Preventive and therapeutic effects of a super-multivalent sialylated filamentous bacteriophage against the influenza virus.

The resurgence of influenza viruses as a significant global threat emphasizes the urgent need for innovative antiviral strategies beyond existing treatments. Here, we present the development and evaluation of a novel super-multivalent sialyllactosylated filamentous phage, termed t-6SLPhage, as a potent entry blocker for influenza A viruses. Structural variations in sialyllactosyl ligands, including linkage type, valency, net charge, and spacer length, were systematically explored to identify optimal binding characteristics against target hemagglutinins and influenza viruses. The selected SLPhage equipped with optimal ligands, exhibited exceptional inhibitory potency in in vitro infection inhibition assays. Furthermore, in vivo studies demonstrated its efficacy as both a preventive and therapeutic intervention, even when administered post-exposure at 2 days post-infection, under 4 lethal dose 50% conditions. Remarkably, co-administration with oseltamivir revealed a synergistic effect, suggesting potential combination therapies to enhance efficacy and mitigate resistance. Our findings highlight the efficacy and safety of sialylated filamentous bacteriophages as promising influenza inhibitors. Moreover, the versatility of M13 phages for surface modifications offers avenues for further engineering to enhance therapeutic and preventive performance.

Novel strategies in HPV­16­related cervical cancer treatment: An in vitro study of combined siRNA-E5 with oxaliplatin and ifosfamide chemotherapy.

BACKGROUND: Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies. METHODS: The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay. RESULTS: E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10-8 M (45.36 µg/ml) to 6.71 × 10-8 M (26.66 µg/ml) and Ifosfamide from 12.52 × 10-5 M (32.7 µg/ml) to 8.206 × 10-5 M (21.43 µg/ml). Flow cytometry analysis demonstrated a significant increase in apoptosis for combination treatments, with apoptosis rates rising from 11.02 % (Oxaliplatin alone) and 16.98 % (Ifosfamide alone) to 24.8 % (Oxaliplatin + E5-siRNA) and 34.9 % (Ifosfamide + E5-siRNA). The sub-G1 cell population increased from 15.7 % (Oxaliplatin alone) and 18 % (Ifosfamide alone) to 21.9 % (Oxaliplatin + E5-siRNA) and 27.1 % (Ifosfamide + E5-siRNA), indicating cell cycle arrest. The colony formation assay revealed a substantial decrease in the number of colonies following combination treatment. qRT-PCR analysis showed decreased expression of stemness-related genes CD44 and Nanog, and migration-related genes MMP2 and CXCL8 in the combination groups. Apoptosis-related genes Casp-3, Casp-9, and pP53 showed increased expression following combination therapy, while BAX expression increased and BCL2 expression decreased relative to the control. CONCLUSION: The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.

Endosialin-positive CAFs promote hepatocellular carcinoma progression by suppressing CD8+ T cell infiltration.

BACKGROUND AND AIMS: Endosialin, also known as tumor endothelial marker1 or CD248, is a transmembrane glycoprotein that is mainly expressed in cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known. APPROACH AND RESULTS: The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (ENKO) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from ENKO mice had increased CD8+ T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8+ T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9/10 expression and secretion, resulting in the suppression of CD8+ T cell infiltration. High level of endosialin protein expression was correlated with low CD8+ T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually. CONCLUSIONS: Endosialin could inhibit CD8+ T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.

Use of, time to, and type of first add-on anti-hyperglycaemic therapy to metformin in Australia, 2018-2022.

AIMS: The aim of this study was to examine contemporary trends in the use of, time to, and type of first add-on anti-hyperglycaemic therapy to metformin in Australia. METHODS: We used the dispensing records of a 10% random sample of Pharmaceutical Benefits Scheme (PBS) eligible people. We included people aged 40 years and older initiating metformin from 1 January 2018 to 31 December 2020. Our primary outcome was first add-on anti-hyperglycaemic medicine within 2 years of metformin initiation. We analysed time to dispensing of first add-on therapy. All analyses were stratified by metformin initiation year. RESULTS: Overall, 38 747 people aged 40 years and older initiated metformin between 2018 and 2020. Approximately one-third (n = 12 946) of people received add-on therapy with the proportion increasing slightly by year of metformin initiation (32.3% in 2018 to 34.8% in 2020). Amongst people with add-on therapy following metformin initiation, sodium-glucose cotransporter 2 inhibitor (SGLT2i) use increased from 28.8% (2018) to 35.0% (2020), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) increased from 3.0% to 9.6%, respectively. Dipeptidyl peptidase-4 inhibitors and sulfonylureas as first add-on therapy decreased and insulin remained stable. One-third of people with add-on therapy initiated the therapy on the same day metformin was initiated, i.e. initial combination therapy. CONCLUSIONS: Amongst people initiating metformin from 2018 to 2020, there was an increasing proportion of SGLT2i and GLP-1 RA being used as first add-on therapy. However, the overall prevalence of add-on therapy was low. Advocacy to promote add-on therapy with cardiorenal beneficial medicines is critical to reduce type 2 diabetes morbidity and mortality.

