Neurofibromatosis type1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1gene. Although congenital pseudarthrosis of the tibia (CPT) has frequently been associated with NF1, the underlying molecular mechanism of CPT in these NF1 patients is yet ill-understood. The aim of the present study was to detect NF1 mutations from genomic DNA and to harbor variants associated with CPT in NF1 patients. Whole-exome sequencing was first carried out with samples from two patients with CPT in one NF1 family, and a novel mutation c.2324A>G (p.E775G) in NF1 gene was identified. Additionally, a missense variant c.455C>T (p.P152L) in BCOR gene completely co-segregated with the CPT phenotype within this family. Subsequently, NF1 and NF2 genes in four other unrelated patients with both NF1 and CPT were screened using targeted sequencing. Four mutations in NF1 gene, including two known mutations (c.2288T>C/p.L763P, c.574 C>T/p.R192*) and two novel mutations (c.768delT/p.F256Lfs*25, c.2229_2230delTG/ p.V744Qfs*23) were detected. Further study confirmed that CPT was present in NF1 families, and NF1 mutations were closely associated with these complex phenotypes. Moreover, the data from the current study indicated that male gender might be a susceptibility factor for CPT in NF1. Therefore, we speculated that BCOR variants might be related to CPT phenotype among male NF1 patients.

This comprehensive analysis thoroughly examines the topic of adversarial attacks in artificial intelligence (AI), providing a detailed overview of the various methods used to compromise machine learning models. It explores different attack techniques, ranging from the simple Fast Gradient Sign Method (FGSM) to the intricate Carlini and Wagner Attack (C&W), emphasising the wide range of adversarial approaches and their intended goals. The discussion also distinguishes between targeted and non-targeted attacks, highlighting the adaptability and versatility of these malicious efforts. Additionally, the study delves into the realm of black-box attacks, revealing the capability of adversarial strategies to compromise models even with limited knowledge. Real-life examples illustrate the tangible consequences and potential dangers of adversarial attacks in various fields such as self-driving cars, multimedia, and voice assistants. These cases highlight the difficulties in ensuring the legitimacy and dependability of AI-powered technologies and programs. The article stresses the importance of ongoing research and innovation to address the growing difficulties posed by advanced methods like deepfakes and disguised voice commands in preserving the security of AI systems. This study provides valuable insights on how different adversarial strategies and defence mechanisms interact within AI. The results emphasise the urgent need for stronger and more secure AI models to combat the increasing number of adversarial threats in today's AI landscape. These findings can guide future research and innovations in developing more resilient AI technologies that can better withstand various adversarial vulnerabilities and challenges.

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.

Background: About 200 new ovarian cancer cases per year are diagnosed in Armenia, an upper-middle-income country. This study aims to summarize the survival outcomes of relapsed ovarian cancer patients in Armenia based on the type of relapse, risk factors, and the choice of systemic treatment. Methods: A retrospective case-control study including 228 patients with relapsed ovarian cancer from 3 different institutions. Results: The median age of the patients was 55. The median follow-up from the relapse and primary diagnosis was 21 and 48 months. The incidence of platinum-sensitive relapse was 81.6% (186), while platinum-resistant relapse was seen only in 18.4% (42) patients. Median survival of the patients starting from the primary diagnosis in the platinum-sensitive compared to the platinum-resistant group was 54 versus 25 months (p < 0.001), and median survival after relapse: was 25 versus 13 months, respectively 3- and 5-year survival in these groups were: 31.2% vs. 23.8%, and 15.1% vs. 9.5%, respectively (p = 0,113). Conclusions: Overall, despite new therapeutic approaches, ovarian cancer continues to be one of the deadly malignant diseases in women, especially, in developing countries with a lack of resources, where, in fact, the main available systemic treatment for the majority of patients remains chemo-therapy. Low survival rates emphasize the urgent need for more research on this group of patients with poor outcomes.

