Candidates For Therapy Research Articles

Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.

Microglia/macrophages (MG/Mφ) play a central role in the pathogenesis of multiple sclerosis (MS). However, the intricacies of the immunomodulatory microenvironment in MS, particularly the heterogeneity and regulatory mechanisms of MG/Mφ subpopulations, remain elusive. The commonly used treatment options for MS have several drawbacks, such as significant side effects and uncertain efficacy. The exploration of developing new drugs targeting MG/Mφ for the treatment of MS remains to be investigated. We identified three distinct subpopulations of MG/Mφ, among which MG/Mφ_3 significantly increased as the experimental autoimmune encephalomyelitis (EAE) progressed. Ifenprodil and RO-25-6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity. The interaction modes of these compounds with the common binding pocket in the GluN1b-GluN2B amino terminal domain heterodimer were elucidated. Virtual docking, based on the N-methyl-D-aspartate (NMDA) receptor, showed that homo-skeleton compounds of ifenprodil potentially exhibit low binding free energy with the receptor, including eliprodil and volinanserin. In vitro cell models corroborated the effective inhibition of inflammatory factor expression and minimal cytotoxicity of eliprodil and volinanserin. CoMFA (standard error of estimate = 0.378, R2 = 0.928, F values = 241.255, Prob. of R2 = 0) and topomer CoMFA (q2 = 0.553, q2 stderr = 0.77, intercept = - 1.48, r2 = 0.908, r2 stderr = 0.35) were established based on the inhibitors of NMDA receptor. The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ.

Synthesis and Biological Evaluation of New Chalcogen Semicarbazone (S, Se) and Their Azole Derivatives against Chagas Disease.

Chagas disease is caused by the eukaryote parasite Trypanosoma cruzi. Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution. We synthesized 57 new chalcogen compounds which were evaluated against T. cruzi, C2C12 cells and cruzain, the main target of this parasite. Additionally, human cathepsin L, was tested for selectivity. Three compounds were selected, based on their activity against the intracellular amastigotes (EC50 < 1 μM, SI > 10) and cruzain (IC50 < 100 nM, SI > 5.55) which compared favorably with the approved drug, Benznidazole, and the well-established cruzain inhibitor K777. Seleno-compounds demonstrated enhanced activity and selenazoles showed a decrease in selenium-associated toxicity. Compound 4-methyl-2-(2-(1-(3-nitrophenyl)ethylidene)hydrazineyl)-1,3-selenazole (Se2h) emerged as a promising candidate, and its binding to cruzain was investigated. Pharmacokinetic assessment was conducted, showing a favorable profile for subsequent in vivo assays.

Novel RGD-Decorated Micelles Loaded with Doxorubicin for Targeted Breast Cancer Chemotherapy

Nanotechnology has emerged as a promising innovative avenue for therapeutic intervention in cancer research. However, achieving satisfactory accumulation of nanoparticles in the tumor and fabricating optimized nanoparticles remain challenging. In this work, we developed a novel polymeric micelle system to actively target integrin receptors, which are usually overexpressed in breast cancer. We first synthesized a targeted peptide-modified cyclic (Arg-Gly-Asp-D-Phe-Cys) (c(RGDfc))-polyethylene glycol-acitretin amphipathic conjugate (RPA) and prepared doxorubicin (DOX)-loaded RPADm (RPA@DOX) micelles with a high drug loading content of more than 11%. Compared with unmodified DOX-containing micelles, RPADm demonstrated increased cytotoxicity and cellular uptake by MCF-7 cells. Importantly, competitive binding experiments confirmed that the observed enhancement effect was attributed to the modification of c(RGDfc) on the surface of the micelles. Furthermore, due to its active tumor-targeting ability, compared with the other DOX-based formulations, the RPADm exhibited the highest tumor distribution and strongest therapeutic efficacy in MCF-7 tumor-bearing nude mice. Additionally, the safety evaluation experiments revealed that the DOX-loaded micelles had no obvious systemic toxicity. These results suggest that the developed micelles modified with c(RGDfc) are promising candidates for tumor-active targeting therapies.

