Serotoninergic antidepressants combination in psilocybin-assisted psychotherapy: a case report.

Psilocybin has reemerged as a promising treatment for difficult-to-treat depression (DTD). Although there is limited evidence regarding interactions between psilocybin and other psychotropic drugs, clinical trials require that patients discontinue their antidepressants before study entry to isolate the benefits of psilocybin and to minimize the risk of adverse events. We present the first case of an adult patient with DTD who received psilocybin-assisted psychotherapy (PAP) in combination with two serotoninergic antidepressants (duloxetine and vortioxetine). Since he displayed a partial response after the first PAP session, he agreed to discontinue duloxetine (but refused to stop vortioxetine) before the second PAP session to see if it could improve the therapeutic efficacy of psilocybin. However, his anxiety and depressive symptoms worsened. Psilocybin was well-tolerated in both PAP sessions; mild headaches were the main adverse effects experienced by the patient, and there were no cardiovascular safety concerns. This case report suggests that serotoninergic antidepressants combination with psilocybin appears to be safe and that antidepressant discontinuation prior to PAP may not be necessary. Since the continuation of antidepressants during PAP has the potential to improve treatment acceptability and accessibility, future research should assess whether psilocybin can be administered concurrently with antidepressants.

Venetoclax combined with azacitidine in blastic plasmacytoid dendritic cell neoplasm: a case report and comprehensive review on the current and future treatment.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematological malignancy with a highly aggressive behavior and median survival of <2 years. Especially, most BPDCN patients present with extensive and non-specific skin lesions, usually leading to misdiagnosis as a skin disease and delay therapy. As for treatment, most patients with BPDCN experience relapse shortly after treatment with the traditional regimens. The alleviation of skin symptoms reflects the effects of clinical treatments. Herein, we report a case of a 71-year-old man with intermittent and gradually expanding skin lesions over his chest, abdomen, and back for 1 year. On admission, physical examination revealed extensive skin lesions and multiple enlarged lymph nodes. Laboratory examinations showed pancytopenia and numerous malignant cells in the peripheral blood smear (60%), bone marrow aspirate smear (73.5%). Immunophenotyping using flow cytometry and immunohistochemistry presented large numbers of BPDCN cells in the bone marrow, cervical lymph nodes and dermal tissue. PET/CT revealed multiple enlarged lymph nodes and splenomegaly. Once the diagnosis was identified as BPDCN, the patient began treatment with the oral BCL2 inhibitor venetoclax and subcutaneously administered azacitidine. After the first course, skin lesions reduced markedly and complete remission was achieved in the bone marrow. Our study and current cumulative data according to reviewing systematically suggest that venetoclax combined with azacitidine is safe, effective, and applicable in the treatment of BPDCN, especially for elderly relapsed/refractory patients. This study, therefore, significantly contributes to the literature on the current and future treatment for BPDCN.

Tri-aryl antimony(V) hydroximato and hydroxamato complexes: Combining lipophilic Sb(III/V) and hydroxamic acids in combating Leishmania.

Six novel tri-aryl antimony(V) hydroximato complexes (3-8) with composition [SbAr3(O2NCR)] (3: Ar = Ph, R = o-(OH)Ph, 4: Ar = Ph, R = Me, 5: Ar = Ph, R = Ph; 6: Ar = Mes, R = Me, 7: Ar = Mes, R = Ph, 8: Ar = Mes, R = o-(OH)Ph (where Ph = phenyl, Me = methyl, Mes = mesityl)), were synthesised and evaluated for anti-parasitic activity towards Leishmania major (L. major) promastigotes and amastigotes. Complexes of the form [SbAr3(O2NCR)], with the dianionic hydroximato ligand binding O,O'-bidentate to the Sb(V) centre, exist in the solid-state for the mesityl-derived complexes. In contrast, the phenyl-ligated Sb(V) complexes crystallise as the hexacoordinate, hydroxamato species [SbPh3(O2NHC(OH))], with the OH ligand derived from entrained H2O in the crystallisation solvent. It is found that both the aryl and hydroximato ligands are found to influence the bioactivity of the Sb(V) complexes. Complexes 3-8 exhibited varied anti-promastigote activity with IC50 values ranging from 1.53 µM for 6 to 36.0 µM for 3, also reflected in varied anti-amastigote activity with a percentage infection range of 5.50% for 6 to 29.00% for 3 at a concentration of 10 µM. The complexes were relatively non-toxic to human fibroblasts with an IC50 value range of 59.3 µM (7) to ≥100 µM (3-6, 8), and exhibited varied toxicity towards J774.1 A macrophages (IC50: 3.97 (6) to ≥100 (8) µM). All complexes showed enhanced activity compared to the parent hydroxamic acids.

