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INTRODUCTION: A three-pronged approach to acne treatment combining an antibiotic, antimicrobial, and retinoid may be more efficacious than single/double treatments while potentially reducing antibiotic resistance. This study evaluated the efficacy and safety of the first fixed-dose, triple-combination topical acne product, clindamycin 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel (CAB) using pooled phase 3 data. METHODS: In two identical phase 3 (N = 183; N = 180), double-blind, 12-week studies, participants aged ≥ 9 years with moderate-to-severe acne were randomized 2:1 to receive once-daily CAB or vehicle gel. Endpoints included ≥ 2-grade reduction from baseline in Evaluators Global Severity Score and clear/almost clear skin (treatment success) and least-squares mean percent change from baseline in acne lesion counts. Treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability were evaluated. RESULTS: At week 12, 50.0% of participants achieved treatment success with CAB versus 22.6% with vehicle gel (P  70% reductions in inflammatory and noninflammatory lesions at week 12 (77.9% and 73.0%, respectively), which were significantly greater than vehicle (57.9% and 48.2%; P

Some patients with chronic thromboembolic pulmonary hypertension (CTEPH) exhibit exercise intolerance due to reduced cardiac output (CO) even after successful balloon pulmonary angioplasty (BPA). Medical therapy is a potential option for such cases; however, it is unclear which patients necessitate it even after BPA. This study included 286 patients with CTEPH who underwent BPA and right heart catheterization 1 year after the final BPA and classified them into no-medication and withdrawal groups. The no-medication group comprised patients without pulmonary hypertension (PH) medications before and after BPA, while the withdrawal group included patients who received PH medications before BPA and discontinued them after BPA. We assessed differences in the changes in CO after BPA from baseline (ΔCO) between the 2 groups. Additionally, we evaluated the ΔCO among different age categories within each group: younger (<60 years), middle-aged (60-70 years), and older adults (≥70 years). After adjusting baseline covariates, overall CO did not differ significantly. However, ΔCO was significantly positive in the no-medication group but negative in the withdrawal group (0.32 and −0.33, difference in ΔCO: −0.65, 95% confidence intervals: −0.90 to −0.40). A significantly positive effect on ΔCO was observed in younger and middle-aged individuals, with a significant interaction between age and ΔCO in no-medication groups. Increasing CO with BPA alone may be challenging with age in patients with CTEPH. Given that discontinuation of PH medication after BPA decreased CO more than the effect of BPA, medical therapy might be necessary even after successful BPA. [ABSTRACT FROM AUTHOR]

Chemotherapy is a widely used therapeutic approach to combat hematopoietic malignancies such as acute myeloid leukemia (AML). Although cisplatin is known as the first-generation platinum-based chemotherapy inhibitor, the wide use of cisplatin eventually leads to drug resistance, which is the biggest impediment to cancer chemotherapy. Histone deacetylase enzyme (HDAC) inhibitors have the ability to induce cell cycle arrest and apoptosis in different types of cancer, which stands as a promising alternative for those cancer patients not appropriate for intensive chemotherapy. This study concluded that there was a significant decrease in the proliferation of MOLM-13 and MV4-11 FLT3-ITD+ AML cell lines with the increasing SAHA and cisplatin concentrations in 48 hours using MTT cell proliferation assay. Moreover, the combination of SAHA and cisplatin led to a reduction in the proliferation of both cell lines correlated with the synergistic effect of the two drugs depending on the combination index (CI). Furthermore, investigating apoptosis for combined administration resulted in increased induction of apoptosis by Annexin-V/PI double staining. In conclusion, although additional studies are needed to fully elucidate the molecular mechanism underlying this combination, we propose a new approach to targeting AML, as AML increases over time with drug resistance and the consequent year-on-year increase in patient mortality. [ABSTRACT FROM AUTHOR]

Abstract Introduction Combination use of atogepant and onabotulinumtoxinA has the potential to be more effective than either alone for the preventive treatment of chronic migraine (CM) due to their complementary mechanisms of action. This analysis collected real-world data to evaluate the safety, tolerability, and effectiveness of adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM. Methods This retrospective, longitudinal, multicenter chart review included adults with CM who received ≥ 2 consecutive cycles of onabotulinumtoxinA before ≥ 1 month of onabotulinumtoxinA and atogepant combination treatment. Charts at atogepant prescription (index date) and two subsequent onabotulinumtoxinA treatment visits (~ 3 and ~ 6 months post-index) were reviewed for change from baseline in monthly headache days (MHDs), ≥ 50% reduction in MHDs, discontinuation rates, and adverse events (AEs). Results Of the 55 charts that met safety analysis criteria, 31 had data on headache days at index and first post-index visit and were eligible for effectiveness analysis (mean age 46.7 years, 94.5% female). For those with data available prior to onabotulinumtoxinA treatment (n = 25), the mean MHD was 24.0 days, reduced by 8.15 days after onabotulinumtoxinA treatment. After atogepant was added, MHD was incrementally reduced by 4.53 days and 8.75 days from index date to the first (N = 31) and second (N = 23) post-index onabotulinumtoxinA treatment visit, respectively. A ≥ 50% reduction in MHDs was achieved by 45.2% of patients ~ 3 months post-index. Atogepant and onabotulinumtoxinA were discontinued by 16.1% and 6.5% of patients, respectively. In the safety population, 32.7% of patients experienced ≥ 1 AE. No serious AEs were reported. Conclusions This real-world study of patients with CM demonstrated that adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM was effective by providing an additional reduction in MHDs over ~ 3 and ~ 6 months of combination treatment. Safety results were consistent with the known safety profiles of onabotulinumtoxinA and atogepant, with no new safety signals identified.

ABSTRACTTyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 (HSPA5) and fibroblast growth factor receptor 1 (FGFR1). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy.

Introduction: Combination use of atogepant and onabotulinumtoxinA has the potential to be more effective than either alone for the preventive treatment of chronic migraine (CM) due to their complementary mechanisms of action. This analysis collected real-world data to evaluate the safety, tolerability, and effectiveness of adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM. Methods: This retrospective, longitudinal, multicenter chart review included adults with CM who received ≥ 2 consecutive cycles of onabotulinumtoxinA before ≥ 1 month of onabotulinumtoxinA and atogepant combination treatment. Charts at atogepant prescription (index date) and two subsequent onabotulinumtoxinA treatment visits (~ 3 and ~ 6 months post-index) were reviewed for change from baseline in monthly headache days (MHDs), ≥ 50% reduction in MHDs, discontinuation rates, and adverse events (AEs). Results: Of the 55 charts that met safety analysis criteria, 31 had data on headache days at index and first post-index visit and were eligible for effectiveness analysis (mean age 46.7 years, 94.5% female). For those with data available prior to onabotulinumtoxinA treatment (n = 25), the mean MHD was 24.0 days, reduced by 8.15 days after onabotulinumtoxinA treatment. After atogepant was added, MHD was incrementally reduced by 4.53 days and 8.75 days from index date to the first (N = 31) and second (N = 23) post-index onabotulinumtoxinA treatment visit, respectively. A ≥ 50% reduction in MHDs was achieved by 45.2% of patients ~ 3 months post-index. Atogepant and onabotulinumtoxinA were discontinued by 16.1% and 6.5% of patients, respectively. In the safety population, 32.7% of patients experienced ≥ 1 AE. No serious AEs were reported. Conclusions: This real-world study of patients with CM demonstrated that adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM was effective by providing an additional reduction in MHDs over ~ 3 and ~ 6 months of combination treatment. Safety results were consistent with the known safety profiles of onabotulinumtoxinA and atogepant, with no new safety signals identified. [ABSTRACT FROM AUTHOR]