Molecular Mechanisms of Polyphenols in Management of Skin Aging.

The natural process of skin aging is influenced by a variety of factors, including oxidative stress, inflammation, collagen degradation, and UV radiation exposure. The potential of polyphenols in controlling skin aging has been the subject of much investigation throughout the years. Due to their complex molecular pathways, polyphenols, a broad class of bioactive substances present in large quantities in plants, have emerged as attractive candidates for skin anti-aging therapies. This review aims to provide a comprehensive overview of the molecular mechanisms through which polyphenols exert their anti-aging effects on the skin. Various chemical mechanisms contribute to reducing skin aging signs and maintaining a vibrant appearance. These mechanisms include UV protection, moisturization, hydration, stimulation of collagen synthesis, antioxidant activity, and anti-inflammatory actions. These mechanisms work together to reduce signs of aging and keep the skin looking youthful. Polyphenols, with their antioxidant properties, are particularly noteworthy. They can neutralize free radicals, lessening oxidative stress that might otherwise cause collagen breakdown and DNA damage. The anti-inflammatory effects of polyphenols are explored, focusing on their ability to suppress pro-inflammatory cytokines and enzymes, thereby alleviating inflammation and its detrimental effects on the skin. Understanding these mechanisms can guide future research and development, leading to the development of innovative polyphenol-based strategies for maintaining healthy skin.

Strong Affinity between Astatine and Silver: An Available Approach to Anchoring 211At in Nanocarrier for Locoregional Oncotherapy.

Recently, 211At-related endoradiotherapy has emerged as an important oncotherapy strategy. Conjugating 211At with a nanocarrier provides a vital candidate for radionuclide therapy of various malignant tumors. In this study, we proposed utilizing the intrinsically high affinity of heavy halogens and sulfhydryl compounds for metallic silver to achieve highly efficient conjugation between 211At and Ag-based nanoparticles in a simple way. 211At@Ag-PEG-FA was obtained via a one-pot assembly of 211At, Ag, and SH-PEG-FA in extremely high radiolabeling yield (>95%) within 15 min and maintained excellent stability in simulated physiochemical media. Additionally, the prepared 211At@Ag-PEG-FA demonstrated specific binding to the breast cancer cell line (4T1), with a high endocytosis rate and low reflux, leading to significant cell growth inhibition. 211At@Ag-PEG-FA exhibits an excellent antitumor effect that completely suppressed tumor growth during the first week, effectively prolonging the median survival of mice to 44 days, relative to 18 days in the control group. All of the mice exhibited minimal side effects from 211At@Ag-PEG-FA in the experiment, indicating its acceptable biosafety. Our work shows that the strong affinity of Ag can be utilized to produce radioactivated nanomedicines with excellent stability and high efficiency, which also provides some valuable insights for the 211At radiolabeling of general compounds.

Novel N-phenyl-2-(aniline) benzamide hydrochloride salt development for colon cancer therapy

IntroductionN-phenyl-2-(aniline) analog N53 is a previously discovered dual inhibitor of Topo I and COX-2, which exhibited significant anti-colon cancer activity in vitro, but the poor solubility and moderate anti-cancer activity in vivo hindered its further development.MethodsTo rectify the suboptimal drug properties of N53, a series of salt forms were developed and further evaluated through in vivo and in vitro experiments.ResultsThe hydrochloride (N53·HCl) has a well-characterized crystal structure and its solubility reached 540.1 μg/mL, which is nearly 1,700 times higher than that of N53 (0.32 μg/mL). Increasing the N53 solubility consistently promotes its effective concentration, further enhancing the COX-2/Topo I inhibitory activity and the anti-tumor activity in vitro (IC50 values of 2.95 ± 0.08 μM for HT29 cells, 7.99 ± 0.85 μM for RKO cells, 10.94 ± 1.30 μM for HCT116 cells), as well as the anti-proliferative and pro-apoptotic activity. Meanwhile, its oral pharmacokinetic property in vivo is also improved. The elimination half-life (T1/2) is prolonged from 10.78 to 22.29 h, the maximum plasma concentration (Cmax) is increased 2-fold, and the area under the plasma drug concentration-time curve (AUC0–∞) is increased 3-fold. In colon cancer xenograft mouse models, the tumor inhibition rate of N53·HCl was 53.7%, superior to that of N53 (34.7%). Moreover, the results of HE staining showed that N53·HCl had no obvious toxic effects and side effects on other organs, indicating that it was safe in vivo.DiscussionThis study demonstrated that N53·HCl exhibits superior pharmacokinetic properties, anti-colon cancer efficacy, and safety, providing a promising drug candidate for colon cancer therapy.