Glucose oxidase and MnO2 functionalized liposome for catalytic radiosensitization enhanced synergistic breast cancer therapy.

In recent years, the integration of radiotherapy and nanocatalytic medicine has gained widespread attention in the treatment of breast cancer. Herein, the glucose oxidase (GOx) and MnO2 nanoparticles co-modified multifunctional liposome of GOx-MnO2@Lip was constructed for enhanced radiotherapy. Introduction of GOx would not only elevate the glucose consumption to starve the cancer cells, but also increased the endogenous H2O2 level. Meanwhile, high intracellular GSH concentration facilitated the release of Mn2+ to amplify the cytotoxic ·OH through cascade catalytic reactions within the tumor microenvironment, resulting in a favorable tumor suppression rate of 74.45 %. Furthermore, the blood biochemical and blood routine demonstrated that GOx-MnO2@Lip had no obvious toxic side effects. Therefore, this work provided a potential vehicle for synergistic cancer starving therapy, chemodynamic therapy and radiotherapy for improving therapeutic efficacy of breast cancer.

Potential therapeutic option for EGFR-mutant small cell lung cancer transformation: a case report and literature review.

Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is rare and is associated with poor prognosis. However, the standard treatment protocols for patients with SCLC transformation remain unknown. Here, we report the case of a patient with advanced EGFR exon 19 deletion (19del) NSCLC who underwent SCLC transformation during targeted therapy. Biopsies and genetic testing were performed to adjust treatment regimens accordingly. The patient responded favorably to a combined treatment regimen comprising etoposide plus cisplatin chemotherapy and adebrelimab plus osimertinib. This case highlights the critical importance of acknowledging tumor heterogeneity in clinical decision-making and identifying potentially effective treatment options for patients with SCLC transformation. Additionally, we reviewed cases of the transformation of NSCLC to SCLC from 2017 to 2023.

Copper and Manganese Complexes of Pyridinecarboxaldimine Induce Oxidative Cell Death in Cancer Cells.

Leveraging the versatile redox behavior of transition metal complexes with heterocyclic ligands offers significant potential for discovering new anticancer therapeutics. This study presents a systematic investigation of a pyridinecarboxaldimine ligand (PyIm) with late 3d-transition metals inhibiting cancer cell proliferation and the mechanism of action. Synthesis and thorough characterization of authentic metal complexes of redox-active late 3d-transition metals enabled the validation of antiproliferative activity in liver cancer cells. Notably, (PyIm)2Mn(II) (1) and (PyIm)2Cu(II) (5) complexes exhibited a good inhibitory profile against liver cancer cells (EC50: 4.0 µM for 1 and 1.7 µM for 5) with excellent selectivity over normal kidney cells (Selectivity index, SI = 17 for 5). Subsequently, evaluation of these complexes in cancers cell lines from four different sites of origin (liver, breast, blood, and bone) demonstrated a predominant selectivity to liver and a moderate selectivity to breast cancer and leukemia cells over the normal kidney cells. The mechanism of action studies highlighted no expected DNA damage in cells, rather, the enhancement of extracellular and intracellular reactive oxygen species (ROS) resulting in mitochondrial damage leading to oxidative cell death in cancer cells. Notably, these complexes potentiated the antiproliferative effect of commercially used cancer therapeutics (cisplatin, oxaliplatin, doxorubicin, and dasatinib) in liver cancer cells. These findings position redox-active metal complexes for further evaluation as promising candidates for developing anticancer therapeutics and combination therapies.

Generation of Novel Tumour-Selective SEA Superantigen-Based Peptides with Improved Safety and Efficacy for Precision Cancer Immunotherapy.