Abstract Background Peptide receptor radionuclide therapy (PRRT) uses [177Lu]Lu-[DOTA0-Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) to treat patients with neuroendocrine tumours (NETs) overexpressing the somatostatin receptor 2A (SSTR2A). It has shown significant short-term improvements in survival and symptom alleviation, but there remains room for improvement. Here, we investigated whether combining [177Lu]Lu-DOTA-TATE with chemotherapeutics enhanced the in vitro therapeutic efficacy of [177Lu]Lu-DOTA-TATE. Results Transfected human osteosarcoma (U2OS + SSTR2A, high SSTR2A expression) and pancreatic NET (BON1 + STTR2A, medium SSTR2A expression) cells were subjected to hydroxyurea, gemcitabine or triapine for 24 h at 37oC and 5% CO2. Cells were then recovered for 4 h prior to a 24-hour incubation with 0.7–1.03 MBq [177Lu]Lu-DOTA-TATE (25 nM) for uptake and metabolic viability studies. Incubation of U2OS + SSTR2A cells with hydroxyurea, gemcitabine, and triapine enhanced uptake of [177Lu]Lu-DOTA-TATE from 0.2 ± 0.1 in untreated cells to 0.4 ± 0.1, 1.1 ± 0.2, and 0.9 ± 0.2 Bq/cell in U2OS + SSTR2A cells, respectively. Cell viability post treatment with [177Lu]Lu-DOTA-TATE in cells pre-treated with chemotherapeutics was decreased compared to cells treated with [177Lu]Lu-DOTA-TATE monotherapy. For example, the viability of U2OS + SSTR2A cells incubated with [177Lu]Lu-DOTA-TATE decreased from 59.5 ± 22.3% to 18.8 ± 5.2% when pre-treated with hydroxyurea. Control conditions showed no reduced metabolic viability. Cells were also harvested to assess cell cycle progression, SSTR2A expression, and cell size by flow cytometry. Chemotherapeutics increased SSTR2A expression and cell size in U2OS + SSTR2A and BON1 + STTR2A cells. The S-phase sub-population of asynchronous U2OS + SSTR2A cell cultures was increased from 45.5 ± 3.3% to 84.8 ± 2.5%, 85.9 ± 1.9%, and 86.6 ± 2.2% when treated with hydroxyurea, gemcitabine, and triapine, respectively. Conclusions Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu]Lu-DOTA-TATE.

Sierra Pellizzari,1 Harjot Athwal,1 Anne Claudine Bonvissuto,1,2 Armen Parsyan1– 4 1Department of Anatomy and Cell Biology, Western University, London, ON, Canada; 2Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON, Canada; 3Department of Oncology, Western University, London, ON, Canada; 4Department of Surgery, St Joseph’s Health Care and London Health Sciences Centre, Western University, London, ON, CanadaCorrespondence: Armen Parsyan, Department of Surgery, St Joseph’s Health Care London, Room D1-104, 268 Grosvenor Street, London, ON, N6A 4V2, Canada, Tel +1-519-646-4831, Email aparsyan@uwo.caAbstract: Breast cancer is a leading cause of cancer-related deaths in females. Triple-negative breast cancer (TNBC) subtype is the most aggressive form of breast cancer that lacks biomarkers and effective targeted therapies. Its high degree of heterogeneity as well as innate and acquired resistance to treatment creates further barriers in achieving positive clinical outcomes in TNBC. Thus, development of novel treatment approaches in TNBC is of high clinical significance. Multimodality approaches with targeted agents and radiotherapy (RT) are promising for increasing efficacy of treatment and circumventing resistance. Here we examined anticancer effects of the Aurora Kinase B (AURKB) inhibitor AZD1152 as a single agent and in combination with RT using various TNBC cell lines, MDA-MB-468, MDA-MB-231 and SUM-159. We observed that AZD1152 alone effectively inhibited colony formation in TNBC cell lines. The combination of AZD1152 at IC50 concentrations together with ionizing radiation further reduced colony formation as compared to the single agent treatment. Our data support the notion that inhibition of the AURKB pathway is a promising strategy for treatment and radiosensitization of TNBC and warrants further translational studies.Plain Language Summary: Breast cancer is a leading cause of cancer death in women globally. The triple negative breast cancer subtype confers the poorest oncologic outcomes and requires novel treatment approaches. Development of new therapeutics as well as combination treatments with radiation are crucial. Aurora Kinase B (AURKB) protein regulates cell division that is often altered in breast cancer, contributing to tumor pathogenesis. This study examined the combination of an AURKB inhibitor, AZD1152, with radiation therapy, compared to single-agent treatments, in treating triple negative breast cancer cells. Our results show that AZD1152 and ionizing radiation alone were able to delay cancer cell proliferation effectively. However, their combination further significantly inhibited cell proliferation compared to single-agent treatments. This suggests that further studies on this combination would be valuable in developing novel treatment strategies for breast cancer.Keywords: breast cancer, Aurora Kinase B, AZD1152, radiation, combination treatment, multimodality treatment, AURKB

Jung-Hee Jang,1,&ast; Hyeong Joon Jun,2,&ast; ChaYoung Lee,3,&ast; Eunjin Sohn,4 Ojin Kwon,1 Dong-Hoon Kang,3 Muhammad Umar,2,5 In Chul Jung,3 Soo-Jin Jeong4 1Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 2Korean Medicine Data Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 3Department of Oriental Neuropsychiatry, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea; 4Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 5Korean Convergence Medical Science, University of Science and Technology, Daejeon, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Soo-Jin Jeong, Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, 34054, Republic of Korea, Tel +82-42-868-9651, Email sjijeong@kiom.re.kr In Chul Jung, Department of Oriental Neuropsychiatry, College of Korean Medicine, Daejeon University, Daejeon, 34520, Republic of Korea, Tel +82-42-470-9000, Email npjeong@dju.krPurpose: We aimed to investigate the efficacy of a combined herbal formula and electroacupuncture (EA) for mild cognitive impairment (MCI), a neurodegenerative disease leading to dementia, and its underlying mechanisms of action.Patients and Methods: This was a prospective open-label observational pilot study at Daejeon Korean Medicine Hospital of Daejeon University in South Korea from March 2022 to March 2023. We included six Korean patients (50% male) aged ≥ 45 years and < 85 years with MCI, a clinical dementia rating score of 0.5, and a Montreal Cognitive Assessment-Korea (MoCA-K) score ≤ 22. The exclusion criterion was impaired cognitive function. Patients received combined therapy, including a herbal formula and EA, for 12– 24 weeks. We prescribed the herbal formulas Gamiguibi-tang, Yukmijihwang-tang, and Banhasasim-tang to the patients for at least 70% of the treatment period, in combination with EA. Moreover, we investigated changes in cognitive and cognition-related symptoms and cytokine expression in the blood following combined traditional medicine therapy. At baseline and after 12 and 24 weeks, we administered the MoCA-K and cognitive-related questionnaires. We analyzed network pharmacology to reflect the herbal formula intervention mechanism comprehensively.Results: The median score [interquartile range] of MoCA-K at baseline was 19.5 [16.0, 22.0], which improved significantly (24.5 [24.0, 26.0], p < 0.01) over 24 weeks following combined therapy. We obtained no significant conclusion regarding cytokine changes due to the small sample size. In network pharmacology, we analyzed the brain, head, heart, peripheral nerves, peripheral nervous system, and pancreas as the enriched organs from the common targets of the three herbal formulas.Conclusion: Combined herbal medicine and EA improved cognitive function in patients with MCI. We assume the underlying mechanism of herbal formulas to be antioxidative and anti-inflammatory changes in cytokine expression. Combined traditional medicine has potential therapeutic application in preventing MCI progression to dementia.Plain Language Summary: This was a single-centered study focusing on the therapeutic effect of combined herbal medicine and electroacupuncture in patients with mild cognitive impairment, including a small number of participants, a relatively long treatment intervention of 12 weeks, and a follow-up assessment of 24 weeks. The intervention was a combination of a herbal formula and electroacupuncture treatment customized for each participant. The blood cytokine analyses of the participants were compared with the network analysis of the predicted target organs and pathways for the herbal formulas administered. Because each participant was not given the exact same intervention, we were unable to identify the specific treatment that produced the predicted effect. The observational study design of the study limited the ability to accurately assess causation between intervention and outcome. However, combined traditional medicine has potential therapeutic application in preventing mild cognitive impairment progression to dementia.Keywords: network pharmacology, inflammation, combination treatment, dementia