Improved Broad Spectrum Antifungal Drug Synergies with Cryptomycin, a Cdc50-Inspired Antifungal Peptide.

Fungal infections in humans are difficult to treat, with very limited drug options. Due to a confluence of factors, there is an urgent need for innovation in the antifungal drug space, particularly to combat increasing antifungal drug resistance. Our previous studies showed that Cdc50, a subunit of fungal lipid translocase (flippase), is essential for Cryptococcus neoformans virulence and required for antifungal drug resistance, suggesting that fungal lipid flippase could be a novel drug target. Here, we characterized an antifungal peptide, Cryptomycinamide (KKOO-NH2), derived from a 9-amino acid segment of the C. neoformans Cdc50 protein. A fungal killing assay indicated that KKOO-NH2 is fungicidal against C. neoformans. The peptide has antifungal activity against multiple major fungal pathogens with a minimum inhibitory concentration (MIC) of 8 μg/mL against C. neoformans and Candida glabrata, 16 μg/mL against Candida albicans and C. auris, and 32 μg/mL against Aspergillus fumigatus. The peptide has low cytotoxicity against host cells based on our hemolysis assays and vesicle leakage assays. Strikingly, the peptide exhibits strong drug synergy with multiple antifungal drugs, including amphotericin B, itraconazole, and caspofungin, depending on the specific species on which the combinations were assayed. The fluorescently labeled peptide was detected to localize to the plasma membrane, likely inhibiting key interactions of Cdc50 with membrane proteins such as P4 ATPases. Cryptococcus cells exposed to sub-MIC of peptide showed increased reactive oxygen species production and intracellular calcium levels, indicating a peptide-induced stress response. Decreased intracellular proliferation within macrophages was observed after 30 min of peptide exposure and 24 h coincubation with macrophages, providing a potential translational mechanism to explore further in vivo. In aggregate, the synergistic activity of our KKOO-NH2 peptide may offer a potential novel candidate for combination therapy with existing antifungal drugs.

Au-H2Ti3O7 nanotubes for non-invasive anticancer treatment by simultaneous photothermal and photodynamic therapy

Treating lung and prostate cancer cells is a major health problem that may be solved through the interactions of laser beams with nanoparticles. In the paper, Au-H2Ti3O7 nanotubes (NTs) are proposed as a treatment agent and the interactions of different laser beams with the nanostructure are considered to solve the mentioned health problem. Also, the NTs are employed to treat the cancers in dark conditions. The results are motivating because Au-H2Ti3O7 NPs do not affect healthy cells, while they strongly affect cancer cells, and the viability percentage of LNCap cells reaches 16% for incubation times of 48 h. Furthermore, treating LNCap cells using the irradiated Au-H2Ti3O7 NTs by NIR beam at 808 nm has no cytotoxicity, while cytotoxicity of 92% is obtained using an irradiation laser beam at 532 nm. Also, applying the laser beam at 635 nm to the NTs leads to a cytotoxicity of ∼53% in lung cancer (A549 cells). In total, the Au-H2Ti3O7 NTs have a selective effect on cancer cells and greatly reduce the viability in the given dark and irradiation conditions, leading to the introduction of them as a promising agent for the non-invasive treatment of prostate cancer and a moderate candidate for lung cancer therapy.

Anti-inflammatory and anti-cancer effects of polysaccharides from Antrodia cinnamomea: A review.