Bacterial superantigens are T-cell-stimulatory protein molecules which produce massive cytokines and cause human diseases. Due to their ability to activate up to 20% of resting T-cells, they have effectively killed T-cell-dependent tumours in vivo. However, the intrinsic toxicity of whole SAg molecules highlights the urgent need to develop more effective and safer SAg-based immunotherapy. With its unique approach, our study is a significant step towards developing safer tumour-targeted superantigen peptides (TTSP). We identified the T-cell activation function regions on the SEA superantigen and produced variants with minimal lethality, ensuring a safer approach to cancer treatment. This involved the creation of twenty 50-amino-acid-long overlapping peptides covering the full-length SEA superantigen (P1-P20). We then screened these peptides for T-cell activation, successfully isolating two peptides (P5 and P15) with significant T-cell activation. These selected peptides were used to design and synthesise tumour-targeted superantigen peptides, which were linked to a cancer-specific third loop (L3) of transforming growth factor-α (TGF-α), TGFαL3 from either a C' or N' terminal with an eight-amino-acid flexible linker in between. We also produced several P15 variants by changing single amino acids or by amino acid deletions. The novel molecules were then investigated for cytokine production and tumour-targeted killing. The findings from our previous study and the current work open up new avenues for peptide-based immunotherapy, particularly when combined with other immunotherapy techniques, thereby ensuring effective and safer cancer treatment.

CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells.

Radiation therapy continues to be the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Therefore, the identification of drugs that promote the ionizing radiation (IR)-induced activation of p53 is expected to increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, while their combination did not result in further decreases. CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53.

Updates on CAR T cell therapy in multiple myeloma.

Multiple myeloma (MM) is a hematological cancer characterized by the abnormal proliferation of plasma cells. Initial treatments often include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). Despite salient progress in diagnosis and treatment, most MM patients typically have a median life expectancy of only four to five years after starting treatment. In recent developments, the success of chimeric antigen receptor (CAR) T-cells in treating B-cell malignancies exemplifies a new paradigm shift in advanced immunotherapy techniques with promising therapeutic outcomes. Ide-cel and cilta-cel stand as the only two FDA-approved BCMA-targeted CAR T-cells for MM patients, a recognition achieved despite extensive preclinical and clinical research efforts in this domain. Challenges remain regarding certain aspects of CAR T-cell manufacturing and administration processes, including the lack of accessibility and durability due to T-cell characteristics, along with expensive and time-consuming processes limiting health plan coverage. Moreover, MM features, such as tumor antigen heterogeneity, antigen presentation alterations, complex tumor microenvironments, and challenges in CAR-T trafficking, contribute to CAR T-cell exhaustion and subsequent therapy relapse or refractory status. Additionally, the occurrence of adverse events such as cytokine release syndrome, neurotoxicity, and on-target, off-tumor toxicities present obstacles to CAR T-cell therapies. Consequently, ongoing CAR T-cell trials are diligently addressing these challenges and barriers. In this review, we provide an overview of the effectiveness of currently available CAR T-cell treatments for MM, explore the primary resistance mechanisms to these treatments, suggest strategies for improving long-lasting remissions, and investigate the potential for combination therapies involving CAR T-cells.

Advances in research on potential therapeutic approaches for Niemann-Pick C1 disease.

Niemann-Pick disease type C1 (NP-C1) is a rare and devastating recessive inherited lysosomal lipid and cholesterol storage disorder caused by mutations in the NPC1 or NPC2 gene. These two proteins bind to cholesterol and cooperate in endosomal cholesterol transport. Characteristic clinical manifestations of NP-C1 include hepatosplenomegaly, progressive neurodegeneration, and ataxia. While the rarity of NP-C1 presents a significant obstacle to progress, researchers have developed numerous potential therapeutic approaches over the past two decades to address this condition. Various methods have been proposed and continuously improved to slow the progression of NP-C1, although they are currently at an animal or clinical experimental stage. This overview of NP-C1 therapy will delve into different theoretical treatment strategies, such as small molecule therapies, cell-based approaches, and gene therapy, highlighting the complex therapeutic challenges associated with this disorder.

Combined miR-181a-5p and Ag Nanoparticles are Effective Against Oral Cancer in a Mouse Model.