Background: Peptide receptor radionuclide therapy (PRRT) uses [177Lu]Lu-[DOTA0-Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) to treat patients with neuroendocrine tumours (NETs) overexpressing the somatostatin receptor 2A (SSTR2A). It has shown significant short-term improvements in survival and symptom alleviation, but there remains room for improvement. Here, we investigated whether combining [177Lu]Lu-DOTA-TATE with chemotherapeutics enhanced the in vitro therapeutic efficacy of [177Lu]Lu-DOTA-TATE. Results: Transfected human osteosarcoma (U2OS + SSTR2A, high SSTR2A expression) and pancreatic NET (BON1 + STTR2A, medium SSTR2A expression) cells were subjected to hydroxyurea, gemcitabine or triapine for 24 h at 37oC and 5% CO2. Cells were then recovered for 4 h prior to a 24-hour incubation with 0.7–1.03 MBq [177Lu]Lu-DOTA-TATE (25 nM) for uptake and metabolic viability studies. Incubation of U2OS + SSTR2A cells with hydroxyurea, gemcitabine, and triapine enhanced uptake of [177Lu]Lu-DOTA-TATE from 0.2 ± 0.1 in untreated cells to 0.4 ± 0.1, 1.1 ± 0.2, and 0.9 ± 0.2 Bq/cell in U2OS + SSTR2A cells, respectively. Cell viability post treatment with [177Lu]Lu-DOTA-TATE in cells pre-treated with chemotherapeutics was decreased compared to cells treated with [177Lu]Lu-DOTA-TATE monotherapy. For example, the viability of U2OS + SSTR2A cells incubated with [177Lu]Lu-DOTA-TATE decreased from 59.5 ± 22.3% to 18.8 ± 5.2% when pre-treated with hydroxyurea. Control conditions showed no reduced metabolic viability. Cells were also harvested to assess cell cycle progression, SSTR2A expression, and cell size by flow cytometry. Chemotherapeutics increased SSTR2A expression and cell size in U2OS + SSTR2A and BON1 + STTR2A cells. The S-phase sub-population of asynchronous U2OS + SSTR2A cell cultures was increased from 45.5 ± 3.3% to 84.8 ± 2.5%, 85.9 ± 1.9%, and 86.6 ± 2.2% when treated with hydroxyurea, gemcitabine, and triapine, respectively. Conclusions: Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu]Lu-DOTA-TATE. [ABSTRACT FROM AUTHOR]

Aim: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium‐glucose cotransporter‐2 (SGLT2) inhibitor and glucagon‐like peptide 1 receptor agonist (GLP‐1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP‐1RA first. Methods: We included 438 patients with CKD (GLP‐1RA‐first group, n = 223; SGLT2 inhibitor‐first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)‐matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. Results: Using the PS‐matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP‐1RA‐first group, 10%; SGLT2 inhibitor‐first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). Conclusion: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was significant. These results suggest that, in GLP‐1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP‐1RA treatment may lead to more favourable renal outcomes. [ABSTRACT FROM AUTHOR]

In the last decade, the standard treatment for advanced renal cell carcinoma (RCC) has evolved, mainly driven by the development and approval of immune checkpoint inhibitors (ICIs). Currently, ICI monotherapy and ICI-based combinations with tyrosine kinase inhibitors and targeted therapies against mammalian target of rapamycin or vascular endothelial growth factor have become new standard treatments for first-line and subsequent-line therapies. ICIs play an important role as an adjuvant postoperative therapy, and this field is the subject of active research. Furthermore, ongoing randomized controlled trials are investigating the clinical value of more intense treatments by combining multiple effective treatments for RCC. Additionally, novel biomarkers for prognosis have been investigated. This study reviews the current evidence on immunotherapy as a treatment for RCC patients, randomized controlled trials, and ongoing studies including RCC patients and recent findings, and discusses future perspectives. [ABSTRACT FROM AUTHOR]

It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17β‐estradiol (E2) signaling is also known to modulate glycolysis markers in cancer cells. However, whether the inhibition of PKM2 combined with E2 treatment could adversely affect glucose metabolism in CRC cells remains to be investigated. First, we confirmed the metabolic plasticity of CRC cells under varying environmental conditions. Next, we identified glycolysis markers that were upregulated in CRC patients and assessed in vitro mRNA levels following E2 treatment. We found that PKM2 expression, which is highly upregulated in CRC clinical samples, is not altered by E2 treatment in CRC cells. In this study, glucose uptake, generation of reactive oxygen species (ROS), lactate production, cell viability, and apoptosis were evaluated in CRC cells following E2 treatment, PKM2 silencing, or a combination of both. Compared to individual treatments, combination therapy resulted in a significant reduction in cell viability and enhanced apoptosis. Glucose uptake and ROS production were markedly reduced in PKM2‐silenced E2‐treated cells. The data presented here suggest that E2 signaling combined with PKM2 inhibition cumulatively targets glucose metabolism in a manner that negatively impacts CRC cell growth. These findings hold promise for novel therapeutic strategies targeting altered metabolic pathways in CRC. Highlights: Colorectal cancer (CRC) cells exhibit a versatile metabolic profile that is responsive to changes in the tumor microenvironment.Estrogen (E2) signaling modulates glycolysis and reduces CRC cell growth and survival.Pyruvate kinase M2 (PKM2) inhibition also modulates glycolysis and reduces CRC cell growth.Combining E2 treatment with PKM2 inhibition precipitates significant cumulative antitumor effects in CRC cells. [ABSTRACT FROM AUTHOR]