Antrodia cinnamomea (Ac), also known as "Niu-Chang-Chih" in Chinese, is a valuable fungus that has been widely used as medicine and food among indigenous people in Taiwan. Ac is rich in polysaccharides (Ac-PS), making it a promising candidate for adjunctive therapy in cancer and inflammation conditions. There are two types of Ac-PS: general (non-sulfated) PS (Ac-GPS) and sulfated PS (Ac-SPS). This review highlights that both Ac-GPS and Ac-SPS possess immunomodulatory, anti-inflammatory and anti-cancer properties. Each type influences interleukin signaling pathways to exert its anti-inflammatory effects. Ac-GPS is particularly effective in alleviating inflammation in the brain and liver, while Ac-SPS shows its efficacy in macrophage models. Both Ac-GSP and Ac-SPS have demonstrated anti-cancer effects supported by in vitro and in vivo studies, primarily through inducing apoptosis in various cancer cell lines. They may also synergize with chemotherapy and exhibit anti-angiogenic properties. Notably, Ac-SPS appears to have superior anti-cancer efficacy, potentially due to its sulfate groups. Furthermore, Ac-SPS has been more extensively studied in terms of its mechanisms and effects on lung cancer compared with Ac-GPS, highlighting its significance in cancer research. In addition, Ac-SPS is often reported for its ability to activate macrophage-mediated responses. Clinically, Ac-GPS has been used as an adjunctive therapy for advanced lung cancer, as noted in recent reports. However, given the numerous studies emphasizing its anti-cancer mechanisms, Ac-SPS may exhibit greater efficacy, warranting further investigation. This review concludes that Ac-derived Ac-GPS or Ac-SPS have the potential to be developed into functional health supplements or adjunctive therapies, providing dual benefits of anti-inflammatory and anti-cancer effects.

Derivation and validation of a multicenter model to identify candidates for advanced HF therapies with high potential to achieve post-LVAD reverse cardiac remodeling

Abstract Background A subset of advanced heart failure (HF) patients can experience significant improvement in their cardiac structure and function while on left ventricular assist device (LVAD) support, which is among the prerequisites for LVAD weaning. Purpose We sought to develop and validate a predictive personalized tool to identify candidates for advanced HF therapies with a high potential to achieve significant improvement in myocardial structure and function post-LVAD. This tool can aid clinicians and patients considering advanced HF therapies options. Methods A total of 884 consecutive LVAD patients were enrolled. The derivation and validation cohorts included 509 patients (from three institutions) and 375 patients from another four institutions), respectively. The primary outcome was "significant reverse remodeling", defined as left ventricular ejection fraction (LVEF) ≥40% and LV end-diastolic diameter ≤6 cm within one year on LVAD support. Bootstrap imputation and LASSO variable selection were used to derive a predictive model which was externally validated. Results Patients were predominantly white (78%), male (80.1%), 57±14 years old. Overall, 12.8% patients were identified as responders. Four variables associated with reverse remodeling were included in the multivariable model achieving a C-statistic of 0.72 (95% CI: 0.66-0.79) in the derivation and 0.75 (95% CI: 0.67-0.84) in the validation cohort (Figure). We created a calculator for individualized prediction of the probability of cardiac recovery and when applied to the studied population, we identified patients with 0.2%-67.6% chance of significant reverse remodeling (see Figure for patient example). Conclusions The Multicenter Recovery Calculator is a predictive tool that provides individualized probability of significant reverse remodeling. This tool may help clinicians and patients to maximize the benefits of both heart transplant and LVAD. Specifically, it may serve to (a) improve patient selection for LVAD as bridge to recovery and (b) benefit transplant waitlist outcomes by prioritizing allocation of donor allografts to patients without a high potential for cardiac reverse remodeling.

The Biphasic Activity of Auricularia Auricula-Judae Extract on Bone Homeostasis Through Inhibition of Osteoclastogenesis and Modulation of Osteogenic Activity.