Purpose: Oral squamous cell carcinoma is the most common type of malignant tumor in the head and neck region. Despite advancements, metastasis and recurrence rates remain high, and patient survival has not significantly improved. Although miRNA therapies are promising for cancer gene therapy, their applications in treating oral cancer are limited. Targeted medication delivery systems based on nanotechnology offer an efficient way to enhance oral cancer treatment efficacy. Methods: We synthesized nanosilver (AgNPs) and loaded them with the tumor suppressor miR-181a-5p. In vitro experiments were conducted to investigate the inhibitory effects of AgNPs and their composites on the malignant behavior of oral cancer cell lines. The xenograft experiment was utilized to examine their effects on tumorigenesis and the potential molecular mechanisms involved. Results: The nanosilver exhibited a spherical morphology with a size distribution ranging from 50 to 100 nm. They exhibited a distinct absorption peak at 330 nm and could be excited to emit green fluorescence. The biocompatible AgNPs effectively shielded miRNA from degradation by RNase and serum. The nanocomposites significantly inhibited the proliferation, invasion, migration, and colony formation of oral cancer cell lines. Notably, treatment with the nanocomposites resulted in substantial tumor growth suppression in the xenograft model. Mechanistically, these composites directly targeted BCL2 and exerted their antitumor effects by suppressing the ß-catenin signaling pathway and other downstream genes without inducing acute toxicity. Conclusion: Collectively, the findings demonstrate that the miR-181a-5p/AgNPs combination significantly impedes the growth and progression of oral cancer both in vitro and in vivo, highlighting a pivotal role for the ß-catenin signaling pathway. This multifaceted approach holds promise as a prospective therapeutic strategy for oral cancer management in the future.

New strategies in soft tissue sarcoma treatment.

Soft tissue sarcomas (STS) have long been a formidable challenge in oncology, partly because of their rarity and diversity, which complicates large-scale studies and slows the advent of new treatments. Traditionally anchored by anthracycline-based chemotherapy, the landscape of STS treatment hasn't shifted dramatically in the past twenty years. However, recent strides in research are starting to paint a more hopeful picture. Leveraging advanced molecular profiling, researchers are now tailoring treatments to the unique genetic makeup of tumors, with targeted therapies showing promise. Innovations such as NTRK inhibitors for NTRK-rearranged sarcomas and gamma-secretase inhibitors for desmoid tumors are changing clinical practices. The rise of immunotherapy, including novel agents like LAG-3 inhibitors and bifunctional proteins that target both TGF-ß and PD-L1, offers new avenues for treatment, particularly when combined with traditional therapies like chemotherapy. Meanwhile, the approval of epigenetic treatments for specific sarcoma subtypes heralds a new wave of strategy based on histological specificity, which could lead to more personalized and effective care. While challenges remain, the field of STS treatment is evolving, driven by a deeper understanding of the disease's biological underpinnings and a commitment to innovative research approaches.

Development of a novel oncolytic adenovirus controlled by CDX2 promoter for esophageal adenocarcinoma therapy.

BACKGROUND: Prognosis of esophageal adenocarcinoma (EAC) is still poor. Therefore, the development of novel therapeutic modalities is necessary to improve therapeutic outcomes in EAC. Here, we report a novel promoter-controlled oncolytic adenovirus targeting CDX2 (Ad5/3-pCDX2) and its specific anticancer effect for EAC. METHODS: We used OE19, OE33, HT29, MKN28, RH30, and HEL299 cell lines. To establish CDX2 overexpressing OE19 cells, pCMV-GLI1 plasmid was transfected to OE19 (OE19 + GLI1). The virus replication and cytocidal effect of replication competent Ad5/3-pCDX2 were analyzed in vitro. Antitumor effect of Ad5/3-pCDX2 was assessed in xenograft mouse models by intratumoral injection of the viruses. Finally, efficacy of combination therapy with Ad5/3-pCDX2 and 5FU was evaluated. RESULTS: EAC cells and HT29 showed high mRNA levels of CDX2, but not MKN28, RH30, and HEL299. We confirmed that deoxycholic acid (DCA) exposure enhanced CDX2 expression in EAC cells and OE19 + GLI1 had persistent CDX2 overexpression without DCA. Ad5/3-pCDX2 showed stronger cytocidal effect in OE19 + GLI1 than OE19, whereas Ad5/3-pCDX2 did not kill CDX2-negative cells. Ad5/3-pCDX2 was significantly replicated in EAC cells and the virus replication was higher in OE19 + GLI1 and OE19 with DCA compared to OE19 without DCA exposure. In vivo, Ad5/3-pCDX2 significantly suppressed OE19 tumor growth and the antitumor effect was enhanced in OE19 + GLI1 tumor. In contrast, Ad5/3-pCDX2 did not show significant antitumor effect in MKN28 tumor. Moreover, Ad5/3-pCDX2 significantly increased the efficacy of 5FU in vitro and in vivo. CONCLUSIONS: Ad5/3-pCDX2 showed specific anticancer effect for EAC, which was enhanced by bile acid exposure. Ad5/3-pCDX2 has promising potential for EAC therapy in the clinical setting.