Quadruple therapies show a higher eradication rate compared to standard triple therapy for Helicobacter pylori infection within the LEGACy consortium. A multicenter observational study in European and Latin American countries.

INTRODUCTION: Gastric cancer (GC) is one of the most lethal malignancies worldwide. Helicobacter pylori is the primary cause of GC; therefore, its eradication reduces the risk of developing this neoplasia. There is extensive evidence regarding quadruple therapy with relevance to the European population. However, in Latin America, data are scarce. Furthermore, there is limited information about the eradication rates achieved by antibiotic schemes in European and Latin American populations. OBJECTIVE: To compare the effectiveness of standard triple therapy (STT), quadruple concomitant therapy (QCT), and bismuth quadruple therapy (QBT) in six centers in Europe and Latin America. METHODS: A retrospective study was carried out based on the LEGACy registry from 2017 to 2022. Data from adult patients recruited in Portugal, Spain, Chile, Mexico, and Paraguay with confirmed H. pylori infection who received eradication therapy and confirmatory tests at least 1 month apart were included. Treatment success by each scheme was compared using a mixed multilevel Poisson regression, adjusting for patient sex and age, together with country-specific variables, including prevalence of H. pylori antibiotic resistance (clarithromycin, metronidazole, and amoxicillin), and CYP2C19 polymorphisms. RESULTS: 772 patients were incorporated (64.64% females; mean age of 52.93 years). The total H. pylori eradication rates were 75.20% (255/339) with STT, 88.70% (159/178) with QCT, and 91.30% (191/209) with QBT. Both quadruple therapies (QCT-QBT) showed significantly higher eradication rates compared with STT, with an adjusted incidence risk ratio (IRR) of 1.25 (p: <0.05); and 1.24 (p: <0.05), respectively. The antibiotic-resistance prevalence by country, but not the prevalence of CYP2C19 polymorphism, showed a statistically significant impact on eradication success. CONCLUSIONS: Both QCT and QBT are superior to STT for H. pylori eradication when adjusted for country-specific antibiotic resistance and CYP2C19 polymorphism in a sample of individuals residing in five countries within two continents.

Polymeric Micelles in Colorectal Cancer Therapy: A Comprehensive Review of Nano-drug Delivery Strategies, Copolymer Types, Physicochemical Characteristics, and Therapeutic Applications.

Polymeric micelles are becoming the method of choice for a nano-drug delivery system, especially in colorectal cancer treatment. These tiny structures have become popular for their amazing qualities that make drug delivery more efficient and therapies better. Colorectal cancer, also known as colon cancer, is one of the most common and deadly cancers in the world. Traditional chemotherapy is good, but it has big downsides, like harming other parts of the body and making people sick all over. Polymeric micelles give a new way to fix these problems by being easier on the body, breaking down naturally, and staying in the blood longer. The polymeric micelles, which are loaded with drugs, are sheltered within the tumor, which leads to a reduction in off-site effects and an increase in the targeting and accumulation of chemotherapeutics at the cancer site. This review paper elaborates on the current status of polymeric micelles as a method for nano-drug delivery for chemotherapy, emphasizing their efficacy in managing cancer. The paper also talks about the various types of copolymers that are used to create polymeric micelles, the different types of micelles, their physicochemical properties, the preparation process, characterization, and their application in cancer diagnostics.

Generation of Soliton Frequency Combs in NEMS.

In this study, we present an innovative approach leveraging combination internal resonances within a NEMS platform to generate mechanical soliton frequency combs (FCs) spanning a broad spectrum. In the time domain, the FCs take the form of a periodic train of narrow pulses, a highly coveted phenomenon within the realm of nonlinear wave-matter interactions. Our method relies on an intricate interaction among multiple vibration modes of a bracket-nanocantilever enabled by the strong nonlinearity of the electrostatic field. Through numerical simulation and experimental validation, we demonstrate that by amplifying the motions of the NEMS with the external electrostatic forcing tuned to excite the superharmonic resonance of order-n of the fundamental mode and exploiting combination internal resonances, we can generate multiple stable localized mechanical wave packets with different lobe sizes embodying soliton states I and II. This represents a significant breakthrough with profound implications for quantum computing and metrology.