Osteoporosis arises from the disturbance of bone homeostasis, a process regulated by osteoblasts and osteoclasts. The treatment and prevention of bone metabolic disorders resulting from an imbalance in bone homeostasis require the use of agents that effectively promote both bone formation and anti-resorptive effects. Therefore, an investigation was carried out to determine the potential of the edible mushroom Auricularia auricula-judae in modulating bone remodeling by inhibiting RANKL-induced osteoclastogenesis and enhancing BMP-2-stimulated osteoblast differentiation. Moreover, this study assessed the mode of action of the Auricularia auricula-judae extracts. The staining of tartrate-resistant acid phosphatase (TRAP), a marker for osteoclast activity, demonstrated that Auricularia auricula-judae water extract (AAJWE) inhibited the formation of multinucleated osteoclasts while exhibiting no cytotoxic effects. The study demonstrated that AAJWE reduced RANKL-induced osteoclast differentiation by inhibiting c-Fos/NFATc1 through the inhibition of ERK and JNK phosphorylation during the RANKL-induced osteoclast differentiation. Moreover, AAJWE exhibited a dose-dependent induction of ALP expression in the presence of BMP-2 during osteoblast differentiation. The AAJWE strengthened BMP-2-induced osteogenesis through the activation of Runx2 and Smad phosphorylation. Therefore, AAJWE emerges as a promising candidate for both prevention and therapy owing to its biphasic effect, which aids in the preservation of bone homeostasis.

Supramolecular Self-Assembled Hydrogel for Antiviral Therapy through Glycyrrhizic Acid-Enhanced Zinc Absorption and Intracellular Accumulation.

Respiratory syncytial virus (RSV) is a common pathogen that causes respiratory infections in infants and children worldwide, significantly impacting hospitalization rates in this age group. Zinc ions are considered to have broad-spectrum antiviral potential against RNA viruses, including RSV. However, poor organism absorption and low intracellular accumulation of zinc require repeated high-dose supplementation, which may lead to unnecessary toxic side effects. In this research, a Zn2+-mediated glycyrrhizinic acid (GA)-based hydrogel (ZnGA Gel) was introduced and potentially developed to be a clinically available drug candidate for RSV therapy. ZnGA Gel was fabricated based on the cooperation of two potential RSV inhibiting molecules (Zn2+ and GA), where Zn2+ promoted self-assembly of GA and reduced its gel concentration and GA promoted zinc absorption and distribution in lung tissue in vivo. The facile construction of supramolecular hydrogel by the self-assembled coordination complex made it an injectable, temperature-sensitive, and pH-responsive controlled-release drug delivery for Zn2+. Most importantly, GA was observed to enhance organism absorption and intracellular accumulation of Zn2+ and was identified as a zinc ionophore for the first time. GA can colonize on the cell membrane and disturb cell membrane potential, resulting in an enhanced cell membrane permeability. In the presence of GA, more than 4.7-fold increasing Zn2+ concentrations materialized in the intracellular cytoplasm, compared to Zn2+ alone administration. This intracellular Zn2+ accumulation directly boosted the antiviral activities through improved inhibition of RSV replication-associated proteins and significantly inhibited RSV replication. Oral administration of ZnGA Gel on the RSV-infected mice model achieved an ideal therapeutic effect by effectively lowering viral load in the lungs, alleviating lung injury symptoms, and reducing inflammatory cell infiltration at pathological sites. The mechanism involved the inhibition of RSV replication-related proteins, aligning with our in vitro results. Additionally, ZnGA Gel had demonstrated biocompatibility, and reasonable supplementation of zinc was acceptable and effective for infants and children in clinical practice. Hence, the ZnGA Gel developed by us holds promise as an effective anti-RSV medicine in the future.

Clinicopathogenomic analysis of PI3K/AKT/PTEN-altered luminal metastatic breast cancer in Japan.

