

AIM: To compare the differential immune T cell subset composition in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes. METHODS: A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cell-mediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively. RESULTS: In comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3+ regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3+ regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss. CONCLUSION: Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.

Synthesis of tetrasubstituted 1-silyloxy-3-aminobutadienes and chemistry beyond Diels-Alder reactions.

Electron-rich dienes have revolutionized the synthesis of complex compounds since the discovery of the legendary Diels-Alder cycloaddition reaction. This highly efficient bond-forming process has served as a fundamental strategy to assemble many structurally formidable molecules. Amino silyloxy butadienes are arguably the most reactive diene species that are isolable and bottleable. Since the pioneering discovery by Rawal, 1-amino-3-silyloxybutadienes have been found to undergo cycloaddition reactions with unparalleled mildness, leading to significant advances in both asymmetric catalysis and total synthesis of biologically active natural products. In sharp contrast, this class of highly electron-rich conjugated olefins has not been studied in non-cycloaddition reactions. Here we report a simple synthesis of tetrasubstituted 1-silyloxy-3-aminobutadienes, a complementarily substituted Rawal's diene. This family of molecules is found to undergo a series of intriguing chemical transformations orthogonal to cycloaddition reactions. Structurally diverse polysubstituted ring architectures are established in one step from these dienes.