Stroke Research Using Administrative Claims Database in Japan: A Narrative Review.

AIMS: Although administrative claims databases have recently been used for clinical research in Japan, no detailed description of their utilization in stroke research is available. We reviewed stroke studies using the Diagnosis Procedure Combination (DPC), the National Database of Health Insurance Claims and Specific Health Checkups (NDB), and several commercial databases sourced from social health insurance associations, focusing on their applications and limitations. METHODS: Original articles on stroke published by April 2024 using the DPC, NDB, and commercial databases were identified in Ovid MEDLINE. The characteristics of each database were compared in terms of comprehensiveness, traceability, baseline information, and outcome assessment in stroke research. RESULTS: A total of 114 studies were included (83 for DPC, 6 for NDB, and 25 for commercial databases). The number of stroke studies using administrative databases in Japan is still approximately 10 per year, although there is a slowly increasing trend. The DPC database was utilized for short-term outcome studies because of its detailed baseline and outcome information, although the inability to track patients once they changed facilities limits their use in long-term studies. The NDB database is potentially useful for long-term studies because of its comprehensiveness and traceability, but difficulties in data access restrict its usage. The most commonly used commercial database utilizes baseline information on lifestyle and blood test data, although the lack of coverage for those over 75 years old may limit its generalizability. CONCLUSIONS: Administrative claims databases are beginning to be used in stroke research in Japan but are not yet fully utilized. Researchers need to understand their applications and limitations.

Monocyte/Macrophage-Mediated Transport of Dual-Drug ZIF Nanoplatforms Synergized with Programmed Cell Death Protein-1 Inhibitor Against Microsatellite-Stable Colorectal Cancer.

Microsatellite-stable colorectal cancer (MSS-CRC) exhibits resistance to programmed cell death protein-1 (PD-1) therapy. Improving the infiltration and tumor recognition of cytotoxic T-lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS-CRC cells is engineered for the co-delivery of ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC, named as Ab@Rg1/Att-ZIF. This system is selectively engulfed by Ly-6C+ monocytes during blood circulation and utilizes a "hitchhiking" mechanism to migrate toward the core of MSS-CRC. Ab@Rg1/Att-ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class-I (MHC-I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS-CRC, significantly improving the tumor inhibition of PD-1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation-guided precise drug co-delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD-1 treatment of MSS-CRC.

Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2).

BACKGROUND: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively. METHODS: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers. RESULTS: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease). CONCLUSIONS: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated. TRIAL REGISTRATION NUMBER: NEON-1 (NCT04186637) and NEON-2 (NCT04920383).

deliVERy of Optimal blood pressure coNtrol in afrICA (VERONICA)-Nigeria study: Rationale and Design of a Randomised Clinical Trial.

BACKGROUND: Blood pressure (BP) control among treated patients in Africa is very suboptimal, with low levels of combination therapy use and therapeutic inertia being among the major barriers to effective control of hypertension. The VERONICA-Nigeria study aims to evaluate, among Black African adults with hypertension, the effectiveness and safety of a triple pill-based treatment protocol compared to Nigeria hypertension treatment protocol for the treatment of hypertension. METHODS: This study involves a randomised, parallel-group and open-label trial. Adults with uncontrolled hypertension (n=300), untreated or receiving monotherapy, with no contraindication to study treatments will be randomly assigned 1:1 to treatment with a triple pill based-treatment protocol or Nigeria hypertension treatment protocol. Follow-up is for 6 months, with interim follow up visits at month 1, 2, and 3. In a non-comparative extension treatment period, participants completing the 6 months randomised period and on ≤3 BP-lowering drugs will receive treatment with the triple pill-based treatment protocol for 12 months. The primary outcome is change in home mean SBP from baseline to month 6, and key secondary efficacy outcome is percentage of participants with clinic BP <140/90 mmHg at month 6. The primary safety outcome is discontinuation of trial treatment due to adverse events from randomization to month 6. Economic evaluation will be conducted to assess the cost-effectiveness of the triple pill-based treatment protocol, and process evaluation will be conducted to understand the context in which the trial was conducted, implementation of the trial and interventions and mechanisms of effect, and potential barriers and facilitators to implementing the intervention in clinical practice. CONCLUSION: The VERONICA-Nigeria trial will provide evidence of effectiveness and safety of the triple-based treatment protocol for the pharmacological management of hypertension, in Black African adults. TRIAL REGISTRATION: PACTR202107579572114.