This rapid communication highlights the correlation between protein kinase B alpha (AKT1)-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)- phosphatase and tensin homolog (PTEN) alterations and clinicopathological factors in Japanese patients with metastatic recurrent breast cancer (mBC). This study analyzed 1967 patients with luminal-type breast cancer who underwent cancer gene panel testing. The results demonstrated that AKT pathway alterations, including PI3K/AKT/PTEN, occurred in 1038 (52.8%)cases. Patients with AKT pathway mutations were older (p = 0.002) and had a higher rate of invasive lobular carcinoma (ILC) histology (p = 0.001), progesterone receptor (PgR) positivity (p = 0.006), and bone metastases (p = 0.001), and a lower rate of germline BRCA2 (p < 0.001). Comprehensive genomic profile results demonstrated a higher tumor mutational burden (TMB) (< 0.001) and lower tumor BRCA1/2 expression (< 0.001) in patients with mutations in the AKT pathway. These results are crucial for characterizing candidates for AKT pathway-targeted molecular therapies and conceptualizing optimal treatment strategies. Clinical trial registration: This study is an observational study and is therefore not registered with the clinical trials registration.

GenePHIT phase 2 study design: a double blind, placebo-controlled trial to assess efficacy, safety, and tolerability of AB-1002 gene therapy in adults with heart failure

Abstract Introduction Heart failure (HF) is associated with substantial morbidity and mortality, highlighting a critical need for novel therapies. AB-1002, an engineered adeno-associated virus (AAV) vector gene therapy candidate, delivers a constitutively active form of protein phosphatase inhibitor (I-1c) to restore cardiomyocyte intracellular calcium homeostasis. Preliminary results from an ongoing Phase (Ph) 1 trial (NCT04179643) of AB-1002 showed favourable safety and tolerability. Here we describe the design of AB-1002 Ph 2 trial (GenePHIT; NCT05598333) to evaluate efficacy, safety, and tolerability. Methods This phase 2 adaptive, double-blind, placebo-controlled, randomised, multi-centre trial (currently United States; European sites planned) includes a 52-week observation and 4-year follow-up period. Eligible patients are ≥18 years of age with non-ischaemic cardiomyopathy and New York Health Association (NYHA) Class III heart failure symptoms (Figure). Patients will be randomised 1:1:1 (n=30–50/treatment arm), including a single dose of AB-1002 administered via antegrade intracoronary infusion at 1 of 2 different doses, or placebo, all in addition to standard of care. The primary endpoint will evaluate efficacy at 52 weeks based on the composite endpoint by modified win ratio, which includes cardiovascular-related death, change in NYHA classification, and for the responders, improvements in left ventricular ejection fraction (LVEF) (≥5%), peak oxygen uptake (pVO2) ≥1.5 mL/kg/min, and 6-min walk test (6MWT) &amp;gt;30 metres. Key secondary efficacy endpoints include functional status and hospitalisations at 24 and 52 weeks, by assessing changes over time in NYHA classification, LVEF, pVO2, 6MWT, biomarkers (N-terminal pro-hormone b-type natriuretic peptide and troponin), quality of life questionnaires (Minnesota Living with Heart Failure, Kansas City Cardiomyopathy), and physiological assessments. Key safety endpoints will be assessed through 52 weeks and include treatment-emergent adverse events (AEs) and serious AEs (SAEs). Exploratory endpoints will evaluate AAV2i8 antibody titres, T-cell response to AAV2i8 capsid and I-1c, and optional right ventricular biopsy testing. Long-term follow-up will assess treatment-emergent AEs and SAEs, and number of HF hospitalisations. Data safety monitoring board assessment will occur every 3 months. Primary efficacy endpoint will compare both active dose groups combined versus placebo using the joint rank test (1). Key secondary endpoints will be analysed using Analysis of Covariance with baseline as a continuous covariate. Multiple imputations will be used to address missing data. Interim efficacy analysis will be performed using a Bayesian adaptive sample size algorithm. Conclusions GenePHIT is currently recruiting and will evaluate the efficacy, safety, and tolerability of intracoronary infusion of AB-1002, an innovative gene therapy targeting ventricular dysfunction in HF.

