Pomalidomide combined with dexamethasone for the treatment of relapsed/refractory multiple myeloma: a systematic review and meta-analysis.

BACKGROUND: To evaluate the efficacy and safety of pomalidomide in combination treatment of relapsed/refractory multiple myeloma (RRMM). METHODS: Published clinical trials were searched in the Cochrane Library, PubMed, EMBASE to February 2023. The literature was screened and evaluated according to the inclusion criteria, and the data were analyzed by a random effect model. Overall response rate (ORR), overall survival (OS), progression-free survival (PFS) and full grade or ≥ 3 adverse events (AEs) were the outcomes. RESULTS: This study included 31 clinical trials, which included 4776 patients. The pooled ORR of the doublet regimens was 33.3% (95%CI: 27-39%) and the triplet regimens was 66% (95%CI: 58-74%). Among the 25 included studies, the median PFS was 8.29 months (95%CI: 7.27-9.31), and nine studies reported median OS of 19.43 months (95%CI: 14.56-24.30). In terms of safety, the most common hematologic AEs of grade ≥ 3 were neutropenia (41%) and anemia (20%); Non-hematologic AEs were pneumonia (14%) and infection/febrile neutropenia (14%). CONCLUSIONS: Pomalidomide combined treatment regimens have shown good clinical efficacy, especially in pomalidomide + dexamethasone combined with other drugs. In terms of safety, it's important to pay attention to the likelihood of hematological adverse events when used clinically. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42023420644.

Effects of allisartan-isoproxil-based combination antihypertensive regimen in hypertensive patients with microalbuminuria or hyperuricemia.

Microalbuminuria and hyperuricemia management are crucial for the integrated management of hypertensive patients. This retrospective post hoc analysis aims to evaluate the optimal allisartan-isoproxil-based combination regimen for hypertensive patients with microalbuminuria or hyperuricemia. A total of 460 hypertensive patients with microalbuminuria and 486 hypertensive patients with hyperuricemia were included in this study. All patients were initially treated with allisartan-isoproxil for 4 weeks. Thereafter, patients with blood pressure (BP) < 140/90 mmHg continued the monotherapy for 8 weeks; patients with BP ≥140/90 mmHg were randomly assigned in a 1:1 ratio to receive allisartan-isoproxil + amlodipine (Group A + C) or allisartan-isoproxil + indapamide (Group A + D) for 8 weeks. The changes of BP, urinary albumin and serum uric acid (UA) were measured. In patients with microalbuminuria, the urinary albumin/creatinine ratio (UACR) significantly decreased by 10.4 mg/g in Group A + C (vs. baseline p = .0035) and 24.2 mg/g in Group A + D (vs baseline p < .0001), intergroup p = NS. In patients with hyperuricemia, serum UA level decreased by 44.5 µmol/L in Group A + C (vs. baseline p = .0003), but increased by 27.2 µmol/L in Group A + D (vs. baseline p = .0167), intergroup p < .0001. The results suggest that for hypertensive patients with microalbuminuria, angiotensin receptor blocker (ARB) + calcium channel blocker (CCB) or ARB+ diuretic both are good choices based on their improvement of microalbuminuria and BP. But for patients with hyperuricemia, ARB + diuretic may further increase the level of UA.

The impact of primary region resection on the therapeutic outcome of combination regimens for metastatic renal cell carcinoma.

The present study aimed to clarify the relationship between the therapeutic outcome of combination regimens, including immune checkpoint inhibitors (ICIs) and/or tyrosine kinase inhibitors (TKIs), and cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC). The present study retrospectively assessed the association between treatment efficacy and prognosis with or without CN, and the timing of CN in 151 patients treated with combination regimens for mRCC who were categorized as intermediate/poor risk. The first-line regimens included the ICI-ICI and ICI-TKI regimens in 98 and 53 cases, respectively. In patients with recurrence after radical surgery (n=66), the 50% PFS times of the ICI-ICI and the ICI-TKI groups were 33.6 months and not reached (NR) (P=0.4032), respectively, and the 50% OS times were 53.7 months and NR (P=0.6886), respectively. Among the 38 patients with metastasis from the initial diagnosis who underwent upfront CN, the 50% PFS times of the ICI-ICI and the ICI-TKI groups were 10.5 and 8.2 months (P=0.5806), respectively, and the 50% OS times were NR and 15.8 months (P=0.0587), respectively. Among the 51 patients who did not receive upfront CN, the 50% PFS time of the ICI-TKI group was significantly higher than that in the ICI-ICI group (4.1 months and NR, respectively; P=0.0210), and the 50% OS times were 29.8 months and NR (P=0.7343), respectively. In conclusion, according to the analysis of real-world data, good therapeutic efficacy can be achieved with any regimen in patients with recurrence after radical surgery. In addition, improved results could be achieved through treatment with ICI-TKI in patients without upfront CN.