(1) Background: This case presents a rare and challenging clinical scenario involving a 50-year-old female patient diagnosed with Inflammatory Carcinoma, a particularly aggressive and rapidly growing form of breast cancer. The disease is characterized by heat, redness, swelling and noticeable changes in the breast's skin texture, resembling the skin of an orange (peau d'orange). This case is important because it contributes to the limited clinical literature on such aggressive forms of breast cancer.; (2) Methods: The multidisciplinary approach was employed. Diagnostic procedures such as imaging tests, biopsy, and histopathological examination were performed to confirm the diagnosis of Inflammatory Carcinoma and assess the extent of the disease. The presence of the HER2 protein on the tumor cells supported the selection of a combination therapy involving systemic chemotherapy and targeted biological therapy.; (3) Results: The patient responded positively to the combination therapy consisting of systemic chemotherapy and targeted biological therapy. The aggressive nature of Inflammatory Carcinoma, characterized by rapid growth and distinct skin changes, was effectively addressed. The presence of the HER2 protein on the tumor cells indicated the potential efficacy of the combination therapy in aggressive forms of breast cancer.; (4) Conclusions: This case highlights the critical importance of a multidisciplinary approach in managing complex cases of breast cancer, especially rare and aggressive subtypes like Inflammatory Carcinoma. The positive response of the patient to the combination therapy involving systemic chemotherapy and targeted biological therapy demonstrates the potential for favorable outcomes in aggressive disease presentations.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.

Most existing cancer therapies negatively affect normal tissue as well as cancerous tissue. A potentially effective strategy for treating cancer that precludes off-target damage and could be an option for most patients would involve targeting one or more mutations that are ubiquitous in the given patient’s tumor(s). To effect this strategy, one would employ multi-region sequencing of a patient’s primary tumor and metastases to seek out mutations that are shared between all or at least most regions. Once the target or targets are known, one would ideally rapidly generate a molecular switch for at least one of said ubiquitous mutations that can distinguish the mutated DNA, RNA, or protein from the wild-type version and subsequently trigger a therapeutic response. I propose that the therapeutic response involve the replication of an oncolytic virus or intracellular bacterium, as any mutation can theoretically be detected by a vector that enters the cell - and automatic propagation could be very helpful. Moreover, the mutation “signal” can be easily enhanced through transcriptional and translational (if the target is an intracellular protein) enhancement. Importantly, RNA may make the best target for the molecular switches in terms of amplification of the signal and ease of targeting.

Chinese Taihe Black-bone silky fowl (TBsf) is the homology of medicine and food and has high nutritional and medical value all over the world. However, the nutritional compositions and specific metabolite advantages of Taihe silky fowl muscle are still poorly understood. In this study, we investigated the differences of nutritional components between TBsf and another similar breed (Black Feathered chicken and laid green-shelled eggs, BF-gsc). Meanwhile, we also explored the divergences in muscle characteristics of Taihe silky fowl fed with two different diets, that is normal chicken feed (TBsf-ncf) and Broussonetia papyrifera-fermented feed (TBsf-bpf). Firstly, the growth performance and biochemical index of Taihe silky fowl was significantly different compared with black-feathered chicken. Secondly, we identified the metabolic alterations in Taihe silky fowl by performing an un-targeted UHPLC-Q-TOF-MS/MS analysis. Our results suggested that the whole metabonomic characteristics had obvious separation between TBsf-ncf, TBsf-bpf and BF-gsc groups both in the positive and negative ion mode by PCA analysis. Next, OPLS-DA multivariate analysis revealed that 57 metabolites (in positive mode) and 49 metabolites (in negative mode) were identified as differential metabolites between TBsf-ncf and BF-gsc group. These differential metabolites were mainly enriched to ABC transporters, biosynthesis of amino acids and aminoacyl-tRNA biosynthesis. Besides, there were 47 metabolites (in positive) and 13 metabolites (in negative) were differentially regulated between TBsf-ncf and TBsf-bpf group, which were majorly involved in histidine metabolism and linoleic metabolism. Furthermore, the integrated network analysis suggested that DL-arginine, DL-isoleucine, linoleoylcarnitine, stearoylcarnitine (positive) and ricionleic acid, D-proline, uric acid (negative) were the significantly metabolic biomarkers in Taihe silky fowl. Moreover, the metabolites of primaquine, ticlpoidine, riboflavin, acetylcarnitine (positive) and salicylic acid, acetaminophen sulfate, glutamic acid (negative) were markedly changed in the Taihe silky fowl fed with BP-fermented feed. In summary, a global survey of the nutritional components and metabolite differences were performed in muscle tissues of Taihe silky fowl between various breeds and feeds. The comprehensive expression profiles of the metabolites in Taihe silky fowl affected by genetic and environmental factors were acquired. This study provided valuable evidence fo breed and feed-induced putative biomarkers as well as improved the economic value of Taihe silky fowl through targeted metabolite regulation.