Prognostic Significance of Angiogenesis in invasive ductal carcinoma

Background: Angiogenesis is essential for tumor growth and metastasis. Axillary lymphnode status has been the most important prognostic factor in operable breast carcinoma, but it does not fully account for the varied disease outcome. More accurate prognostic indicators would help in selection of patients at high risk for disease recurrence and death who are candidates for systemic adjuvant therapy. Microvessel density in invasive ductal carcinoma (measures of tumor angiogenesis) is associated with metastasis and thus may be a prognostic indicator. Objective: To correlate intratumoral and peritumoral angiogenic microvessel density with lymphnode metastasis in invasive ductal carcinoma. Material and Methods: It is a cross sectional observational study, carried out at the department of Pathology, BSMMU from January 2016 to December 2017. A total 48 mastectomy samples with axillary nodes from histologically confirmed invasive ductal carcinoma were included in this study. Weidner method was used for calculating micro vessels density. Sections examined to evaluate the density of angiogenic vessels by immuohistological stain with vWF expression in invasive breast cancer. Correlation between angiogenic vessels density with or without lymphnode metastasis was taken. Results: In this study angiogenic vessel count is more in the intratumoral area than peritumoural area. There was a positive significant correlation between lymphnode metastasis with micro vessel density in both peritumoral and intratumoral areas in Weidner method in vWF stain. J Shaheed Suhrawardy Med Coll 2023; 15(1): 59-65

Staphylococcus felis C4 exhibits invitro antimicrobial activity against methicillin-resistant Staphylococcus pseudintermedius in a novel canine skin explant model.

Canine superficial pyoderma is a common bacterial skin infection of dogs, generally caused by Staphylococcus pseudintermedius. The C4 strain of Staphylococcus felis was recently discovered to have strong antimicrobial activity against S. pseudintermedius in mice. We aimed to evaluate invitro if this antimicrobial activity was maintained using a novel canine skin explant model. Punch biopsies (8 mm) of skin from recently euthanised dogs were collected and placed into six-well plates on top of an agarose pedestal. Histological examination of the skin explants showed an intact dermal-epidermal organisation and a stratum corneum that was successfully colonised by S. pseudintermedius after topical application. The number of colony forming units of S. pseudintermedius showed a 2 log increase after 24 h colonisation, indicating that the explant supported bacterial growth. By contrast, co-treatment with S. felis C4 live bacteria and its sterile protein product significantly reduced the growth of a methicillin-susceptible (ST540, p = 0.0357) and a methicillin-resistant (MR) strain (ST71, p = 0.0143) of S. pseudintermedius. No detectable bacteria were recovered from or visualised on skin 24 h posttreatment with the S. felis C4 sterile protein product. Using a novel canine explant model, we demonstrate that the S. felis C4 strain inhibits the growth of S. pseudintermedius and that it is a promising candidate for a new probiotic therapy to treat cutaneous infections caused by S. pseudintermedius, including MR strains.

Deep learning analysis of histopathological images predicts immunotherapy prognosis and reveals tumour microenvironment features in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a crucial treatment option for patients with advanced NSCLC. However, only a subset of patients experience clinical benefit from ICIs. Therefore, identifying biomarkers that can predict response to ICIs is imperative for optimising patient selection. Hematoxylin and eosin (H&E) images of NSCLC patients were obtained from the local cohort (n = 106) and The Cancer Genome Atlas (TCGA) (n = 899). We developed an ICI-related pathological prognostic signature (ir-PPS) based on H&E stained histopathology images to predict prognosis in NSCLC patients treated with ICIs using deep learning. To accomplish this, we employed a modified ResNet model (ResNet18-PG), a widely-used deep learning architecture well-known for its effectiveness in handling complex image recognition tasks. Our modifications include a progressive growing strategy to improve the stability of model training and the use of the AdamW optimiser, which enhances the optimisation process by adjusting the learning rate based on training dynamics. The deep learning model, ResNet18-PG, achieved an area under the receiver operating characteristic curve (AUC) of 0.918 and a recall of 0.995 on the local cohort. The ir-PPS effectively risk-stratified NSCLC patients. Patients in the low-risk group (n = 40) had significantly improved progression-free survival (PFS) after ICI treatment compared to those in the high-risk group (n = 66, log-rank P = 0.004, hazard ratio (HR) = 3.65, 95%CI: 1.75-7.60). The ir-PPS demonstrated good discriminatory power for predicting 6-month PFS (AUC = 0.750), 12-month PFS (AUC = 0.677), and 18-month PFS (AUC = 0.662). The low-risk group exhibited increased expression of immune checkpoint molecules, cytotoxicity-related genes, an elevated abundance of tumour-infiltrating lymphocytes, and enhanced activity in immune stimulatory pathways. The ir-PPS signature derived from H&E images using deep learning could predict ICIs prognosis in NSCLC patients. The ir-PPS provides a novel imaging biomarker that may help select optimal candidates for ICIs therapy in NSCLC.