Purpose: Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and gentamicin is recommended for invasive manifestations. However, evidence to support this treatment approach remains limited due to a lack of randomised controlled trials. To explore this critical issue further, we conducted this retrospective, single-center study. Methods: We identified all patients hospitalized with invasive listeriosis at the University Medical Center Hamburg-Eppendorf between 2009 and 2020 and analyzed the effect of gentamicin combination treatment versus monotherapy on 90-day mortality. Results: In total, 36 patients with invasive listeriosis were included, of which 21 patients received gentamicin combination treatment and 15 received monotherapy. The mean age-adjusted Charlson Comorbidity Index (aaCCI) value was lower in the gentamicin combination treatment group (5.4 vs. 7.4). Neurolisteriosis was more common in the gentamicin group (81% vs. 20%). The 90-day mortality was with significantly lower in the gentamicin combination treatment group (10%) compared to the monotherapy group (60%). Multivariable cox regression analysis, adjusted for a propensity score computed based on neurolisteriosis, aaCCI and sex, revealed a significantly reduced hazard ratio of 0.07 (95% CI: 0.01–0.53, p = 0.01) for 90-day mortality for the gentamicin combination treatment. Conclusion: This retrospective study highlights the benefit of gentamicin combination treatment in reducing the 90-day mortality rate among patients with invasive listeriosis. The high prevalence of monotherapy in this study cohort raises concerns about the adequacy of antibiotic therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Patients with severe carbapenem-resistant Acinetobacter baumannii (CRAB) infections currently face significant treatment challenges. When patients display signs of infection and the clinical suspicion of CRAB infections is high, appropriate treatment should be immediately provided. However, current treatment plans and clinical data for CRAB are limited. Inherent and acquired resistance mechanisms, as well as host factors, significantly restrict options for empirical medication. Moreover, inappropriate drug coverage can have detrimental effects on patients. Most existing studies have limitations, such as a restricted sample size, and are predominantly observational or non-randomized, which report significant variability in patient infection severity and comorbidities. Therefore, a gold-standard therapy remains lacking. Current and future treatment options of infections due to CRAB were described in this review. The dose and considerable side effects restrict treatment options for polymyxins, and high doses of ampicillin-sulbactam or tigecycline appear to be the best option at the time of initial treatment. Moreover, new drugs such as durlobactam and cefiderocol have substantial therapeutic capabilities and may be effective salvage treatments. Bacteriophages and antimicrobial peptides may serve as alternative treatment options in the near future. The advantages of a combination antimicrobial regimen appear to predominate those of a single regimen. Despite its significant nephrotoxicity, colistin is considered a primary treatment and is often used in combination with antimicrobials, such as tigecycline, ampicillinsulbactam, meropenem, or fosfomycin. The Infectious Diseases Society of America (IDSA) has deemed high-dose ampicillin-sulbactam, which is typically combined with high-dose tigecycline, polymyxin, and other antibacterial agents, the best option for treating serious CRAB infections. A rational combination of drug use and the exploration of new therapeutic drugs can alleviate or prevent the effects of CRAB infections, shorten hospital stays, and reduce patient mortality. [ABSTRACT FROM AUTHOR]

Osteoporosis, a prevalent systemic degenerative disease, poses significant challenges to China's national health, particularly due to complications such as fractures. Therapeutic interventions for osteoporosis primarily involve bone resorption inhibitors (antiresorptive) and bone formation promoters (anabolic). Numerous studies underscore the importance of sequential and combination treatments using diverse drug types. Such approaches have shown considerable efficacy in increasing bone mineral density, reducing fracture risk, and preventing the progression of osteoporosis. This article aimed to consolidate various sequential treatment schemes, offering valuable insights for clinicians in their practice. Keywords: Osteoporosis; Sequential treatment; Combination treatment [ABSTRACT FROM AUTHOR]

The PI3K signaling pathway plays an essential role in cancer cell proliferation and survival. PI3K pathway inhibitors are now FDA-approved as a single agent treatment or in combination for solid tumors such as renal cell carcinoma or breast cancer. However, despite the high prevalence of PI3K pathway alterations in gynecological cancers and promising preclinical activity in endometrial and ovarian cancer models, PI3K pathway inhibitors showed limited clinical activity in gynecological cancers. In this review, we provide an overview on resistance mechanisms against PI3K pathway inhibitors that limit their use in gynecological malignancies, including genetic alterations that reactivate the PI3K pathway such as PIK3CA mutations and PTEN loss, compensatory signaling pathway activation, and feedback loops causing the reactivation of the PI3K signaling pathway. We also discuss the successes and limitations of recent clinical trials aiming to address such resistance mechanisms through combination therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Scientists are studying proteins like kinesin spindle protein and Aurora B, crucial for cell division and potential targets in cancer treatment. Drugs aimed at these proteins show promise in lab tests for killing cancer cells, but in clinical trials alone, they are not always effective, possibly due to varied cancer cell responses. To enhance their efficacy, researchers are exploring combinations with other cell-killing drugs. Our study focused on Navitoclax, an inducer of cancer cell death, tested alongside Ispinesib and Barasertib, targeting kinesin spindle protein and Aurora B, respectively. Together, these drugs induced significant cancer cell death, mainly through apoptosis. Moreover, imaging techniques revealing their combined effects suggest that combining these drugs could be a potent cancer treatment strategy, warranting further investigation in clinical trials. Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness. [ABSTRACT FROM AUTHOR]

Due to the rising annual incidence of lung cancer (LC), new treatment strategies are needed. While various options exist, many, if not all, remain suboptimal. Several studies have shown cryoablation to be a promising approach. Yet, a lack of basic information pertaining to LC response to freezing and requirement for percutaneous access has limited clinical use. In this study, we investigated the A549 lung carcinoma cell line response to freezing. The data show that a single 5 min freeze to −15 °C did not affect cell viability, whereas −20 °C and −25 °C result in a significant reduction in viability 1 day post freeze to <10%. These populations, however, were able to recover in culture. Application of a repeat (double) freeze resulted in complete cell death at −25 °C. Studies investigating the impact of adjunctive gemcitabine (75 nM) pretreatment in combination with freezing were then conducted. Exposure to gemcitabine alone resulted in minimal cell death. The combination of gemcitabine pretreatment and a −20 °C single freeze as well as combination treatment with a −15 °C repeat freeze both resulted in complete cell death. This suggests that gemcitabine pretreatment may be synergistically effective when combined with freezing. Studies into the modes of cell death associated with the increased cell death revealed the increased involvement of necroptosis in combination treatment. In summary, these results suggest that repeat freezing to −20 °C to −25 °C results in a high degree of LC destruction. Further, the data suggest that the combination of gemcitabine pretreatment and freezing resulted in a shift of the minimum lethal temperature for LC from −25 °C to −15 °C. These findings, in combination with previous reports, suggest that cryoablation alone or in combination with chemotherapy may provide an improved path for the treatment of LC. [ABSTRACT FROM AUTHOR]

The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage. Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease (IBD). Oral administration is the most common route for intestinal diseases. In this study, a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment, which can interrupt the pathological process of IBD, resulting in the significantly improved efficacy of existing treatments. Based on the specific pH values and high reactive oxygen species (ROS) levels in inflammatory sites of IBD, an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed, and confirmed in vitro and in vivo. The antiinflammatory drug dexamethasone acetate (Dex) and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions (TJs). The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis. In brief, a drug delivery system and a therapeutic strategy for IBD are successfully developed. [ABSTRACT FROM AUTHOR]