Targeted radionuclide therapy (TRT) has recently seen a surge in popularity, with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results – an example being chimeric antigen receptor (CAR) T-cells therapy in hematologic malignancies. Moreover, TRT and CAR T therapies possess unique features that require special consideration when determining how to dose, time, and sequence combination treatments, including the distribution of TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate additive or synergistic effects of combination therapies and warrant a mathematical treatment which includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here we combine two previously published mathematical models in a multiple myeloma setting to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell based therapies. We find that for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR T therapies.

Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.

Host ribosome-associated scaffold protein Receptor for Activated C Kinase 1 (RACK1) is utilized by a diverse group of human viruses for Internal Ribosomal Entry Sites (IRES) – mediated translation of viral mRNAs. We recently reported inhibition of herpes virus by small molecules targeting the RACK1 functional site. Here, we tested these molecules against HIV-1 and HCV, as HIV-1 contains two potential IRES sites and HCV translation occurs exclusively through IRES. Compounds significantly downregulated activities of HIV-1- and HCV-related dicistronic reporter constructs in transfected HEK293T cells. The compounds also strongly downregulated production of the HIV-1 capsid protein p24 in HIV-infected cells, as well as production of HIV-1 Gag precursor p55 and p55-derived proteins p24 and p17 in cells infected with the HIV-1 virus. Hepatitis C virus (HCV) IRES activities were also significantly inhibited by RACK1 inhibitor compounds. Since a number of human and plant pathogenic viruses are reported to use IRES, the RACK1 compounds can be established as broad host-targeted antivirals.

The development of targeted therapeutics for cancer continues to receive intense research attention as laboratories and pharmaceutical companies seek to develop drugs and technologies that improve treatment efficacy and mitigate harmful side effects. In the aftermath of World War I, it was discovered that mustard gas destroys rapidly dividing cells and could be used to treat cancer. Since then, chemotherapy has remained a predominant treatment for cancer; however, the destruction of dividing cells throughout the body yields devastating side effects including off-target damage of the digestive tract, bone marrow, skin, and reproductive tract. Furthermore, the high mutation rate of cancerous cells often renders chemotherapy ineffective long-term. Therapies with improved specificity, localization, and efficacy are redefining cancer treatment. Herein, we define and summarize the principal advancements in targeted cancer treatment and briefly comment on the march towards personalized medicine in the treatment of human cancer.

Acute myeloid leukemia (AML) remains a challenging hematologic malignancy. The presence of TP53 mutations in AML poses a therapeutic challenge, considering that standard treatments face significant setbacks in achieving meaningful responses. There is a pressing need for the development of innovative treatment modalities to overcome resistance to conventional treatments attributable to the unique biology of TP53-mutated (TP53mut) AML. This review underscores the role of TP53 mutations in AML, examines the current landscape of treatment options, and highlights novel therapeutic approaches, including targeted therapies, combination regimens, and emerging immunotherapies as well as agents being explored in preclinical studies, for their potential to address the unique hurdles posed by TP53mut AML.

Casein Kinase ІІ (CK2) is one of the most versatile kinases. Its involvement in almost all cellular pathways makes it the Master Regulator of biochemical processes in a cell. This kinase is essential in regulating inflammation, cell differentiation, and cell cycle regulation. Often simultaneously. Its emerging role in senescence also indicates its function's centrality in cellular metabolism. The strategy to target this kinase to treat musculoskeletal disorders seems effective. These disorders often include a component of inflammation, dysregulated cell differentiation, and aging. This review focuses on CK2 target discovery and the diversity of its substrate interactions. We then transition toward the implication of CK2 in musculoskeletal disorders. Through a summary of current strategies for CK2 targeting with a new approach, we discuss the potential aspects that could be addressed in future drug research.

Oxidative stress initiates and facilitates the disruption of the structural integrity of hepatic mitochondria, which leads to steatosis, steatohepatitis, fibrosis, and cirrhosis. It is now evident that mitochondrial dysfunction could be responsible for alcoholic liver disease (ALD). The challenge in treating ALD has been the limited availability of hepatoprotective agents and the lack of highly efficient delivery systems. Recent studies have shown that mitochondria-targeted therapies could address mitochondrial dysfunction (MD), which may greatly improve hepatoprotection and ALD treatment. This mini-review discusses the potential role of mitochondria-targeted antioxidants (MTAs) in the maintenance of hepatocellular integrity. This report also considers the mechanism of liver injury induced by alcohol and the progression of ALD from a mitochondrial oxidative damage perspective as well as the possible mechanistic actions of hepatoprotective antioxidants. Preliminary studies suggest the prospect of MTAs as anti-ALD and hepatoprotective agents.

Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to be purely stochastic processes, very recent genomic analyses have shown that temporal tumor evolution in CCRCC may follow some deterministic pathways that give rise to different clones and sub-clones randomly spatially distributed across the tumor. This fact makes each case unique, unrepeatable and unpredictable. Precise and complete molecular information is crucial for patients with cancer since it may help in establishing a personalized therapy. Intratumor heterogeneity (ITH) detection relies on the correctness of tumor sampling and this is part of the pathologist’s daily work. International protocols for tumor sampling are insufficient today. They were conceived decades ago, when ITH was not an issue, and have remained unchanged until now. Noteworthy, an alternative and more efficient sampling method for detecting ITH has been developed recently. This new method, called multisite tumor sampling (MSTS), is specifically addressed to large tumors that are impossible to be totally sampled, and represent an opportunity to improve ITH detection without extra costs.

The RAINBOW Phase III study established the efficacy of the combination of paclitaxel and ramucirumab, a monoclonal antibody targeting VEGF receptor-2 (VEGF-R2), as second-line therapy. We retrospectively analyzed the data of patients treated with ramucirumab plus paclitaxel at our Institution to evaluate the impact of clinical heterogeneous figures on the efficacy and safety of this combination paclitaxel/ramucirumab in a real- life cohort of patients. After a median follow-up of 10.74 months, the median progression-free survival (PFS) was 5.8 months (95% CI: 3.04 - 5,63). Disease control rate (DCR) was 61% and the median duration of response (DOR) was 5.8 months. Median overall survival (OS) was 8.3 months. A trend toward better outcome was observed in HER2 positive patients. In multivariate analysis, nutritional status (p = 0.0001) and number of metastatic sites (p = 0.0266) resulted significantly related with longer PFS. Our analysis confirmed the efficacy and safety of the combination of ramucirumab with paclitaxel also in the real-life practice and the median PFS is significantly longer than that reported for Western population in previous studies. Subgroup analysis confirms the key-role of nutritional status as prognostic factor and suggests a possible interaction between EGF and angiogenesis pathways that deserves further investigations.

Delivery of drugs through the nasal route provides an alternative, yet highly efficacious modality for administering both large and small pharmaceutic molecules. This method proves particularly advantageous for drugs that are unstable during oral administration, as they undergo significant degradation in the gastrointestinal tract or metabolization through the first-pass effect in the liver. Nasal administration stands as a viable alternative to parenteral therapy and is also suitable for long-term medical management. The nasal mucosa, characterized by high vascularity and permeability, facilitates rapid pharmaceutical absorption, ensuring a swift onset of therapeutic action. Despite its noninvasive nature, the nasal delivery technique finds broad applicability for both local treatment and systemic therapy, as the drug directly enters systemic circulation. This article explores the feasibility of a novel spray delivery mechanism for intranasal drug deposition. The study aims to determine whether users can correctly follow the state-of-the-art application instructions for a nasal spray with an optimal nozzle placement angle (namely, 12-15°) at the nostril while maintaining sufficient safety and efficacy, and without engaging in preventable usage errors that could harm the user. Additionally, the study evaluates the effectiveness of device labeling, instructions for use, and a short video in supporting the correct application of the nasal spray at the optimal angle (12-15°) and assesses whether users can differentiate the product from others with similar appearances. We have also performed physical spray tests to experimentally evaluate drug penetration to the nasopharynx (a key target site for viral infections) for two different nozzle placements – one for current package instructions coming with over-the-counter spray products and the other for the optimal spray usage procedure to enhance targeted drug delivery. Human Factors (HF) validation studies were also conducted, instructing users to follow the application instructions of the nasal spray bottle with the nozzle placed at the optimal angle to target the nasopharynx. The experimental tests consistently confirmed improved penetration with the 12-15° nozzle placement, with visual cues proving effective when used in tandem with written instructions for guiding the study participants to adhere to the recommended usage procedures.