Identifying the best candidate for focal therapy: a comprehensive review.

Despite the evidence supporting the use of focal therapy (FT) in patients with localized prostate cancer (PCa), considerable variability exists in the patient selection criteria across current studies. This study aims to review the most recent evidence concerning the optimal approach to patient selection for FT in PCa. PubMed database was systematically queried for studies reporting patient selection criteria in FT for PCa before December 31, 2023. After excluding non-relevant articles and a quality assessment, data were extracted, and results were described qualitatively. There is no level I evidence regarding the best patient selection approach for FT in patients with PCa. Current international multidisciplinary consensus statements recommend multiparametric magnetic resonance imaging (mpMRI) followed by MRI-targeted and systematic biopsy for all candidates. FT may be considered in clinically localized, intermediate risk (Gleason 3 + 4 and 4 + 3), and preferably unifocal disease. Patients should have an acceptable life expectancy. Those with prostate volume >50 ml and erectile dysfunction should not be excluded from FT. Prostate-specific antigen (PSA) level of < 20 (ideally < 10) ng/mL is recommended. However, the utility of other molecular and genomic biomarkers in patient selection for FT remains unknown. FT may be considered in well-selected patients with localized PCa. This review provides a comprehensive insight regarding the optimal approach for patient selection in FT.

Progress on Carbon Dots with Intrinsic Bioactivities for Multimodal Theranostics.

Carbon dots (CDs) with intrinsic bioactivities are candidates for bioimaging and disease therapy due to their diverse bioactivities, high biocompatibility, and multiple functionalities in multimodal theranostics. It is a multidisciplinary research hotspot that includes biology, physics, materials science, and chemistry. This progress report discusses the CDs with intrinsic bioactivities and their applications in multimodal theranostics. The relationship between the synthesis and structure of CDs is summarized and analyzed from a material and chemical perspective. The bioactivities of CDs including anti-tumor, antibacterial, anti-inflammatory etc. are discussed from biological points of view. Subsequently, the optical and electronic properties of CDs that can be applied in the biomedical field are summarized from a physical perspective. Based on the functional review of CDs, their applications in the biomedical field are reviewed, including optical diagnosis and treatment, biological activity, etc. Unlike previous reviews, this review combines multiple disciplines to gain a more comprehensive understanding of the mechanisms, functions, and applications of CDs with intrinsic bioactivities.

Kallikrein-related peptidases: mechanistic understanding for potential therapeutic targeting in cancer.

Human kallikrein-related peptidases (KLKs) represent a subgroup of 15 serine endopeptidases involved in various physiological processes and pathologies, including cancer. This review aims to provide a comprehensive overview of the KLK family, highlighting their genomic structure, expression profiles and substrate specificity. We explore the role of KLKs in tumorigenesis, emphasizing their potential as biomarkers and therapeutic targets in cancer treatment. The dysregulated activity of KLKs has been linked to various malignancies, making them promising candidates for cancer diagnostics and therapy. : Recent advancements in understanding the mechanistic pathways of KLK-related tumorigenesis offer new prospects for developing targeted cancer treatments. Expert opinion suggests that while significant progress has been made, further research is necessary to fully exploit KLKs' potential in clinical applications.