Abstract Introduction A three-pronged approach to acne treatment combining an antibiotic, antimicrobial, and retinoid may be more efficacious than single/double treatments while potentially reducing antibiotic resistance. This study evaluated the efficacy and safety of the first fixed-dose, triple-combination topical acne product, clindamycin 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel (CAB) using pooled phase 3 data. Methods In two identical phase 3 (N = 183; N = 180), double-blind, 12-week studies, participants aged ≥ 9 years with moderate-to-severe acne were randomized 2:1 to receive once-daily CAB or vehicle gel. Endpoints included ≥ 2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin (treatment success) and least-squares mean percent change from baseline in acne lesion counts. Treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability were evaluated. Results At week 12, 50.0% of participants achieved treatment success with CAB versus 22.6% with vehicle gel (P 70% reductions in inflammatory and noninflammatory lesions at week 12 (77.9% and 73.0%, respectively), which were significantly greater than vehicle (57.9% and 48.2%; P

Abstract Background Identifying molecular biomarkers for predicting responses to anti-cancer drugs can enhance treatment precision and minimize side effects. This study investigated the novel cancer-targeting mechanism of combining SH003, an herbal medicine, with docetaxel in non-small cell lung cancer (NSCLC) cells. Also, the present study aimed to identify the genetic characteristics of cancer cells susceptible to this combination. Methods Cell viability was analyzed by WST-8 assay. Apoptosis induction, BrdU incorporation, and cell cycle analysis were performed using flow cytometry. Metabolites were measured by LC–MS/MS analysis. Real-time PCR and western blotting evaluated RNA and protein expression. DNA damage was quantified through immunofluorescence. cBioPortal and GEPIA data were utilized to explore the mutual co-occurrence of TP53 and UMPS and UMPS gene expression in NSCLC. Results The combination treatment suppressed de novo pyrimidine nucleotide biosynthesis by reducing the expression of related enzymes. This blockade of pyrimidine metabolism led to DNA damage and subsequent apoptosis, revealing a novel mechanism for inducing lung cancer cell death with this combination. However, some lung cancer cells exhibited distinct responses to the combination treatment that inhibited pyrimidine metabolism. The differences in sensitivity in lung cancer cells were determined by the TP53 gene status. TP53 wild-type lung cancer cells were effectively inhibited by the combination treatment through p53 activation, while TP53 mutant- or null-type cells exhibited lower sensitivity. Conclusions This study, for the first time, established a link between cancer cell genetic features and treatment response to simultaneous SH003 and docetaxel treatment. It highlights the significance of p53 as a predictive factor for susceptibility to this combination treatment. These findings also suggest that p53 status could serve as a crucial criterion in selecting appropriate therapeutic strategies for targeting pyrimidine metabolism in lung cancer.

Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.

Purpose of the study. Preventive pressurised intraperitoneal aerosol chemotherapy (PIPAC) safety assessment in the combined treatment of gastric cancer (GC).Patients and methods. The study included 48 patients with morphologically confirmed resectable GC and cardio esophageal transition, having at least one criterion that is a predictor of the development of peritoneal carcinomatosis, e. g. tumor spread to the serous layer (≥ T4a), diffuse tumor type, affected regional lymph nodes, large tumor, young age (up to 45 years), subtotally and totally affected stomach. 36 out of those patients received treatment according to the protocol. All patients received 4 cycles of neoadjuvant chemotherapy according to the FLOT scheme, radical surgical treatment in combination with a PIPAC session, 4 cycles of adjuvant chemotherapy according to the FLOT scheme. The safety assessment was carried out according to the classification of surgical complications according to Clavien-D indo and the international scale for toxicity scaling NCI–CTCAE v5.0.Results. Postoperative complications were diagnosed in 25 %, >III grade complications were revealed in 11 % of cases according to the Clavien-D indo classification. The postoperative mortality rate was 0 %.Conclusion. Preventive PIPAC of locally advanced GC and CET in combined treatment is a reproducible and safe method, which is characterized by the absence of an increase in the number of postoperative complications and mortality rate.

Abstract Background Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with a poor prognosis, particularly in patients presenting with distant metastasis (DM). This study aimed to assess the effect of combination treatment strategies on survival in ATC patients with DM. Methods A retrospective analysis was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database to identify primary ATC cases with DM at diagnosis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent risk factors for survival. Results Of the 315 ATC patients with DM included in the study, surgery to the primary tumor, radiotherapy, chemotherapy, and lung metastasis were identified as independent risk factors for survival. Patients who received primary tumor surgery plus chemotherapy or surgery plus chemoradiation exhibited a superior outcome compared to those who received only one treatment modality. Conclusion Our findings suggest that a combination treatment approach, particularly surgery combined with radiotherapy or surgery combined with chemoradiotherapy, may provide the most optimal treatment option for ATC patients with DM. These results may provide some evidence for clinical decision making, but larger sample cohorts are still needed for validation.

Background: The use of meal replacement products (MRPs) to obtain a caloric deficit while maintaining micro- and macronutrient requirements, has a long tradition in obesity medicine. Limitations include low compliance, variability in efficacy, adverse events (related to acute changes in nutrient intake), and risk of weight regain when discontinued, and their popularity has declined after the emergence of potent GLP-1 receptor analogues (GLP1-RAs). However, GLP-1RAs have limitations, including dose-dependent risk for adverse events (AEs), high cost, as well as weight regain when discontinued. Although concomitant use of MRPs and GLP-1RAs could address some of the limitations, there is a scarcity of data reported on this. Herein we report real world clinical experience of such combined use. Methods: This retrospective case evaluation involved people with obesity that concomitantly used MRPs (Optifast) and a GLP-1RA and were followed at one of three weight management centers in Australia or South Africa. Parameters collected were gender, age, co-morbidities, height, weight, frequency/amount of MRPs used, dose/type of GLP-1RA used, duration of combined use, and occurrence of AEs. Written informed consent for use of data was obtained from each individual, and the data were managed in an anonymized form and summarized descriptively. Result: A total of seven (5 females) individuals (mean [min, max] age 49 [30,66] years, BMI 44.8 [30.7, 57.9] kg/m2) initiated either semaglutide (n=4) or liraglutide (n=3) concomitantly with daily MRPs (starting number of servings/day 2.7 [1,6]) for a duration of 12 [4, 25] months. Change in weight/BMI/% TBW was -32.0 (-9.6, -77.8) kg/-10.3 (-3.4, -24.5) kg/m2/-24.2 %. Five individuals experienced ≥1 GLP-1RA related AE (nausea, reflux, burping, diarrhea, constipation). One individual discontinued GLP-1RA, whereas two persons discontinued the use of MRPs. Conclusions: MRPs can be initiated concomitantly with a GLP-1 RA for weight management. This might enhance weight-loss effectiveness, with potential additional benefits that should be elucidated in further and larger studies.