Kidney and cardiovascular-protective benefits of combination drug therapies in chronic kidney disease associated with type 2 diabetes.

Given the substantial burden of chronic kidney disease associated with type 2 diabetes, an aggressive approach to treatment is required. Despite the benefits of guideline-directed therapy, there remains a high residual risk of continuing progression of chronic kidney disease and of cardiovascular events. Historically, a linear approach to pharmacologic management of chronic kidney disease has been used, in which drugs are added, then adjusted, optimized, or stopped in a stepwise manner based on their efficacy, toxicity, effects on a patient's quality of life, and cost. However, there are disadvantages to this approach, which may result in missing a window of opportunity to slow chronic kidney disease progression. Instead, a pillar approach has been proposed to enable earlier treatment that simultaneously targets multiple pathways involved in disease progression. Combination therapy in patients with chronic kidney disease associated with type 2 diabetes is being investigated in several clinical trials. In this article, we discuss current treatment options for patients with chronic kidney disease associated with type 2 diabetes and provide a rationale for tailored combinations of therapies with complementary mechanisms of action to optimize therapy using a pillar-based treatment strategy. [This article includes a plain language summary as an additional file].

The value of intervention with radiotherapy after first-line chemo-immunotherapy in locally advanced or metastatic esophageal squamous cell carcinoma: A multi-center retrospective study.

Background: Chemotherapy plus immunotherapy has become the standard first-line treatment of advanced or metastatic esophageal squamous cell carcinoma (ESCC), but median duration of response is only 7.0-8.3 months and progression-free survival (PFS, ∼6 months) is still far from satisfactory. We aim to evaluate whether early involvement of radiotherapy might improve the treatment outcome if objective response to first-line chemo-immunotherapy was observed in locally advanced or metastatic ESCC. Methods: Patients were retrospectively collected from 3 institutions in China. Patients with histopathologically confirmed diagnoses of locally advanced or metastatic ESCC were identified, who objectively responded to first-line chemo-immunotherapy (complete or partial response, or stable disease) and also received radiotherapy of primary lesions with radiation dose of over 40 Gy, with or without radiotherapy of metastatic lesions before the first disease progression. Results: A total of 72 eligible patients were identified. With median follow-up duration of 14.6 (range, 7.1-34.8) months, median progression-free survival (PFS) and overall survival (OS) were 13.5 (95 % CI,10.4-NA) months and 31.8 (95 % CI, 23.0-NA) months, respectively. Median duration from initiation of chemo-immunotherapy to radiotherapy was 2.9 (range, 0-15.1) months. Besides lower tumor burden as a significant factor of better treatment outcome, radiation dose ≥ 50 Gy was associated with superior PFS, while OS might be mainly related to tumor response to the induction chemo-immunotherapy. A low incidence of Grade 3 or above treatment-related adverse events were observed (19 %), and no treatment-related death occurred. Conclusion: Our multi-center retrospective study showed survival benefit brought by early involvement of radiotherapy after first-line chemo-immunotherapy for patients with locally advanced or metastatic ESCC. However, further investigation is warranted in future prospective, controlled trials to assess the value of radio-immunotherapy in advanced or metastatic ESCC.

Combination Atezolizumab, Cobimetinib, and Vemurafenib as a Treatment Option in BRAF V600 Mutation-Positive Melanoma: Patient Selection and Perspectives.

The treatment landscape for advanced and metastatic melanoma has drastically changed in recent years, with the advent of novel therapeutic options such as immune checkpoint inhibitors and targeted therapies offering remarkable efficacy and significantly improved patient outcomes compared to traditional approaches. Approximately 50% of melanomas harbor activating BRAF mutations, with over 90% resulting in BRAF V600E. Tumors treated with BRAF inhibitor monotherapy have a high rate of developing resistance within six months. Combination therapy with MEK inhibitors helped to mitigate this treatment resistance and led to improved outcomes. Due to the up-regulation of PD-1/PD-L1 receptors in tumors treated with BRAF/MEK inhibitor therapy, further studies included a third combination agent, anti-PD-1/PD-L1 inhibitors. This triple combination therapy may have superior efficacy and a manageable safety profile when compared with single or double agent therapy regimens.

Effective treatment of advanced and metastatic melanoma can be challenging. Newer treatment methods for patients with BRAF-mutated tumors include a combination of drugs with different complementary mechanisms. These drugs include BRAF-inhibitors, MEK-inhibitors, and PD-1/PD-L1 inhibitors. When these three medications are used in combination, patients may have better response rates and survival outcomes, when compared to using just one or two of these medications together. Toxicity rates are higher with a triple-medication regimen, so careful patient selection is important to consider.