Triple negative breast cancer (TNBC) has a higher mRNA expression of programmed cell death ligand 1 (PD-L1) which is a ligand to programmed cell death protein 1 (PD-1). The binding of the ligand leads to suppressed activity of T-cell-mediated immune response against cancer cells. The approval of anti-PD-L1 drugs including pembrolizumab and atezolizumab in subgroups of TNBC offer potential improvement to the current treatment regimens available for TNBC. We conducted a meta-analysis to review the efficacy of pembrolizumab and atezolizumab for the treatment of TNBC in both adjuvant and neo-adjuvant settings. A systematic strategy was used as per the PRISMA 2020 statement. All statistical analyses were conducted using Review Manager 5.4. Outcome measures included objective response rate, progression free survival, overall survival in adjuvant therapy groups, and pathological complete response rates in neoadjuvant groups. Six clinical trials were included. For adjuvant therapies, the ORR (OR=1.26, P = 0.04) of Atezolizumab/Pembrolizumab plus chemotherapy was higher in intention to treat (ITT) arms than the placebo groups in TNBC. A positive effect size was found for PFS in the ITT arms (Cohen’s d = 1.55, P<0.001). The Atezolizumab plus chemotherapy group had a positive effect size for OS compared to the control groups (Cohen’s d = 0.52, P<0.001). In the neo-adjuvant setting, patients in ITT arms had higher pCR rates as compared to the control groups (OR= 1.61, P = 0.001). Our findings collate evidence of pembrolizumab and atezolizumab as a viable treatment option among patients with TNBC with PDL1+ subgroups deriving benefits.

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.

Background: We assess locoregional drug targeting effectiveness of intraoperative (IO) cryoprobe-assisted injection of blue dye (BD) and cytotoxic-tracer mixture (TTM), in VX2 tumor model, and its translational value to cryo-assisted breast tumor surgery with BD alone. Methods: Under computed tomography (CT) guidance, we injected two ml TTM in five aliquots in the margin of 16 frozen or normothermic VX2 tumors. We evaluated the IO and post-operative drug targeting and therapeutic efficacy in tumor-host interface (T-HI) by CT, gross examination, and histopathology. In twenty-six T1 to T4 primary breast cancer (BRCA) we performed ultrasound-guided (US) cryoprobe-assisted tumor freezing, BD guided lymphatic mapping, and surgery. We evaluated, IO and in freshly resected specimen, BD distribution pattern in T-HI, lymph node(s), breast parenchyma, and resection cavity. Results: Fluids-impervious frozen VX2 or breast tumor transported drug(s) an arc-like pattern at T-HI regardless of freeze dose, number of freeze-thaw cycles, drug dose fractionation, tumor characteristics or dimensions. During melting, TTM spread within fifty percent VX2 tumor mirrored that of T-HI; it was massive in normothermia. In VX2 twenty percent focal margin necrosis at pathology coincided with CT gap; in both studies, BD dose-staining spread in T-HI and tumor was linear. Eighty-four patients had one to twelve stained axillary lymph nodes; sixty-nine percent and all respectively, had another quadrant and resection cavity stained. Conclusion: Intraoperative freezing-assisted drug delivery and targeting techniques during cryoablation of VX2 tumor translate successfully to locoregional BD targeting, lymphatic mapping during cryo-assisted surgery of breast cancer.

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeding events (one severe and three mild) in three patients were considered treatment-related. No significant fibrinogen reductions were reported. Greater improvement in mean P/F ratio from baseline to end of study was observed in C1 compared with MHC [C1; 154 to 299 vs MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in P/F ratio was observed in NIRS patients [NIRS; 126 to 240 vs IMV; 120 to 188) and they required fewer treatment days (NIRS; 7.86 vs IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, showing a trend of improved oxygenation and faster recovery in patients with acute COVID-19-induced respiratory failure requiring respiratory support; this effect was more pronounced in the NIRS group. Further investigation is required to study the potential of this novel treatment approach.

Advances in nanomedicine bring the attention of researchers to the molecular targets which can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide on the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby the recent advances in the field of applications of various nanoplatforms which are able to reach the GRPR expressing cells are reviewed.

Safe administration of highly cytotoxic chemotherapeutic drugs is a challenging problem in cancer treatment due to the adverse side effects and collateral damage to non-tumorigenic cells. To mitigate these problems, new promising approaches, based on the paradigm of controlled targeted drug delivery (TDD), utilizing drug nanocarriers with biorecognition ability to selectively target neoplastic cells, are being considered in cancer therapy. Herein, we report on the design and testing of a nanoparticle-grid based biosensing platform to aid in the development of new targeted drug nanocarriers. The proposed sensor grid consists of superparamagnetic gold-coated core-shell Fe₂Ni@Au nanoparticles, further functionalized with folic acid targeting ligand, model thiolated chemotherapeutic drug doxorubicin (DOX), and a biocompatibility agent, 3,6,-dioxa-octanethiol (DOOT). The employed dual transduction based on electrochemical and enhanced Raman scattering detection have enabled efficient monitoring of the drug loading onto the nanocarriers, attached to the sensor surface, as well as the drug release under simulated intracellular conditions. The grid’s nanoparticles serve here as the model nanocarriers for new TDD systems under design and optimization. The superparamagnetic properties of the Fe₂Ni@Au NPs aid in nanoparticles’ handling and constructing a dense sensor grid with high plasmonic enhancement of the Raman signals due to the minimal interparticle distance.