Background: Identifying molecular biomarkers for predicting responses to anti-cancer drugs can enhance treatment precision and minimize side effects. This study investigated the novel cancer-targeting mechanism of combining SH003, an herbal medicine, with docetaxel in non-small cell lung cancer (NSCLC) cells. Also, the present study aimed to identify the genetic characteristics of cancer cells susceptible to this combination. Methods: Cell viability was analyzed by WST-8 assay. Apoptosis induction, BrdU incorporation, and cell cycle analysis were performed using flow cytometry. Metabolites were measured by LC–MS/MS analysis. Real-time PCR and western blotting evaluated RNA and protein expression. DNA damage was quantified through immunofluorescence. cBioPortal and GEPIA data were utilized to explore the mutual co-occurrence of TP53 and UMPS and UMPS gene expression in NSCLC. Results: The combination treatment suppressed de novo pyrimidine nucleotide biosynthesis by reducing the expression of related enzymes. This blockade of pyrimidine metabolism led to DNA damage and subsequent apoptosis, revealing a novel mechanism for inducing lung cancer cell death with this combination. However, some lung cancer cells exhibited distinct responses to the combination treatment that inhibited pyrimidine metabolism. The differences in sensitivity in lung cancer cells were determined by the TP53 gene status. TP53 wild-type lung cancer cells were effectively inhibited by the combination treatment through p53 activation, while TP53 mutant- or null-type cells exhibited lower sensitivity. Conclusions: This study, for the first time, established a link between cancer cell genetic features and treatment response to simultaneous SH003 and docetaxel treatment. It highlights the significance of p53 as a predictive factor for susceptibility to this combination treatment. These findings also suggest that p53 status could serve as a crucial criterion in selecting appropriate therapeutic strategies for targeting pyrimidine metabolism in lung cancer. [ABSTRACT FROM AUTHOR]

Background: Facial hyperpigmentation can negatively affect an individual's emotional and psychosocial well‐being. Aims: Assess safety and tolerability of a combination of microdermabrasion (DG) procedures using a novel brightening pro‐infusion serum (EC‐DG) with a targeted at‐home treatment regimen in subjects with mild to severe facial hyperpigmentation, including melasma, post‐inflammatory hyperpigmentation, and dark spots. Patients/Methods: This 12‐week, open‐label study enrolled 18 subjects (Fitzpatrick skin types I–IV) who underwent 6 in‐office DG procedures with EC‐DG (one procedure administered biweekly), along with daily topical application of a brightening treatment serum and dark spot cream. End points included change from baseline across multiple skin quality attributes and the Melasma Area and Severity Index (MASI), self‐assessment questionnaires, and tolerability assessments. Results: The combination treatment was well tolerated and resulted in significant (p ≤ 0.05) improvements from baseline in radiance, tactile roughness, and moisturization/hydration immediately after the first treatment, in MASI score at day 3, and in overall hyperpigmentation at week 4. Most (94.1%) subjects were satisfied with treatment. Conclusions: DG procedures using EC‐DG combined with a targeted at‐home skincare regimen are effective and tolerable for treating facial hyperpigmentation across a broad range of skin types. [ABSTRACT FROM AUTHOR]

Purpose: Combination therapy is a strategy aimed at the combined use of agents targeting different mechanisms in cancer treatment. This study aimed to examine the cytotoxic and apoptotic effects of the traditional chemotherapeutic agent doxorubicin (DOX) and the next-generation HSP90 inhibitor MPC-3100 on breast cancer cell lines. Methods: Firstly, molecular docking analyses were performed, and then the MTT test was conducted to evaluate the individual and combined cytotoxic effects of DOX and MPC-3100 on MCF-7 and MDA-MB-231 breast cancer cell lines. The effect of two drugs combination was assessed by the Chou and Talalay approach. To further investigate the underlying molecular mechanism responsible for this synergistic effect, the gene expression levels of apoptotic and heat shock proteins (HSP), as well as the protein expression levels, were examined using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western Blotting, respectively. Results: Based on the molecular docking results, it was observed that MPC-3100 specifically binds to the ATP binding pocket of Hsp90, exhibiting an estimated free binding energy of -7.9 kcal/mol. MTT results indicated that both DOX and MPC-3100, as well as their combination, exhibited dose-dependent cytotoxicity. The drug combination showed a synergistic effect on both MCF-7 and MDA-MB-231 cell lines. Finally, the investigated molecular mechanism demonstrated that the combination of DOX and MPC-3100 induced apoptosis in breast cancer cells more efficiently than either drug alone. Conclusions: This study showed a possible coordinated mechanism of action between DOX and MPC-3100, pointing to the possibility of a more effective therapeutic strategy for breast cancer therapy. [ABSTRACT FROM AUTHOR]

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs. [ABSTRACT FROM AUTHOR]

Salivary adenoid cystic carcinoma (SACC) is one of the most common salivary gland malignancies. Current clinical therapies have limitations and cannot efficiently prevent the SACC development and metastasis. Hematogenous and neural spread are the two major routes of SACC metastasis. In this study, a precise and intelligent nanomedicine, RCDT, is designed to combine antivascular photodynamic therapy and neuroinhibitory chemotherapy against SACC. A tumor vessel‐targeted and reactive oxygen species (ROS)‐responsive photosensitizer (RC) is synthesized by linking cRGD to chlorin e6 (Ce6) via a bridge between the poly(ethylene glycol) and diselenide bonds. A neural‐targeted and pH‐responsive cytotoxic prodrug (DT) is synthesized by conjugating doxorubicin (DOX) with Tet1, a neural‐targeting peptide, via an acidic‐cleavable hydrazone bond. RC and DT are assembled to form RCDT via hydrophobic interactions, thereby shielding Tet1. Under the guidance of cRGD and the photodynamic action of Ce6, RCDT can precisely disrupt the tumor vasculature and simultaneously disintegrate to expose Tet1 by rupturing the diselenide bond. Guided by Tet1, disintegrated RCDT can be specifically internalized into neurons and release DOX to exert neuroinhibitory effects by cleaving the hydrazone bond. Using these stepwise dual‐targeting and dual‐responsive strategies, RCDT can efficiently suppress the growth and metastasis of SACC. [ABSTRACT FROM AUTHOR]

The magnetic hyperthermia‐based combination therapy (MHCT) is a powerful tumor treatment approach due to its unlimited tissue penetration depth and synergistic therapeutic effect. However, strong magnetic hyperthermia and facile drug loading are incompatible with current MHCT platforms. Herein, an iron foam (IF)‐drug implant is established in an ultra‐facile and universal way for ultralow‐power MHCT of tumors in vivo for the first time. The IF‐drug implant is fabricated by simply immersing IF in a drug solution at an adjustable concentration for 1 min. Continuous metal structure of IF enables ultra‐high efficient magnetic hyperthermia based on eddy current thermal effect, and its porous feature provides great space for loading various hydrophilic and hydrophobic drugs via "capillary action". In addition, the IF has the merits of low cost, customizable size and shape, and good biocompatibility and biodegradability, benefiting reproducible and large‐scale preparation of IF‐drug implants for biological application. As a proof of concept, IF‐doxorubicin (IF‐DOX) is used for combined tumor treatment in vivo and achieves excellent therapeutic efficacy at a magnetic field intensity an order of magnitude lower than the threshold for biosafety application. The proposed IF‐drug implant provides a handy and universal method for the fabrication of MHCT platforms for ultralow‐power combination therapy. [ABSTRACT FROM AUTHOR]