Randomized controlled trial comparing efficacy of a combination regime containing two cervical sensitizers (mifepristone + Foley's catheter) versus single agent mifepristone or Foley's catheter for labor induction in women attempting TOLAC at late third trimester with a dead fetus in utero.

Randomized controlled trial comparing efficacy of a combination regime containing two cervical sensitizers (mifepristone + Foley's catheter) versus single agent mifepristone or Foley's catheter for labor induction in women attempting TOLAC at late third trimester with a dead fetus in utero. AIM: To compare efficacy and safety of a new combination regime comprising of two cervical sensitizers used simultaneously with single agents, for labor induction in women attempting TOLAC at ≥34 weeks' gestation with a dead fetus. METHOD: This was a multiarm randomized controlled trial (RCT) where participants received one of the three regimes-single agent oral Mifepristone 200 mg, intracervical Foley's catheter (16 Fr size, filled with 40 mL normal saline after intracervical instillation), and combination regime consisting of both used simultaneously. Number of women undergoing vaginal birth within 48 h of induction (VB48 ) was the primary outcome compared between groups. RESULTS: VB48 was higher in participants on combination regime in comparison to participants on Foley's catheter (54 vs. 42). Total vaginal births were higher in participants on combination regime compared to both single agents (58 vs. 48 and 44). Duration and dose of oxytocin augmentation was lower in participants on combination regime compared to both single agents. Induction birth interval was short in participants on combination regime compared to those on Foley's catheter. Maternal complications between groups were similar. CONCLUSION: Combination of cervical sensitizers for labor induction in late third trimester among women with dead fetus attempting TOLAC resulted in higher proportion of vaginal births and might reduce risk of scar dehiscence due to requirement of a lower dose of oxytocin for augmentation.

Development of a combination antibiogram for empirical treatments of Pseudomonas aeruginosa at a university-affiliated teaching hospital.

INTRODUCTION: The significantly higher mortality rate in the critical illness patients with Pseudomonas aeruginosa (PA) infection is linked to inappropriate selecting of empirical treatment. Traditional local antibiogram provides clinicians the resistant rate of a single antimicrobial agent to the pathogen in the specific setting. The information is valuable to the clinicians in selecting suitable empirical antibiotic therapy. However, traditional local antibiogram can only provide information for single agent empirical antibiotic not combination regimens. The combination antibiogram should be developed to facilitate the selection of appropriate antibiotics to broader the coverage rate of resistant PA. METHODS: The susceptibility to the ß-lactam antibiotics (piperacillin/tazobactam (PTZ), ceftazidime, cefepime, imipenem, or meropenem) or to those administered in combination with an aminoglycoside (gentamicin or amikacin) or fluoroquinolone (ciprofloxacin or levofloxacin) was calculated. The chi-square test was used to compare the differences of combination coverage rates between non-ICU and ICU isolates. RESULTS: 880 PA isolates were isolated during study period. The susceptibility of single agents ranged from 83.1% to 89.7%. The combination regimens containing amikacin provide the highest cover rate (98.9%-99.1%) and those containing levofloxacin provide less coverage rate (92.3%-93.9%). The susceptibility to five ß-lactam single agents in ICU isolates significantly lower than non-ICU isolates. The non-ICU isolates exhibited significantly higher susceptibility to the PTZ-gentamicin (p = 0.002) and ceftazidime-gentamicin (p = 0.025) than ICU isolates. CONCLUSION: Our results support the use of aminoglycosides instead of fluoroquinolones as additive agents in empirical combination treatments for patients with critical infections caused by PA.