There is a rich history of cancer treatments which provides a number of important lessons for present and future cancer therapies. We outline this history by looking in the past, reviewing the current landscape of cancer treatments, and by glancing at the potential future cancer therapies.

Glioblastoma multiforme (GBM) is a glioma and the most aggressive type of brain tumor with a dismal average survival time, despite the standard of care. One promising alternative therapy is boron neutron capture therapy (BNCT), which is a noninvasive therapy for treating locally invasive malignant tumors, including glioma. BNCT involves boron-10-released radiation directly into tumor cells with minimal damage to healthy tissues. This therapy lacks clinically approved targeted blood-brain-barrier-permeating delivery vehicles for therapeutic drug/ boron-10. Nanoparticles, particularly gold nanoparticles (GNPs), are selective and effective drug-delivery vehicles because of their desirable properties, facile synthesis, and biocompatibility. This review discusses historical and current GNP therapeutic applications as a drug delivery vehicle for treating glioma. Furthermore, GNPs loaded with therapeutic drugs, imaging agents, and GBM-targeting antibodies/ peptides to treat GBM will be discussed. Additionally, the importance of upper and lower limits on therapeutic efficacy will be described and explored followed by highlighting their advantages, limitations, and possible toxicity. Recent research and selected important findings for GNP-mediated pharmaceutics in GBM will also be considered.

Prostate cancer (PCa) is a major cause of cancer-related mortality worldwide, with a rising incidence observed over the years. The androgen receptor (AR) signaling pathway plays a pivotal role in male development and maintaining masculine characteristics. Dysregulation of AR signaling in prostate cancer can lead to disease progression and resistance to standard therapies. Understanding the intricate regulation and function of AR in both healthy and diseased states is crucial for developing effective treatment strategies. This review comprehensively explores the role of androgen receptors in prostate cancer susceptibility, disease progression, and treatment response by analyzing recent literature. An extensive search of peer-reviewed publications in major databases, including PubMed, Scopus, and Web of Science, was conducted using specific keywords related to androgen receptor, prostate cancer, disease progression, and treatment resistance. Relevant conference abstracts and clinical trial reports were also included. The review presents an overview of the role of androgen receptors in prostate cancer initiation, progression, and treatment resistance. It highlights emerging biomarkers associated with AR signaling dysregulation and their potential utility for early detection and personalized treatment approaches. Additionally, recent advances in targeting the AR pathway for novel therapeutic strategies to improve patient outcomes and overcome treatment resistance in advanced prostate cancer are discussed. The findings contribute to a comprehensive understanding of the AR signaling pathway in prostate cancer and offer insights into its multifaceted role in disease development and treatment response. They may pave the way for innovative therapeutic interventions and precision medicine approaches based on specific AR signaling profiles, enhancing patient care and reducing the burden of this lethal disease.

DNA origami has emerged in recent years as a powerful technique for designing and building 2D and 3D nanostructures. While the breadth of structures that have been produced is impressive, one of the remaining challenges, especially for DNA origami structures intended to carry out useful biomedical tasks in vivo, is to endow them with the ability to detect and respond to molecules of interest. Target molecules may be disease indicators or cell surface receptors, and the responses may include conformational changes leading to release of therapeutically relevant cargo. Nucleic acid aptamers are ideally suited to this task and are beginning to be used in DNA origami designs. In this review we consider examples of uses of DNA aptamers in DNA origami structures and summarise what is currently understood regarding aptamer-origami integration. We review three major roles for aptamers in such applications: protein immobilisation, triggering of structural transformation, and cell targeting. Finally, we consider future perspectives for DNA aptamer integration with DNA origami.

The breeding of stress-tolerant cultivated plants that would allow for a reduction in harvest losses and undesirable decrease in quality attributes requires a new quality of knowledge on molecular markers associated with relevant agronomic traits, on quantitative metabolic responses of plants on stress challenges, and on the mechanisms controlling the biosynthesis of these molecules. By combining metabolomics with genomics, transcriptomics and proteomics datasets a more comprehensive knowledge of the composition of crop plants used for food or animal feed is possible. In order to optimize crop trait developments, to enhance crop yields and quality, as well as to guarantee nutritional and health factors, that provides the possibility to create functional food or feedstuffs, the knowledge about the plants’ metabolome is crucial. Next to classical metabolomics studies, this review focusses on several metabolomics based working techniques, such as sensomics, lipidomics, hormonomics and phytometabolomics, which were used to characterize metabolome alterations during abiotic and biotic stress, to find resistant food crops with a preferred quality or at least to produce functional food crops are highlighted.