Nanodelivery Optimization of IDO1 Inhibitors in Tumor Immunotherapy: Challenges and Strategies.

Tryptophan (Trp) metabolism plays a vital role in cancer immunity. Indoleamine 2.3-dioxygenase 1 (IDO1), is a crucial enzyme in the metabolic pathway by which Trp is degraded to kynurenine (Kyn). IDO1-mediated Trp metabolites can inhibit tumor immunity and facilitate immune evasion by cancer cells; thus, targeting IDO1 is a potential tumor immunotherapy strategy. Recently, numerous IDO1 inhibitors have been introduced into clinical trials as immunotherapeutic agents for cancer treatment. However, drawbacks such as low oral bioavailability, slow onset of action, and high toxicity are associated with these drugs. With the continuous development of nanotechnology, medicine is gradually entering an era of precision healthcare. Nanodrugs carried by inorganic, lipid, and polymer nanoparticles (NPs) have shown great potential for tumor therapy, providing new ways to overcome tumor diversity and improve therapeutic efficacy. Compared to traditional drugs, nanomedicines offer numerous significant advantages, including a prolonged half-life, low toxicity, targeted delivery, and responsive release. Moreover, based on the physicochemical properties of these nanomaterials (eg, photothermal, ultrasonic response, and chemocatalytic properties), various combination therapeutic strategies have been developed to synergize the effects of IDO1 inhibitors and enhance their anticancer efficacy. This review is an overview of the mechanism by which the Trp-IDO1-Kyn pathway acts in tumor immune escape. The classification of IDO1 inhibitors, their clinical applications, and barriers for translational development are discussed, the use of IDO1 inhibitor-based nanodrug delivery systems as combination therapy strategies is summarized, and the issues faced in their clinical application are elucidated. We expect that this review will provide guidance for the development of IDO1 inhibitor-based nanoparticle nanomedicines that can overcome the limitations of current treatments, improve the efficacy of cancer immunotherapy, and lead to new breakthroughs in the field of cancer immunotherapy.

Unlocking T cell exhaustion: Insights and implications for CAR-T cell therapy.

Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.

Ceftazidime-avibactam: Combination therapy versus monotherapy in the challenge of pneumonia caused by carbapenem-resistant Klebsiella pneumoniae.

This research focused on evaluating the clinical results of patients suffering from pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP), who received treatment with either ceftazidime-avibactam (CZA) alone or in combination with other antibiotics. From January 2020 to December 2023, we retrospectively analyzed CRKP-related pneumonia patients treated in two Chinese tertiary hospitals. Mortality was measured at 14 and 30 days as the primary outcome. Secondary outcomes included the 14-day microbiological cure rate and the 14-day clinical cure rate. Factors contributing to clinical failure were evaluated via both univariate analysis and multivariate logistic regression. To account for confounding factors, propensity score matching (PSM) was utilized. Among the 195 patients with CRKP infections, 103 (52.8 %) received CZA combination therapy, and 92 (47.2 %) patients received CZA monotherapy. The combination therapy group exhibited superior clinical and microbiological cure rates compared to the monotherapy group, with a 14-day clinical cure rate of 60.1 % vs. 45.7 % (P = 0.042) and a 14-day microbiological cure rate of 72.8 % vs. 58.6 % (P = 0.038), respectively. Combination therapy reduced mortality rates at 14 days (7.8 % vs. 17.4 %, P = 0.041), but not at 30 days (14.6 % vs. 25.0 %, P = 0.066). Even after using PSM, the group treated with the CZA combination continued to had a lower mortality rate at 14 days (5.9 % vs. 17.6 %, P = 0.039). The 14-day clinical cure rate for the combination therapy group was 63.2 %, and the 14-day microbial cure rate was 77.9 %. Both of these statistics were notably greater than those observed in the monotherapy group. Furthermore, the multivariate logistic regression model indicated a significant link between combination therapy and a decrease in clinical failure. Carbapenems were noted to be the most effective class of concomitant agents. Our findings indicate that patients with pneumonia due to CRKP benefit from combination treatment of CZA rather than monotherapy; administering carbapenem in combination with CZA in the early stages could provide considerable survival benefits.

Systematic Review and Meta-analysis Indicating Curcumin to Enhance the Synergistic Potential of Paclitaxel and Reduce Cell Viability, Tumor Volume, and Drug Resistance in Different Cancers.

