Dual-targeted treatment for inflammatory bowel disease: Whether fecal microbiota transplantation can be an important part of it.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease. With the emergence of biologics and other therapeutic methods, two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD. Although treatment strategies for IBD are being optimized, their efficacy and risks still warrant further consideration. This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation (FMT) may have for use in combination therapy for IBD. We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment. In this new therapy regimen, FMT represents a promising combination therapy.

Intra-arterial chemotherapy combined with BCG immunotherapy is more effective than intra-arterial chemotherapy plus intravesical chemotherapy or standard BCG immunotherapy in preventing the recurrence and progression of high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Up to 45% of patients with high-risk non-muscle-invasive bladder cancer (NMIBC) will not benefit from adjuvant intravesical instillation. We aimed to introduce intra-arterial chemotherapy (IAC) to existing intravesical treatment and evaluate its feasibility and safety. MATERIALS AND METHODS: We collected data from 170 patients who had been diagnosed with high-risk NMIBC and underwent transurethral resection of bladder tumor (TURBT) over the last 5 years. Twenty-seven patients were excluded according to specific exclusion criteria. The remaining 143 patients were divided into 3 groups according to their treatment: intravesical instillation of Bacillus Calmette - Guerin (BCG), BCG+ intra-arterial chemotherapy (IAC), and intravesical chemotherapy (IVC)+IAC groups. All groups received standard intravesical instillation of BCG or chemotherapeutic agents. In contrast, both the BCG+IAC and IVC+IAC groups received four courses of IAC (injection of cisplatin [60 mg/m2] and epirubicin [50 mg/m2] in the internal iliac arteries via Seldinger's percutaneous technique). RESULTS: The median follow-up time was 47 months, ranging from 20 to 60 months. The restricted mean survival time (RMST), which represents the recurrence and progression rate of the BCG+IAC group, differed significantly when compared with the BCG group (P = 0.029 and 0.004, respectively) and the IVC+IAC group (P = 0.004 and 0.006, respectively). Kaplan-Meier plots revealed that the recurrence and progression-free survival of the BCG+IAC group were significantly higher than the BCG and IVC+IAC groups (P = 0.033 and 0.028, respectively). In contrast, the BCG and IVC+IAC groups showed similar RMST (P = 0.156 and 0.935, respectively), recurrence (P = 0.627), and progression-free (P = 0.931) survival. A small proportion of patients (20%) suffered from the adverse effects of IAC while 65% suffered from adverse reactions to intravesical instillation. Most adverse effects were ranked as grade I or II according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. CONCLUSION: Analysis showed that tumor recurrence and progression rate in the BCG+IAC group was lower than the BCG and IVC+IAC groups while patients in the IVC+IAC group suffered from milder adverse effects in cystitis and flu-like symptoms. Our findings may provide a new perspective for urologists when treating patients with high-risk NMIBC.

Poly (ADP-ribose) polymerase inhibitor sensitized DNA damage caused by an alkylating pyrrole-imidazole polyamide targeting MYCN in neuroblastoma cells.

MYCN amplification (MYCN-amp) is a significant prognostic factor and early genetic marker of high-risk neuroblastoma (NB). MYCN induces the DNA damage response (DDR) and modulates the insensitivity of NB cells to Poly (ADP-ribose) polymerase (PARP) inhibitors. We previously reported that CCC-002, a DNA-alkylating agent conjugated with pyrrole-imidazole polyamide targeting MYCN, inhibits NB cell proliferation and induces DNA damage signaling. In this study, we investigated the synergistic effects of CCC-002 and PARP inhibitors on MYCN-amp NB cells. Combination treatment with PARP inhibitors significantly enhanced the sensitivity of MYCN-amp NB cells to CCC-002. DNA damage signals, such as phosphorylation of H2AX and RPA32 elicited after CCC-002 treatment, were further enhanced by PARP inhibitors, as detected through western blotting and immunofluorescence analyses. The potent cytotoxicity of this combination treatment was confirmed by the significant increase in the subG0-G1 phase. Although MYCN knockdown showed no synergistic effect with PARP inhibitors, fluorescence in situ hybridization and quantitative PCR analyses indicated that PARP inhibitors enhanced the effect of CCC-002 to reduce MYCN copy number and suppress its expression. Overall, our study provides novel insights into a therapeutic approach that combines CCC-002 and PARP inhibition to effectively induce DNA damage and apoptosis in MYCN-amp NB cells.

Deoxypodophyllotoxin Mediates Autophagy Death through Inhibition of GRP78 in Human Osteosarcoma.