Cardiovascular adverse events associated with cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone with or without rituximab ((R)-CDOP) in non-Hodgkin's lymphoma: A systematic review and meta-analysis.

Background: The (R)-CDOP combination regimen, based on pegylated liposomal doxorubicin, is increasingly used for elderly patients with non-Hodgkin's lymphoma. However, the cardiotoxicity and efficacy of the (R)-CDOP regimen compared with conventional anthracyclines have not been demonstrated in the general population. Therefore, this systematic review and meta-analysis evaluated the risk of cardiotoxicity and efficacy associated with the (R)-CDOP regimen in patients with non-Hodgkin's lymphoma. Methods: PubMed, Embase, Cochrane Library, CNKI, WanFang Database, and VIP were searched. The search covered the period from the start of the clinical use of (R)-CDOP to April 2022. We searched the literature for cardiovascular adverse events associated with (R)-CDOP in non-Hodgkin's lymphoma. The data were analyzed using R 4.2.0 and Stata 12.0. Results: From the included studies, the important findings were as follows: total cardiovascular event rate, 7.45% (95% confidence interval [CI] = 4.86%-10.44%); non-serious cardiovascular adverse event rate, 6.48% (95% CI = 3.70%-9.8%); serious cardiovascular adverse event rate, 0.67% (95% CI = 0.00%-2.12%); heart failure rate, 0.55% (95% CI = 0.00%-1.93%); rate of treatment discontinuation attributable to left ventricular dysfunction or heart failure, 0.02% (95% CI = 0.00%-0.57%); and cardiovascular death rate, 0.00% (95% CI = 0.00%-0.37%). Compared with the (R)-CHOP regimen, the (R)-CDOP regimen reduced the risk of cardiovascular events, including total cardiovascular adverse events (odds ratio [OR] = 0.161, 95% CI = 0.103-0.251, p < 0.001, and NNT = 3.7), non-serious cardiovascular adverse events (OR = 0.171, 95% CI = 0.093-0.314, p < 0.001, and NNT = 3.6), serious cardiovascular adverse events (OR = 0.252, 95% CI = 0.119-0.535, p < 0.001, and NNT = 6.8), and heart failure (OR = 0.294, 95% CI = 0.128-0.674, p = 0.004, and NNT = 9.5). To evaluate the survival benefits, we compared (R)-CDOP and (R)-CHOP regimens. We found that the (R)-CDOP regimen was no less efficacious, including complete remission (CR) (OR = 1.398, 95% CI = 0.997-1.960, and p = 0.052), partial response (PR) (OR = 1.631, 95% CI = 1.162-2.289, and p = 0.005), objective response rate (ORR) (OR = 2.236, 95% CI = 1.594-3.135, and p < 0.001), stable disease (SD) (OR = 0.526, 95% CI = 0.356-0.776, and p = 0.001), and progressive disease (PD) (OR = 0.537, 95% CI = 0.323-0.894, and p = 0.017). Conclusion: Our findings suggested that the (R)-CDOP regimen had a lower risk of cardiovascular adverse events in non-Hodgkin's lymphoma than the (R)-CHOP regimen, demonstrating its safety with regard to cardiotoxicity. In addition, this study found the (R)-CDOP regimen was no less efficacious than the (R)-CHOP regimen in the treatment of non-Hodgkin's lymphoma. These findings need to be validated by higher-quality research because of the limited number and quality of included studies.

Human and nonclinical disposition of [14C]bictegravir, a potent integrase strand-transfer inhibitor for the treatment of HIV-1 infection.

Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, metabolism, distribution, and elimination (ADME) characteristics of BIC were determined through in vivo nonclinical and clinical studies (IND 121318).[14C]BIC was rapidly absorbed orally in mice, rats, monkeys and human. The cumulative dose recovery was high in nonclinical species (>80%) and humans (95.3%), with most of the excreted dose recovered in faeces. Quantifiable radioactivity with declining concentration was observed in rat tissues suggesting reversible binding. Unchanged BIC was the most abundant circulating component in all species along with two notable metabolites M20 (a sulphate conjugate of hydroxylated BIC) and M15 (a glucuronide conjugate of BIC). BIC was primarily eliminated by hepatic metabolism followed by excretion of the biotransformed products into faeces. In vitro drug-drug interaction (DDI) studies with M15 and M20 demonstrated that no clinically relevant interactions were expected.Overall, BIC is a novel and potent INSTI with a favourable resistance, PK, and ADME profile that provides important improvements over other currently available INSTIs for the treatment of HIV-1.