It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis.

The psychedelic renaissance has reignited interest in the therapeutic potential of psychedelics for mental health and well-being. An emerging area of interest is the potential modulation of psychedelic effects by the gut microbiome - the ecosystem of microorganisms residing in our digestive tract. This review explores the intersection of the gut microbiome and psychedelic therapy, underlining potential implications for personalized medicine and mental health. We delve into the current understanding of the gut-brain axis, its influence on mood, cognition, and behavior, and how the microbiome may affect the metabolism and bioavailability of psychedelic substances. We also discuss the role of microbiome variations in shaping individual responses to psychedelics, along with potential risks and benefits. Moreover, we consider the prospect of microbiome-targeted interventions as a fresh approach to boost or modulate psychedelic therapy's effectiveness. By synthesizing insights from the fields of psychopharmacology, microbiology, and neuroscience, our objective is to advance knowledge about the intricate relationship between the microbiome and psychedelic substances, thereby paving the way for novel strategies to optimize mental health outcomes amid the ongoing psychedelic renaissance.

Generating long-lived mucosal and systemic antibodies through respiratory immunization with protective antigens encapsulated in nanoscale biodegradable particles could potentially decrease or eliminate the incidence of many infectious diseases but requires incorporation of a suitable mucosal immunostimulant. We previously found that respiratory immunization with a model protein antigen (LPS-free OVA) encapsulated in PLGA 50:50 nanoparticles (~380 nm diameter) surface modified with complement peptide-derived immunostimulant 02 (CPDI-02; formerly EP67) through 2kDa PEG linkers increases mucosal and systemic OVA-specific memory T-cells with long-lived surface phenotypes in young, naïve female C57BL/6 mice. Here, we determined if respiratory immunization with LPS-free OVA encapsulated in similar PLGA 50:50 microparticles (~1 μm diameter) surface modified with CPDI-02 (CPDI-02-MP) increases long-term OVA-specific mucosal and systemic antibodies. We found that, compared to MP surface modified with inactive, scrambled scCPDI-02 (scCPDI-02-MP), intranasal administration of CPDI-02-MP in 50 μL sterile PBS greatly increased titers of short-term (14 days post-immunization) and long-term (90 days post-immunization) antibodies against encapsulated LPS-free OVA in nasal lavage fluids, bronchoalveolar lavage fluids, and sera of young, naïve female C57BL/6 mice. Thus, surface modification of biodegradable microparticles with CPDI-02 is likely to increase long-term mucosal and systemic antibodies against encapsulated protein antigen after respiratory and possibly other routes of mucosal immunization.

Biomarker directed selection of targeted anti-neoplastic agents such as immune check-point inhibitors, small molecule inhibitors and monoclonal antibodies form an important aspect of cancer treatment. Immunohistochemistry (IHC) analysis of the tumor tissue is the method of choice to evaluate the presence of these biomarkers. However, a significant barrier to biomarker testing on tissue is the availability of an adequate amount of tissue and need for repetitive sampling due to tumor evolution. Also, tumor tissue testing is not immune to inter- and intra-tumor heterogeneity. We describe the analytical and clinical validation of a Circulating Tumor Cell (CTC) assay to accurately assess the presence of PD-L1 22C3 and PD-L1 28.8, ER, PR and HER2, from patients with solid tumors to guide the choice of suitable targeted therapies. Analytically, the test has high sensitivity, specificity, linearity and precision. Based on a blinded case control study, the clinical sensitivity and specificity for PD-L1 (22C3 and 28.8) was determined to be 90% and 100% respectively. The clinical sensitivity and specificity was 83% and 89% for ER; 80% and 94% for PR; 63% and 89% for HER2 (by ICC); and 100% and 92% for HER2 (by FISH), respectively. The performance characteristics of the test support its suitability and adaptability for routine clinical use.