Construction and Evaluation of BAL-PTX Co-Loaded Lipid Nanosystem for Promoting the Anti-Lung Cancer Efficacy of Paclitaxel and Reducing the Toxicity of Chemotherapeutic Drugs.

Purpose: The present study aimed to develop a lipid nanoplatform, denoted as "BAL-PTX-LN", co-loaded with chiral baicalin derivatives (BAL) and paclitaxel (PTX) to promote the anti-lung cancer efficacy of paclitaxel and reduce the toxicity of chemotherapeutic drugs. Methods: BAL-PTX-LN was optimized through central composite design based on a single-factor experiments. BAL-PTX-LN was evaluated by TEM, particle size, encapsulation efficiency, hemolysis rate, release kinetics and stability. And was evaluated by pharmacokinetics and the antitumor efficacy studied both in vitro and in vivo. The in vivo safety profile of the formulation was assessed using hematoxylin and eosin (HE) staining. Results: BAL-PTX-LN exhibited spherical morphology with a particle size of 134.36 ± 3.18 nm, PDI of 0.24 ± 0.02, and with an encapsulation efficiency exceeding 90%, BAL-PTX-LN remained stable after 180 days storage. In vitro release studies revealed a zero-order kinetic model of PTX from the liposomal formulation. No hemolysis was observed in the preparation group. Pharmacokinetic analysis of PTX in the BAL-PTX-LN group revealed an approximately three-fold higher bioavailability and twice longer t1/2 compared to the bulk drug group. Furthermore, the IC50 of BAL-PTX-LN decreased by 2.35 times (13.48 µg/mL vs 31.722 µg/mL) and the apoptosis rate increased by 1.82 times (29.38% vs 16.13%) at 24 h compared to the PTX group. In tumor-bearing nude mice, the BAL-PTX-LN formulation exhibited a two-fold higher tumor inhibition rate compared to the PTX group (62.83% vs 29.95%), accompanied by a ten-fold decrease in Ki67 expression (4.26% vs 45.88%). Interestingly, HE staining revealed no pathological changes in tissues from the BAL-PTX-LN group, whereas tissues from the PTX group exhibited pathological changes and tumor cell infiltration. Conclusion: BAL-PTX-LN improves the therapeutic effect of poorly soluble chemotherapeutic drugs on lung cancer, which is anticipated to emerge as a viable therapeutic agent for lung cancer in clinical applications.

The many dimensions of combination therapy: How to combine antibiotics to limit resistance evolution.

In combination therapy, bacteria are challenged with two or more antibiotics simultaneously. Ideally, separate mutations are required to adapt to each of them, which is a priori expected to hinder the evolution of full resistance. Yet, the success of this strategy ultimately depends on how well the combination controls the growth of bacteria with and without resistance mutations. To design a combination treatment, we need to choose drugs and their doses and decide how many drugs get mixed. Which combinations are good? To answer this question, we set up a stochastic pharmacodynamic model and determine the probability to successfully eradicate a bacterial population. We consider bacteriostatic and two types of bactericidal drugs-those that kill independent of replication and those that kill during replication. To establish results for a null model, we consider non-interacting drugs and implement the two most common models for drug independence-Loewe additivity and Bliss independence. Our results show that combination therapy is almost always better in limiting the evolution of resistance than administering just one drug, even though we keep the total drug dose constant for a 'fair' comparison. Yet, exceptions exist for drugs with steep dose-response curves. Combining a bacteriostatic and a bactericidal drug which can kill non-replicating cells is particularly beneficial. Our results suggest that a 50:50 drug ratio-even if not always optimal-is usually a good and safe choice. Applying three or four drugs is beneficial for treatment of strains with large mutation rates but adding more drugs otherwise only provides a marginal benefit or even a disadvantage. By systematically addressing key elements of treatment design, our study provides a basis for future models which take further factors into account. It also highlights conceptual challenges with translating the traditional concepts of drug independence to the single-cell level.

Implementation status of comprehensive geriatric assessment among older inpatients: A nationwide retrospective study.