Pigment epithelium-derived factor (PEDF), a serine protease inhibitor (Serpin) family member, shows promise in inhibiting tumour growth. In our study, we explored the effects of PEDF on the efficacy of the frontline chemotherapy agent doxorubicin (Dox) in BC cells. We found that Dox+PEDF treatment significantly reduced glucose uptake in MDA-MB-231 cells compared to the control (p = 0.0005), PEDF (p = 0.0137), and Dox (p = 0.0171) alone but paradoxically increased it in MCF-7 cells. Our findings further revealed that PEDF, Dox, and Dox+PEDF substantially hindered tumour cell migration from tumour spheroids, with Dox+PEDF showing the most significant impact (p < 0.0001). We also observed notable decreases in the expression of metastatic markers (uPAR, uPA, CXCR4, MT1-MMP, TNF-α) across all treatment groups (p < 0.0001) in both cell lines. When it comes to metabolic pathways, PEDF increased phosphorylated IRS-1 (p-IRS1) levels in MDA-MB-231 and MCF-7 (p < 0.0001), while Dox decreased it, and the combination led to an increase. In MDA-MB-231 cells, treatment with PEDF, Dox, and the combination led to a notable decrease in both phosphorylated AKT (p-AKT) and total AKT levels. In MCF-7, while PEDF, Dox, and their combination led to a reduction in p-AKT, total levels of AKT increased in the presence of Dox and Dox+PEDF. Combining PEDF with Dox enhances the targeting of metastatic and metabolic pathways in breast cancer cell lines. This synergy, marked by PEDF's increasing roles in cancer control, may pave the way for more effective cancer treatments. [ABSTRACT FROM AUTHOR]

Introduction: Non‐severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. Methods: Non‐severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri‐operative combination treatment. In the single‐arm DAVID study intravenous desmopressin (0.3 μg/kg) once‐a‐day was, after sampling, immediately followed by PK‐guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK‐guided combination treatment (intervention arm) or PK‐guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. Results: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL. Conclusion: Peri‐operative combination treatment with desmopressin and PK‐guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with a poor prognosis, particularly in patients presenting with distant metastasis (DM). This study aimed to assess the effect of combination treatment strategies on survival in ATC patients with DM. Methods: A retrospective analysis was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database to identify primary ATC cases with DM at diagnosis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent risk factors for survival. Results: Of the 315 ATC patients with DM included in the study, surgery to the primary tumor, radiotherapy, chemotherapy, and lung metastasis were identified as independent risk factors for survival. Patients who received primary tumor surgery plus chemotherapy or surgery plus chemoradiation exhibited a superior outcome compared to those who received only one treatment modality. Conclusion: Our findings suggest that a combination treatment approach, particularly surgery combined with radiotherapy or surgery combined with chemoradiotherapy, may provide the most optimal treatment option for ATC patients with DM. These results may provide some evidence for clinical decision making, but larger sample cohorts are still needed for validation. [ABSTRACT FROM AUTHOR]

Background. Malaria has been appraised as a significant vector-borne parasitic disease with grave morbidity and high-rate mortality. Several challenges have been confronting the efficient diagnosis and treatment of malaria. Method. Google Scholar, PubMed, Web of Science, and the Egyptian Knowledge Bank (EKB) were all used to gather articles. Results. Diverse biochemical and physiological indices can mirror complicated malaria e.g., hypoglycemia, dyslipidemia, elevated renal and hepatic functions in addition to the lower antioxidant capacity that does not only destroy the parasite but also induces endothelial damage. Multiple trials have been conducted to improve recent points of care in malaria involving biosensors, lap on-chip, and microdevices technology. Regarding recent therapeutic trials, chemical falcipain inhibitors and plant extracts with anti-plasmodial activities are presented. Moreover, antimalaria nano-medicine and the emergence of nanocarrier (either active or passive) in drug transportation are promising. The combination therapeutic trials e.g., amodiaquine + artemether + lumefantrine are presented to safely counterbalance the emerging drug resistance in addition to the Tafenoquine as a new anti-relapse therapy. Conclusion. Recognizing the pathophysiology indices potentiate diagnosis of malaria. The new points of care can smartly manipulate the biochemical and hematological alterations for a more sensitive and specific diagnosis of malaria. Nano-medicine appeared promising. Chemical and plant extracts remain points of research. [ABSTRACT FROM AUTHOR]

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Combining multiple drugs broadens the window of therapeutic opportunities and is crucial for diseases that are currently lacking fully curative treatments. A powerful emerging tool for selecting effective drugs and combinations is the high-throughput drug screening (HTP). The histone deacetylase inhibitor (HDACi) givinostat (ITF2357) has been shown to act effectively against CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), a subtype characterized by poor outcome and enriched in children with Down Syndrome, very fragile patients with a high susceptibility to treatment-related toxicity. The aim of this study is to investigate possible synergies with givinostat for these difficult-to-treat patients by performing HTP screening with a library of 174 drugs, either approved or in preclinical studies. By applying this approach to the CRLF2-r MHH-CALL-4 cell line, we identified 19 compounds with higher sensitivity in combination with givinostat compared to the single treatments. Next, the synergy between givinostat and the promising candidates was further validated in CRLF2r cell lines with a broad matrix of concentrations. The combinations with trametinib (MEKi) or venetoclax (BCL2i) were found to be the most effective and with the greatest synergy across three metrics (ZIP, HAS, Bliss). Their efficacy was confirmed in primary blasts treated ex vivo at concentration ranges with a safe profile on healthy cells. Finally, we described givinostat-induced modifications in gene expression of MAPK and BCL-2 family members, supporting the observed synergistic interactions. Overall, our study represents a model of drug repurposing strategy using HTP screening for identifying synergistic, efficient, and safe drug combinations.

The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA+ cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8+ T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8+ T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.

Abstract Background Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy. Methods We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models. Results The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4+ and CD8+ T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines. Conclusions Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.