BACKGROUND: Glucose-regulated protein 78 (GRP78), as a chaperone protein, can protect the endoplasmic reticulum of cells and is expressed to influence chemoresistance and prognosis in cancer. Deoxypodophyllotoxin (DPT) is a compound with antitumor effects on cancers. DPT inhibits the proliferation of osteosarcoma by inducing apoptosis, necrosis, or cell cycle arrest. OBJECT: This study was performed to demonstrate the molecular mechanism by which DPT attenuates osteosarcoma progression through GRP78. METHODS: Natural compound libraries and western blot (WB) were used to screen the inhibitors of osteosarcoma GRP78. The expression of mitochondria-related genes in cancer cells of the treatment group was detected by quantitative real-time PCR (qPCR) and WB. 3-(4,5)- Dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and 5-ethynyl-2'- deoxyuridine (EDU) were used to discover the activity and proliferation of osteosarcoma cells treated with DPT. We constructed an in vivo mouse model of DPT drug therapy and carried out immunohistochemical detection of xenografts. The treated osteosarcoma cells were analyzed using bioinformatics and electron microscopy. The data were analyzed finally. RESULTS: DPT inhibited osteosarcoma cell survival and the growth of tumor xenografts. It promoted up-regulation of BCL2-associated X protein (Bax) and B-cell CLL/lymphoma 2 (Bcl-2), which serves to mediate and attenuate, respectively, the killing activities of DPT through mitochondria dysfunction. The effect of DPT against cancer cells could be attenuated by the overexpression of GRP78, characterized by the inactivation of the caspase cascade. The loss of GRP78 in osteosarcoma cells negatively mediated the basal level of autophagyassociated genes. DPT stimulated autophagy via the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog (AKT), a mechanistic target of rapamycin (mTOR) axis. The autophagy caused by DPT played an active role in the osteosarcoma of humans and blocked the apoptotic cascade. CONCLUSION: Combination treatment with the GRP78 inhibitor DPT and pharmacological autophagy inhibitors will be a meaningful method of obviating osteosarcoma cells.

Real-World Evidence of the Safety and Effectiveness of Atogepant Added to OnabotulinumtoxinA for the Preventive Treatment of Chronic Migraine: A Retrospective Chart Review.

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.

Atomoxetine and spironolactone combine to reduce obstructive sleep apnea severity and blood pressure in hypertensive patients.

BACKGROUND: Norepinephrine reuptake inhibitors such as atomoxetine (ato) can improve OSA by increasing pharyngeal muscle activity. Mineralocorticoid antagonists such as spironolactone, may potentiate the reduction of OSA severity and reduce blood pressure. We evaluated whether adding spironolactone to atomoxetine (ato-spiro) improved responses in hypertensive OSA patients. METHODS: Twenty-one patients with an apnea-hypopnea index (AHI) between 10 and 50 events/h and a history of hypertension were recruited and crossed-over in random order to ato 80 mg and ato-spiro 80/50 mg for 1 week after a 3-day low dose run-in period. Two dropped out due to drug related side effects. Polysomnography and 24-hour blood pressure (BP) monitoring were performed at baseline and after each treatment period. RESULTS: AHI decreased on both ato and ato-spiro from a baseline median(IQR) of 20.3(18.8 to 28.5) to 8.2(7 to 13.1) and 6.2(5.7 to 14.1), respectively (p < 0.001 for both). Systolic BP (mmHg) fell by mean(95%CI) -4.5(-13.8 to 4.8, p = 0.33) on ato and - 10.3(-19.2 to -1.5, p = 0.02) on ato-spiro, and diastolic BP dropped by -3.0(-8.0 to 2.0, p = 0.23) on ato and - 5.0(-9.1 to -0.9; p = 0.02) on ato-spiro. Both ato and ato-spiro led to a significant shift from apnea to hypopnea predominance (p < 0.001), and significant reductions in hypoxic burden (p ≤ 0.001) and REM sleep (p ≤ 0.001). CONCLUSIONS: Both ato-spiro and ato alone decreased OSA severity similarly, but ato-spiro led to even greater, statistically significant and clinically meaningful falls in systolic and diastolic BP. BP reductions were likely due to ato-related improvements in upper airway patency and hypoxemia, and to spiro-related reduced fluid retention. These findings show promise for ato-spiro as an oral treatment for hypertensive OSA patients. REGISTERED AT CLINICALTRIALS.GOV: NCT04905979.

Estrogen treatment in combination with pyruvate kinase M2 inhibition precipitate significant cumulative antitumor effects in colorectal cancer.

It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17ß-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.

Enhancing [177Lu]Lu-DOTA-TATE therapeutic efficacy in vitro by combining it with metronomic chemotherapeutics.

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.

Synergistic drug interactions of the histone deacetylase inhibitor givinostat (ITF2357) in CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia identified by high-throughput drug screening.

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.

Role of AURKB Inhibition in Reducing Proliferation and Enhancing Effects of Radiotherapy in Triple-Negative Breast Cancer.

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.

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.

[Liposome co-delivery of quercetin and doxorubicin in inhibiting retinoblastoma by regulating epithelial-mesenchymal transition process].