BACKGROUND: To treat diseases like cancer, conventional Paclitaxel (PTX)- based monotherapy treatment regimens are becoming less effective due to the development of resistance. In this aspect, the phytomolecule curcumin (Cur), having ethnopharmacological importance in traditional South Asian remedies, like Ayurveda and Chinese traditional medicine, has been studied as a promising chemo-sensitizing and synergistic partner of PTX. AIM: This study aimed to evaluate the combined effect of PTX and Cur compared to PTX therapy alone in the in vitro and in vivo environments. MATERIAL AND METHODS: An extensive PubMed search was performed wherein 169 papers were shortlisted and screened to identify 30 studies that have reported the effect of PTX and Cur either in vitro, in vivo, or both. The pooled Odds Ratio (OR) was calculated at a 95% Confidence Interval (CI) for determining the effect of combination therapy. RESULTS: The meta-analysis has indicated PTX and Cur combination therapy to be associated with a significant decrease in cell viability (OR: 0.37, 95% CI: 0.27-0.51; p < 0.01) and tumor volume (OR: 0.32, 95% CI: 0.15-0.71; p = 0.01). Additionally, the effect of this combination on drug-resistant cell lines has exhibited a significant decrease in the odds of cell viability (OR: 0.45, 95% CI: 0.35-0.57; p < 0.01). CONCLUSION: Overall, the current meta-analysis has shown PTX and Cur combination to effectively inhibit the viability of cancer cells, reduce tumor volume, and diminish the growth of drug-resistant cancer cells.

Pathways to personalized medicine-Embracing heterogeneity for progress in clinical therapeutics research in Alzheimer's disease.

Biological and clinical heterogeneity is a major challenge in research for developing new treatments for Alzheimer's disease (AD). AD may be defined by its amyloid beta and tau pathologies, but we recognize that mixed pathologies are common, and that diverse genetics, central nervous system (CNS) and systemic pathophysiological processes, and environmental/experiential factors contribute to AD's diverse clinical and neuropathological features. All these factors are rational targets for therapeutic development; indeed, there are hundreds of candidate pharmacological, dietary, neurostimulation, and lifestyle interventions that show benefits in homogeneous laboratory models. Conventional clinical trial designs accommodate heterogeneity poorly, and this may be one reason that progress in translating candidate interventions has been so difficult. We review the challenges of AD's heterogeneity for the clinical trials enterprise. We then discuss how advances in repeatable biomarkers and digital phenotyping enable novel "single-case" and adaptive trial designs to accelerate therapeutics development, moving us closer to personalized research and medicine for AD. HIGHLIGHTS: Alzheimer's disease is diverse in its clinical features, course, risks, and biology. Typical randomized controlled trials are exclusive and necessarily large to attain arm comparability with broad outcomes. Repeated blood biomarkers and digital tracking can improve outcome measure precision and sensitivity. This enables the use of novel "single-case" and adaptive trial designs for inclusivity, rigor, and efficiency.

IMT-P8 potentiates Gram-positive specific antibiotics in intrinsically resistant Gram-negative bacteria.

Gram-negative bacteria (GNB) pose a major global public health challenge as they exhibit a remarkable level of resistance to antibiotics. One of the factors responsible for promoting resistance against a wide range of antibiotics is the outer membrane (OM) of Gram-negative bacteria. The OM acts as a barrier that prevents the entry of numerous antibiotics by reducing their influx (due to membrane impermeability) and enhancing their efflux (with the help of efflux pumps). Our study focuses on analyzing the effect of IMT-P8, a cell-penetrating peptide (CPP), to enhance the influx of various Gram-positive specific antibiotics in multi-drug resistant Gram-negative pathogens. In the mechanistic experiments, IMT-P8 permeabilizes the OM at the same concentrations at which it enhances the activity of various antibiotics against GNB. Cytoplasmic membrane permeabilization was also observed at these concentrations, indicating that IMT-P8 acts on both the outer and cytoplasmic membranes. IMT-P8 interferes with the intrinsic resistance mechanism of GNB and has the potential to make Gram-positive specific antibiotics effective against GNB. IMT-P8 extends the post-antibiotic effect and in combination with antibiotics shows anti-persister activity. The IMT-P8/fusidic acid combination is effective in eliminating intracellular pathogens. IMT-P8 with negligible toxicity displayed good efficacy in murine lung and thigh infection models. Based on these findings, IMT-P8 is a potential antibiotic adjuvant to treat Gram-negative bacterial infections that pose a health hazard.