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin.

The combination regimen of trastuzumab (Tras) plus Nab-paclitaxel (Nab) is recommended to treat HER2-positive (HER2+) cancers. However, they exert effects in different mechanisms: Tras need to stay on cell membranes, while Nab need to be endocytosed, therefore the concurrent combination regimen may not be the best one in HER2+ tumors treatment. Caveolin-1 (Cav-1) is a key player in mediating their endocytosis and is associated with their efficacy, but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy. Herein, we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+ Cav-1High tumor treatment. In the regimen, lovastatin (Lova) was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression, increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+ Cav-1High cells but not in HER2+ Cav-1Low cells. Therefore, by exchanging the dosing sequence of Nab and Tras, and by adding Lova at appropriate time points, the precise three-drug-sequential regimen (PTDS, Nab(D1)-Lova(D2)-Lova & Tras(D2+12 h)) was established. Compared with the concurrent regimen, the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+ Cav-1High tumors, which might be a promising combination regimen for these patients in clinics.

Tumor microenvironment adrenergic nerves blockade liposomes for cancer therapy.

Adrenergic nerves, which are innervated in the tumor, regulate tumor initiation, angiogenesis, and the establishment of the tumor immunosuppressive microenvironment. The study aimed to evaluate the effectiveness of propranolol liposomes (Lipo pro) in inhibiting adrenergic nerve signaling in cancer therapy. Lipo pro significantly regulated the distribution of tumor microenvironment adrenergic nerves, tumor blood vessels, and immunosuppressive microenvironment. Furthermore, it displayed considerable therapeutic effects on prostatic cancer, pancreatic ductal adenocarcinoma, and melanoma. The combination therapeutic regimen, in which Lipo pro was the primary treatment and was supplemented by chemotherapy, showed significant advantages over any single treatment, effectively restraining tumor growth in situ and metastasis, thereby prolonging the survival of mice. This study established a proof-of-concept by targeting tumor adrenergic nerve signaling for cancer therapy.

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways.

Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.

Omadacycline Pharmacokinetics/Pharmacodynamics in the Hollow Fiber System Model and Potential Combination Regimen for Short Course Treatment of Mycobacterium kansasii Pulmonary Disease.

The 12-month therapy duration for the treatment of Mycobacterium kansasii pulmonary disease calls for more efficacious drugs for better treatment outcomes and to shorten the therapy duration. We performed (i) omadacycline MIC with M. kansasii ATCC 12478 strain and 21 clinical isolates, (ii) dose-response study in the hollow fiber system model of M. kansasii (HFS-Mkn) with six human equivalent omadacycline daily doses to determine the optimal drug exposure for the maximal kill, and (iii) a second HFS-Mkn study to determine the efficacy of omadacycline (300 mg/day) plus moxifloxacin (600 mg/day) plus tedizolid (200 mg/day) combination regimen with standard regimen as comparator. GraphPad Prism was used for data analysis and graphing. MIC of the reference strain was 4 mg/L but ranged from 8 to 32 mg/L among the 21 clinical isolates. In the HFS-Mkn, the exposure required for 50% of the maximal effect (EC50) was an omadacycline area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 1.95. The optimal exposure was an AUC0-24/MIC of 3.05, which could be achieved with 300 mg/day clinical dose. The omadacycline-moxifloxacin-tedizolid combination sterilized the HFS-Mkn in 14 days with a linear-regression based kill rate of -0.309 ± 0.044 log10 CFU/mL/day compared to the kill rate of -0.084 ± 0.036log10 CFU/mL/day with the standard regimen or 3.7-times faster. Omadacycline has efficacy against M. kansasii and could be used at 300 mg/day in combination with moxifloxacin and tedizolid for the treatment of M. kansasii pulmonary diseases with the potential to shorten the currently recommended 12-month therapy duration.