Regulating the process of epithelial-mesenchymal transition(EMT) is an essential strategy to inhibit tumor growth and metastasis. This study is based on the EMT process of retinoblastoma and constructs quercetin(QUE) and doxorubicin(DOX) co-loaded liposome(QD Lipo) to investigate the therapeutic effect and mechanisms of combined QUE and DOX treatment on retinoblastoma. Single-factor experiments were conducted to optimize the prescription process of QD Lipo. Eventually, spherical particles with a diameter of(108.87±1.93) nm, a PDI of 0.13±0.02, and a Zeta potential of(-34.83±1.92) mV were obtained. The encapsulation rates of QUE and DOX were 96.20%±4.40% and 91.17%±4.41%, respectively. Y79 human retinoblastoma cells were used as an in vitro cellular model, and confocal microscopy demonstrated that QD Lipo could enhance Y79 uptake efficiency. The CCK-8 assay confirmed that the optimal combination therapy effect of QUE and DOX occurred at a mass ratio of 1∶1 to 1∶2. Flow cytometry showed that QD Lipo enhanced the induction of apoptosis in Y79 cells. Western blot analysis revealed that QD Lipo significantly reduced the expression of EMT pathway-related proteins vimentin and α-SMA. Fluorescence assays detected a significant decrease in ROS levels in Y79 cells after treatment with QD. These results indicated that liposomal co-delivery of QUE and DOX can enhance drug delivery efficiency to retinoblastoma cells, inhibit the EMT process in retinoblastoma by downregulating ROS levels, and enhance the cytotoxicity of DOX against retinoblastoma.

Using the Zebrafish Larval Model of Infection to Investigate Antibiotic Efficacy and Combination Treatments Against Staphylococcus aureus.

There is an increasing need for new treatment regimens to combat antibiotic-resistant strains of bacteria. Staphylococcus aureus is a clinically important, opportunist pathogen that has developed resistance to a range of antibiotics. The zebrafish larval model of systemic disease has been increasingly utilized to elucidate S. aureus virulence mechanisms and host-pathogen interactions. Here, we outline how this model can be used to investigate the effects of different antibiotics alone and in combination against S. aureus.

A Synergistic Strategy Combining Chemotherapy and Photodynamic Therapy to Eradicate Prostate Cancer.

Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop a novel theranostic agent, PSMA-1-MMAE-Pc413, which integrates a PSMA-targeting ligand, the photosensitizer Pc413, and the microtubular inhibitor monomethyl auristatin E (MMAE) for synergistic therapeutic efficacy. In vitro uptake studies revealed that PSMA-1-MMAE-Pc413 demonstrated selective and specific uptake in PSMA-positive PC3pip cells but not in PSMA-negative PC3flu cells, with the uptake in PC3pip cells being approximately three times higher. In vitro cytotoxicity assays showed that, when exposed to light, PSMA-1-MMAE-Pc413 had a synergistic effect, leading to significantly greater cytotoxicity in PSMA-positive cells (IC50 = 2.2 nM) compared to PSMA-1-Pc413 with light irradiation (IC50 = 164.9 nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50 = 12.6 nM). In vivo imaging studies further demonstrated the selective uptake of PSMA-1-MMAE-Pc413 in PC3pip tumors. In in vivo studies, PSMA-1-MMAE-Pc413 dramatically improves the therapeutic outcome for prostate cancer by providing a synergistic effect that surpasses the efficacy of each treatment modality alone in PC3pip tumors. These findings suggest that PSMA-1-MMAE-Pc413 has strong potential for clinical application in improving prostate cancer treatment.

Gentamicin combination treatment is associated with lower mortality in patients with invasive listeriosis: a retrospective analysis.

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.

Treatment Approaches for Posttraumatic Stress Disorder Derived From Basic Research on Fear Extinction.

This brief review article will describe treatment approaches for posttraumatic stress disorder (PTSD) based on findings from basic research. The focus of this review will be fear conditioning and extinction models, which provide a translational model of PTSD that can help translate basic research in nonhuman animals through well-controlled trials confirming the efficacy of treatment approaches in humans with PTSD such as prolonged exposure therapy. Specific cognitive aspects of fear extinction processes, including consolidation and reconsolidation, are reviewed along with behavioral and pharmacological treatment strategies based on basic research in these areas including attempts to prevent the development of PTSD as well as the treatment of chronic PTSD. Pharmacological, behavioral, and device-based augmentation strategies of PTSD treatment based in basic science findings are reviewed, including those that disrupt noradrenergic receptor processes, medications that act on NMDA receptors, physical exercise, cannabinoids, estradiol, dexamethasone, yohimbine, losartan, dopamine, and MDMA, along with the evidence for their efficacy in human clinical samples. While fear extinction provides an exciting translational opportunity to improve PTSD based on basic science findings, we review limitations and challenges of the extant literature as well as future directions.

Treatment of infections caused by carbapenem-resistant Acinetobacter baumannii.

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, ampicillin-sulbactam, 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.

Therapeutic Potential of Combined Herbal Medicine and Electroacupuncture in Mild Cognitive Impairment Through Cytokine Modulation: An Observational Study.

Purpose: 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.

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.

Combination Therapy Approach to Overcome the Resistance to PI3K Pathway Inhibitors in Gynecological Cancers.

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.

HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation.

Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.

Rapamycin circumvents anti PD-1 therapy resistance in colorectal cancer by reducing PD-L1 expression and optimizing the tumor microenvironment.

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.