Background: Angiotensin receptor/neprilysin inhibitor (ARNI) and sodiumglucose cotransporter 2 inhibitor (SGLT2i) have shown a significant protective role against cardiovascular diseases and type 2 diabetes mellitus (T2DM), and there is a growing proportion of patients who are undergoing combined therapy with the two drugs. However, the effect of this combination treatment on renal function has not yet been determined. Methods: This study included 539 patients who were diagnosed with cardiovascular disease combined with T2DM. According to the use of SGLT2i and ARNI, patients were divided into the combination treatment group, SGLT2i group, ARNI group and control group. Primary outcomes were serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) changes in the 6th month and 12th month. Results: In the ARNI group, no significant changes in Scr or eGFR were observed during the follow-up period, while the above indicators showed a trend of deterioration in the other three groups. The univariate analysis results showed that at 6 months of follow-up, the renal function indicators of patients treated with ARNI (either alone or in combination) were better than those treated with SGLT2i alone. After 12 months of follow-up, the Scr results were the same as before, while the difference in eGFR between groups disappeared. After multivariate analysis, in terms of delaying the progression of Scr, the ARNI group was superior to the other groups at the end of follow-up. No significant difference in eGFR was observed between groups during follow-up. Conclusion: In patients with cardiovascular disease and T2DM, combination therapy with ARNI and SGLT2i did not show an advantage over monotherapy in delaying renal insufficiency progression, and renal function seems to be better preserved in patients treated with ARNI alone. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aims to describe the current state of the art in the field of immunotherapy applied to patients with cancer-harboring microsatellite instability, giving a comprehensive landscape of the possible therapeutical strategies in these patients. We discuss the potential of combination strategies and novel therapeutic approaches that may change the management of microsatellite-instable cancer in the future. High microsatellite instability (MSI-H) derives from genomic hypermutability due to deficient mismatch repair function. Colorectal (CRC) and endometrial cancers (EC) are the tumor types that more often present MSI-H. Anti-PD(L)-1 antibodies have been demonstrated to be agnostically effective in patients with MSI-H cancer, but 50–60% of them do not respond to single-agent treatment, highlighting the necessity of expanding their treatment opportunities. Ipilimumab (anti-CTLA4) is the only immune checkpoint inhibitor (ICI) non-targeting PD(L)-1 that has been approved so far by the FDA for MSI-H cancer, namely, CRC in combination with nivolumab. Anti-TIM3 antibody LY3321367 showed interesting clinical activity in combination with anti-PDL-1 antibody in patients with MSI-H cancer not previously treated with anti-PD(L)-1. In contrast, no clinical evidence is available for anti-LAG3, anti-TIGIT, anti-BTLA, anti-ICOS and anti-IDO1 antibodies in MSI-H cancers, but clinical trials are ongoing. Other immunotherapeutic strategies under study for MSI-H cancers include vaccines, systemic immunomodulators, STING agonists, PKM2 activators, T-cell immunotherapy, LAIR-1 immunosuppression reversal, IL5 superagonists, oncolytic viruses and IL12 partial agonists. In conclusion, several combination therapies of ICIs and novel strategies are emerging and may revolutionize the treatment paradigm of MSI-H patients in the future. A huge effort will be necessary to find reliable immune biomarkers to personalize therapeutical decisions. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is one of the most lethal gynecological cancers among women worldwide. Cisplatin (Cis) is an effective chemotherapeutic agent used to treat several types of cancer. Silymarin (SLM) is an extract of medicinal plant Silybum marianum (milk thistle) with anti-inflammatory, anti-angiogenesis, antioxidant, and anticancer properties used alone or in combination with other drugs. Objective: This study aimed to explore the effects of co-treatment with SLM and Cis on A2780 human ovarian cancer cell lines. Methods: In this study, A2780 cells were treated with various concentrations of SLM and Cis, separately and in combination. Cell cytotoxicity, scratch, clonogenic, and flow-cytometry assays were accomplished to estimate cell viability, migration, colony formation, and apoptosis, respectively. Real-time PCR was utilized to determine the expression levels of miR-155 and miR-27a. Results: SLM significantly reduced the proliferation of A2780 cells in a concentration- and time-dependent manner. Combination treatment with SLM and Cis was more potent than either single treatment in reducing viability, suppressing migration, inhibiting colony formation, and promoting the induction of apoptosis. Additionally, gene expression analysis revealed a significant decline in the expression levels of miR-155 and miR-27a in response to all separate and combined treatments, and co-treatment was more effective than individual treatments in altering miRNAs expression. Conclusion: Based on our findings, SLM boosts the anticancer activity of Cis and mitigates its side effects. Thus, the co-treatment of SLM and Cis can be proposed as a promising therapeutic strategy for further investigation. [ABSTRACT FROM AUTHOR]

Despite efforts in osteosarcoma (OS) research, the role of inductive moderate hyperthermia (IMH) in delivering and enhancing the antitumor effect of liposomal doxorubicin formulations (LDOX) remains unresolved. This study investigated the effect of a combination treatment with LDOX and IMH on Saos-2 human OS cells. We compared cell viability using a trypan blue assay, apoptosis and reactive oxygen species (ROS) measured by flow cytometry and pro-apoptotic Bax protein expression examined by immunocytochemistry in response to IMH (42 MHz frequency, 15 W power for 30 min), LDOX (0.4 μg/mL), and LDOX plus IMH. The lower IC50 value of LDOX at 72 h indicated increased accumulation of the drug in the OS cells. LDOX plus IMH resulted in a 61% lower cell viability compared to no treatment. Moreover, IMH potentiated the LDOX action on the Saos-2 cells by promoting ROS production at temperatures of <42 °C. There was a 12% increase in cell populations undergoing early apoptosis with a less heterogeneous distribution of Bax after combination treatment compared to those treated with LDOX (p < 0.05). Therefore, we determined that IMH could enhance LDOX delivery and its antitumor effect via altered membrane permeabilization, ROS generation, and a lower level of visualized Bax heterogeneity in the Saos-2 cells, suggesting the potential translation of these findings into in vivo studies. [ABSTRACT FROM AUTHOR]

Objective Despite having normal thyroid-stimulating hormone levels, many hypothyroid patients are dissatisfied with the treatment. The primary aim of this study was to evaluate the effect of twice-daily, combination therapy with levothyroxine (LT4) and liothyronine (LT3), at doses adapted according to TSH-level, on peripheral tissues as reflected by sex hormone binding globulin (SHBG) levels in totally thyroidectomized patients. Changes in other tissue markers and quality of life considering DIO2 -rs225014 and MCT10 -rs17606253 genetic variants were also assessed. Design Double-blind, randomized, placebo-controlled. Methods One hundred and forty-one subjects were randomized to LT4 + LT3 group (LT4 + LT3 in the morning and LT3 in the evening; n = 70) or placebo group (LT4 in the morning and placebo in the evening; n = 71). Pituitary-thyroid axis compensation was assessed after 6, 12, and 24 weeks. Clinical parameters, quality of life, and tissue markers (sex hormone binding globulin, serum lipids, bone markers) were evaluated at 12 and 24 weeks. DIO2 and MCT10 single nucleotide polymorphisms were genotyped. Results The LT4 + LT3 group was treated with mean daily LT3 doses of 5.00 µg, with a mean daily LT4 reduction of 15 µg. After 6 months of treatment, neither SHBG and other tissue markers nor quality of life differed significantly between groups. Combination treatment required greater dose adjustments than placebo (25% vs 54%, P <.001), due to thyroid-stimulating hormone reduction, without hyperthyroidism signs or symptoms. At the end of treatment, the LT4 + placebo group had significantly lower fT3/fT4 compared to the LT4 + LT3 group (0.26 ± 0.05 vs 0.32 ± 0.08, P <.001). No preference for combination therapy was found. Genetic variants did not influence any outcomes. Conclusions Six months of combination therapy with twice-daily LT3 dose adapted according to TSH-level do not significantly change peripheral tissue response or quality of life, despite an increase in the fT3/fT4 ratio. [ABSTRACT FROM AUTHOR]

Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection. These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates. They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance, making them an invaluable asset in the era of antibiotic resistance. Numerous depolymerases have been investigated preclinically, with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models. Additionally, some formulation approaches have been developed for improved stability and activity of depolymerases. However, depolymerase formulation is limited to liquid dosage form and remains in its infancy, posing a significant hurdle to their clinical translation, compounded by challenges in their applicability and manufacturing. Future development must address these obstacles for clinical utility. Here, after unravelling the history, diversity, and therapeutic use of depolymerases, we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases. Finally, the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development. Phage-derived polysaccharide depolymerases are useful as antibiofilm agents and antimicrobial adjuvants. Their preclinical efficacy was reviewed, and their challenges and prospects for clinical translation were discussed. [Display omitted] [ABSTRACT FROM AUTHOR]