Human pharmacokinetics prediction with an in vitro-in vivo correction factor approach and in vitro drug-drug interaction profile of bictegravir, a potent integrase-strand transfer inhibitor component in approved biktarvy® for the treatment of HIV-1 infection.

Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The in vitro properties, pharmacokinetics (PK), and drug-drug interaction (DDI) profile of BIC were characterised in vitro and in vivo.BIC is a weakly acidic, ionisable, lipophilic, highly plasma protein-bound BCS class 2 molecule, which makes it difficult to predict human PK using standard methods. Its systemic plasma clearance is low, and the volume of distribution is approximately the volume of extracellular water in nonclinical species. BIC metabolism is predominantly mediated by cytochrome P450 enzyme (CYP) 3A and UDP-glucuronosyltransferase 1A1. BIC shows a low potential to perpetrate clinically meaningful DDIs via known drug metabolising enzymes or transporters.The human PK of BIC was predicted using a combination of bioavailability and volume of distribution scaled from nonclinical species and a modified in vitro-in vivo correlation (IVIVC) correction for clearance. Phase 1 studies in healthy subjects largely bore out the prediction and supported the methods used. The approach presented herein could be useful for other drug molecules where standard projections are not sufficiently accurate. .

Post-antifungal effect of the combination of anidulafungin with amphotericin B and fluconazole against fluconazole-susceptible and -resistant Candida albicans.

Background and Purpose: Invasive candidiasis is a life-threatening condition that kills a large number of immunocompromised patients each year worldwide. We used post-antifungal effect studies to analyze the activities of anidulafungin (AFG), as a clinically crucial antifungal drug, amphotericin B (AMB), and fluconazole (alone and in combinations) against FLC-susceptible and -resistant Candida albicans (C. albicans) isolates obtained from the cancer patients. Materials and Methods: We tested the phenomenon of post antifungal effects of FLC, AMB, AFG, and combinations of FLC+AFG, AFG+AMB, and FLC+AMB against 17 C. albicans isolates obtained from the oral cavity of cancer patients. Isolates that had not been exposed to antifungals, served as a control group. Colony counts were performed at 0, 2, 4, 6, and 24 h after a brief (1 h) exposure to antifungal. Results: The FLC had no detectable post-antifungal effect independent of antifungal concentration and resembled drug-free FLC (control). Significant variations in the post-antifungal effect were observed when all AMB and AFG were compared to FLC. The combination of AFG and AMB with FLC resulted in effective activity compared to FLC alone. Combination regimens were rated as indifferent in general. Interestingly, low dosages of the AFG displayed increasing fungistatic action as it approached a fungistatic endpoint against C. albicans isolates (n=17). Conclusion: Our findings suggested that brief exposure to AFG, in combination with FLC and AMB, at low concentrations of the medicines utilized, could be effective in the evaluation and optimization of new dosage regimens to manage candidiasis. However, future studies will determine the clinical utility of our findings.

Comparison of intravesical adjuvant therapy in bladder cancer with two different maintenance regimens of mitomycin and BCG.

OBJECTIVE: To compare recurrence rate and side effects with two different maintenance regimens of postoperative intravesical therapy with mitomycin and BCG in T1 bladder cancer. METHODS: Eighty were enrolled in this study and all received immediate post operative mitomycin. They were then allocated to two groups of 40, one group receiving intravesicle BCG and other a combination BCG and Mitomycin. They were followed up to a period of 2 years. RESULT: Two year recurrence rate after transurethral resection of bladder tumour with high grade T1 disease in the Combination group is low (20%) as compared to the BCG group (37.5%). CONCLUSION: Two year recurrences reduced with use of intravesical Mitomycin during maintenance in the combination group which though not statistically significant favours the trial with combination therapy in future studies. Side effect profile did not worsen with combination of Mitomycin and BCG.

Response to pazopanib-based combination regimen in a case of FGFR3 amplified gastric adenocarcinoma.

Angiogenesis inhibitors (AGI) are not presently used for the treatment of gastric cancers. This report demonstrates that angiogenesis inhibitor can be safely and effectively used in combination with cytotoxic anti-cancer agents for treatment of Gastric cancers.

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas.

Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)-specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.