Over recent years, nanocarriers have played an ever-increasing role in clinical and biomedical applications owing to their unique physicochemical properties and surface functionalities. Lately, much effort has been directed towards the development of smart, stimuli-responsive nanocarriers that are capable of releasing their cargos in response to specific stimulus. These intelligent-responsive nanocarriers can be further surface-functionalized so as to achieve active tumor targeting in a sequential manner, which can be simply modulated by the stimuli. By applying this methodological approach, these intelligent-responsive nanocarriers can be directed to different target-specific organs, tissues or cells, and exhibit on-demand controlled drug release that may enhance therapeutic effectiveness and reduce systemic toxicity. Light, an external stimulus, is one of the most promising triggers for use in nanomedicine to stimulate on-demand drug release from nanocarriers. Light-triggered drug release can be achieved by light irradiation at different wavelengths, either in UV, visible or even NIR region, depending on the photophysical properties of the photo-responsive molecule embedded in the nanocarrier system, the structural characteristics and material composition of the nanocarrier system. In this review, we highlighted the emerging functional role of light in nanocarriers, with emphasis on light-responsive liposomes and dual-targeted stimuli-responsive liposomes. Moreover, we provided the up-to-date phototriggered targeting strategies and mechanisms of light-triggered drug release from liposomes and NIR-responsive nanocarriers. Lastly, we addressed the current challenges, advances, and future perspectives for the deployment of light-responsive liposomes in targeted drug delivery and therapy.

Alzheimer’s Disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induces adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that mitochondria in AD dendrites exist primarily as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple mitochondria-ER contact sites (MERCS) known to contribute to abnormal lipid and calcium homeostasis. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis. These data provide novel information on the role MOAS play in AD and additional support for further development of partial MCI inhibitors as disease modifying strategy for AD.

Background: Newer personalized medicine including targeted therapies such as PARP inhibitors and CDK 4/6 inhibitors have shown to improve survival of breast and gynaecological cancer patients. However, efficacy outcomes may be hampered by treatment discontinuation due to targeted therapy-related adverse drug reactions or resistance. Studies suggest that add-on mistletoe (Viscum album L., VA) improves quality of life and ameliorates cytotoxic side effects of standard oncological therapy in cancer patients. The primary objective of this real-world data study was to determine the safety profile of targeted therapy in combination with add-on Helixor® VA therapy in breast and gynecological cancer patients. Methods: The present study is a real-world data study utilizing demographic and treatment data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted with or without Helixor® VA therapy as well as safety - associated variables were evaluated by univariate and adjusted multivariable regression analyses. Results: All stage breast or gynecological cancer patients (n = 242) were on average 54.5±14.2 years old. One hundred and sixty patients (66.1%) were in the control (CTRL, targeted therapy) and 82 patients (33.9%) in the combinational (COMB, targeted plus Helixor® VA therapy) group. The addition of Helixor® VA did not hamper the safety profile (χ2 = 0.107, p-value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group. Conclusions: The present study is the first of its kind showing the applicability of Helixor® VA in combination with targeted therapies. The results indicate that add-on Helixor® VA does not negatively alter the safety profile of targeted therapies in breast and gynaecological cancer patients.

Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic vasculature forming in the regenerating tissues has a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine

SARS-CoV-2 Omicron variant spike RBD epitopes in complex with spike (S) -protein D614G mutations now predominate globally and increase infectivity by assembling more functional S proteins into the virion. On average, homeopathic medicine contains less than one molecule per dose on average. Single variable SphericalHarmonicY, LaguerreL, WhittakerM, SphericalBesselJ, LegendreP, LegendreQ, LaguerreL, ChebyshevT, and Hypergeometric1F1 Functions pFqarise in connection with the power series solution of the Schrodinger equation or in the summation of perturbation expansions in quantum mechanics. A quantum interpretation of the homeopathic method is presented here through a novel algebraic topology approach to supersymmetry and symmetry breaking in quantum fields and quantum gravity theory with the aim of developing a wide range of physical-based drug design applications in a Small Molecule Quantized Water Memory Network suggesting that the Hidden Black Hole Paradox of Information Loss might be solved under suitable conditions.

The SARS-CoV-2 virus that causes the COVID-19 disease has wreaked havoc on the world community in terms of every imaginable parameter. The research output on COVID-19 has been nothing short of phenomenal, especially in the medical and biomedical sciences, where the search for a potential vaccine is being conducted in earnest. Much of the advanced research has been distributed in the leading medical journals, including the Journal of the American Medical Association (JAMA), where the latest research is distributed on a daily basis. The purpose of this paper is to provide some perspectives on 44 interesting and highly topical research papers that have been published in JAMA, at the time of writing, within the past two weeks. The diverse topics include public health, general medicine, internal medicine, oncology, paediatrics, geriatrics, and biostatistics.