AIM: The importance of comprehensive geriatric assessment (CGA) is increasing in aging societies worldwide. However, there are few comprehensive studies on CGA, resulting in a limited understanding of its implementation rate, temporal changes and factors associated with its implementation. We aimed to investigate the implementation status of CGA and its regional variance in Japan. METHODS: Using the Diagnosis Procedure Combination database, we investigated CGA trends, and identified the patient, hospital and regional factors associated with its implementation. We identified patients aged ≥65 years who were admitted for the first time between 2016 and 2020 with a diagnosis of stroke, heart failure, pneumonia, bone fracture or colorectal cancer. We examined the CGA implementation rate according to patient and hospital characteristics. We also investigated temporal changes and tendencies to carry out CGA in different prefectures. RESULTS: A total of 1 974 817 patients were analyzed, of whom 570 696 (28.9%) underwent CGA. The implementation trend increased steadily from 25.3% in fiscal year 2016 to 33.4% in fiscal year 2019. The implementation rate also increased with patient age (30.3% in patients aged ≥95 years). Regional variations in its implementation status were observed, with a higher tendency to be implemented in areas near major metropolitan regions. A trend toward carrying out CGA for colorectal cancer, but not for other diseases, has been observed in eastern Japan. CONCLUSION: Although CGA is increasingly carried out, considerable regional differences remain in its implementation status. Initiatives to reduce variations are necessary. Geriatr Gerontol Int 2024; ••: ••-••.

Optimum combined MET according to tolerability with efficacy, Silodosin Tadalafil versus Silodosin Vardenafil for distal ureteric stone: a prospective, double blinded, randomized clinical trial.

OBJECTIVES: To determine the optimum combination therapy of Silodosin-Tadalafil versus Silodosin-Vardenafil in terms of both tolerability and efficacy for the management of distal ureteric stones. METHODS: This prospective, double blinded, randomized clinical trial included 140 patients with distal ureteric stones, randomized into two groups: Group I (n = 67) received Silodosin 8 mg once daily combined with Tadalafil 5 mg once daily, and Group II (n = 68) received Silodosin 8 mg once daily combined with Vardenafil 10 mg once daily. The primary outcome was the tolerability of the combination therapies, assessed through the incidence of adverse events. Secondary outcomes included stone expulsion rate, expulsion time, and the need for analgesics. RESULTS: Both combination therapies demonstrated similar efficacy, with no significant differences in stone expulsion rate (70.1% vs. 67.6%, P = 0.754), expulsion time (19 ± 3 days for both groups, P = 0.793), and analgesic requirements (P > 0.05). However, the Silodosin-Tadalafil combination showed a significantly lower occurrence of adverse events, with notable differences in headache (23.9% vs. 57.4%, P < 0.001), dizziness (32.8% vs. 60.3%, P = 0.001), and gastrointestinal upset (9% vs. 66.2%, P < 0.001), and other adverse effects. The overall occurrence of any adverse event was significantly lower in the Silodosin-Tadalafil group (88.1% vs. 98.5%, P = 0.017). CONCLUSIONS: Both Silodosin-Tadalafil and Silodosin-Vardenafil therapies are effective in managing distal ureteric stones. However, the Silodosin-Tadalafil combination is associated with a significantly lower incidence of adverse events, making it a more tolerable option for patients.

The current therapeutic cancer vaccines landscape in non-small cell lung cancer.

Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.

The next frontier in immunotherapy: potential and challenges of CAR-macrophages.

Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages' phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.

Mathematical Modeling of Tumor Immune Interactions: The Role of Anti-FGFR and Anti-PD-1 in the Combination Therapy.

Bladder cancer poses a significant global health burden with high incidence and recurrence rates. This study addresses the therapeutic challenges in advanced bladder cancer, focusing on the competitive mechanisms of ligand or drug binding to receptors. We developed a refined mathematical model that integrates the dynamics of tumor cells and immune responses, particularly targeting fibroblast growth factor receptor 3 (FGFR3) and immune checkpoint inhibitors (ICIs). This study contributes to understanding combination therapies by elucidating the competitive binding dynamics and quantifying the synergistic effects. The findings highlight the importance of personalized immunotherapeutic strategies, considering factors such as drug dosage, dosing schedules, and patient-specific parameters. Our model further reveals that ligand-independent activated-state receptors are the most essential drivers of tumor proliferation. Moreover, we found that PD-L1 expression rate was more important than PD-1 in driving the dynamic evolution of tumor and immune cells. The proposed mathematical model provides a comprehensive framework for unraveling the complexities of combination therapies in advanced bladder cancer. As research progresses, this multidisciplinary approach contributes valuable insights toward optimizing therapeutic strategies and advancing cancer treatment paradigms.