Novel Rotational Combination Regimen of Skin Topicals Improves Facial Photoaging: Efficacy Demonstrated in Double-Blinded Clinical Trials and Laboratory Validation.

Topical antiaging products are often a first-line intervention to counter visible signs of facial photoaging, aiming for sustained cosmetic improvement. However, prolonged application of a single active topical compound was observed clinically to lead to a plateau effect in improving facial photoaging. In view of this, we set out to reduce this effect systematically using a multi-tiered approach with laboratory evidence and clinical trials. The objective of the study was to evaluate the effects of active topical ingredients applied either alone, in combination, or in a rotational manner on modulation of facial photoaging. The study methodology included in vitro, organotypic, and ex vivo skin explants; in vivo biopsy study; as well as clinical trials. We demonstrate for the first time that a pair of known antiaging ingredients applied rotationally, on human dermal fibroblasts, maximized pro-collagen I production. Indeed, rotational treatment with retinol and phytol/glycolic acid (PGA) resulted in better efficacy than application of each active ingredient alone as shown by explants and in vivo biopsy study, with penetration of active ingredients confirmed by Raman spectroscopy. Furthermore, two split-face, randomized, double-blinded clinical trials were conducted, one for 12 months to compare treated vs. untreated and the other for 6 months followed by a 2-month regression to compare treated vs. commercially marketed products. In both studies, rotational regimen showed superior results to its matching comparison as assessed by clinical grading and image analysis of crow's feet wrinkles. In conclusion, rotational regimen using retinol and PGA is effective in treating facial photoaging signs with long-lasting benefits.

Combination Therapy of Navitoclax with Chemotherapeutic Agents in Solid Tumors and Blood Cancer: A Review of Current Evidence.

Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.

Overcoming physical stromal barriers to cancer immunotherapy.

Immunotherapy has emerged as an unprecedented hope for the treatment of notoriously refractory cancers. Numerous investigational drugs and immunotherapy-including combination regimens are under preclinical and clinical investigation. However, only a small patient subpopulation across different types of cancer responds to the therapy due to the presence of several mechanisms of resistance. There have been extensive efforts to overcome this limitation and to expand the patient population that could be benefited by this state-of-the-art therapeutic modality. Among various causes of the resistance, we here focus on physical stromal barriers that impede the access of immunotherapeutic drug molecules and/or native and engineered immune cells to cancer tissues and cells. Two primary stromal barriers that contribute to the resistance include aberrant tumor vasculatures and excessive extracellular matrix build-ups that restrict extravasation and infiltration, respectively, of molecular and cellular immunotherapeutic agents into tumor tissues. Here, we review the features of these barriers that limit the efficacy of immunotherapy and discuss recent advances that could potentially help immunotherapy overcome the barriers and improve therapeutic outcomes.

Promoting apical-to-basolateral unidirectional transport of nanoformulations by manipulating the nutrient-absorption pathway.

The epithelium is a formidable barrier to the absorption of orally delivered nano-vehicles. Here, by exploring a nutrient-absorption pathway, a self-amplified nanoplatform was developed to promote apical-to-basolateral transcytosis across the epithelium. The nanoplatform consisted of fructose-modified polyethylene glycol coated nanoparticles (Fru-PEG NPs) and a sweetener, acesulfame potassium (AceK) in combination. Compared with regular PEGylated nanoparticles, the combination exhibited a 3.9-fold increase of absorption following oral gavage in mice and an 8.8-fold increase of transepithelial transport in vitro. When encapsulated with insulin, the combination regimen elicited a stronger hypoglycemic effect, with a pharmacological bioavailability of 18.56%, which was 3.2-fold higher than that of PEG NPs. We demonstrated that a large proportion of Fru-PEG NPs underwent internalization and basolateral exocytosis via a glucose transporter type 2 (GLUT2)-dependent process, which is an important fructose assimilation pathway. Notably, co-administered AceK could prime the epithelial cells with increased apical distribution of GLUT2, thus amplifying this unidirectional transcytosis of nanoparticles. This work is the first proof-of-concept study of manipulating and amplifying a nutrient-absorption pathway to facilitate the unidirectional trans-epithelial transport of orally administered nano-delivery vehicles.