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Simple Summary: Glioblastoma (GBM) uses the Leloir pathway to catabolize D-Galactose (Gal) for tumor growth. Selective targeting of the Leloir pathway with Gal-based antimetabolites has potential for the treatment of GBM. Here, we tested the effect of a Gal-based antimetabolite, 4-deoxy-4-fluorogalactose (4DFG) on the viability and metabolism of GBM cells in culture. 4DFG is a good Glut3/Glut14 substrate and acts as a potent glioma chemotherapeutic. GBM cell cultures were used to examine toxicity and alterations in glycan composition. 4DFG is moderately potent against GBM cells in vitro (IC50: 125–300 µM). Glycosylation in GBM was disrupted by 4DFG. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using 13C NMR-based tracer studies. 13C-NMR-based metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Survival analysis in an intracranial mouse model during treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) showed improved outcomes by three-fold (p < 0.01). 4DFG is metabolized by GBM in vitro and in vivo, and is lethal to GBM tumors, but well tolerated in mice. A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. Background: Glioblastoma (GBM) uses Glut3 and/or Glut14 and the Leloir pathway to catabolize D-Galactose (Gal). UDP-4-deoxy-4-fluorogalactose (UDP-4DFG) is a potent inhibitor of the two key enzymes, UDP-galactose-4-epimerase (GALE) and UDP-Glucose 6-dehydrogenase (UGDH), involved in Gal metabolism and in glycan synthesis. The Gal antimetabolite 4-deoxy-4-fluorogalactose (4DFG) is a good substrate for Glut3/Glut14 and acts as a potent glioma chemotherapeutic. Methods: Primary GBM cell cultures were used to examine toxicity and alterations in glycan composition via lectin binding in fixed cells and by Western blots. Toxicity/efficacy in vivo data was performed in mouse flank and intracranial models. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using 13C NMR-based tracer studies. Results: 4DFG is moderately potent against GBM cells (IC50: 125–300 µM). GBM glycosylation is disrupted by 4DFG. Survival analysis in an intracranial mouse model showed that treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) improved outcomes by three-fold (p < 0.01). Metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Conclusion: A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. 4DFG is metabolized by GBM in vitro and in vivo, is lethal to GBM tumors, and is well tolerated in mice. [ABSTRACT FROM AUTHOR]

Simple Summary: Pseudocirrhosis is a nodularity in the liver that it is typically associated with breast cancer liver metastases, and may occur as a response to chemotherapy and other systemic anticancer treatments. The types of patients who develop pseudocirrhosis, the treatments that they have received, and their outcomes are not well known. This study reviewed 170 patients with a diagnosis of pseudocirrhosis. A variety of different anticancer treatments were received, with taxanes (74.7%) and capecitabine (67.1%) being the most common. The median time between diagnosis of liver metastases and diagnosis of pseudocirrhosis was 17.1 months. The median overall survival once diagnosed with pseudocirrhosis was 7.6 months and patients with HER2+ disease had a statistically significant longer overall survival. To our knowledge, this is the largest dataset of pseudocirrhotic patients that has been published. It provides information to patients and clinicians on risk factors to develop pseudocirrhosis, and prognosis in different subtypes. Pseudocirrhosis is a diffuse nodularity of the liver that radiologically mimics cirrhosis but is a distinct pathological process. It is seen almost exclusively in patients with liver metastases and may represent a response to systemic treatment. Data on the risk factors for pseudocirrhosis and outcomes are limited. In total, 170 patients with a diagnosis of breast cancer and pseudocirrhosis in a 10-year period were identified and retrospectively analysed. Data were collected on baseline patient characteristics, treatments received, and outcomes. Median time between diagnosis of liver metastases and diagnosis of pseudocirrhosis was 17.1 months (range, 0–149 months). In total, 89.4% of patients received chemotherapy between their diagnosis of breast cancer liver metastases and their diagnosis of pseudocirrhosis, most commonly a taxane (74.7%) or capecitabine (67.1%), and the median treatment lines received was 3. Median OS from first diagnosis of pseudocirrhosis was 7.6 months (95% CI: 6.1–9.6 months) and was longer in patients with HER2+ disease at 16.7 months (95% CI: 6.4–32.9 months), which was statistically significant. In our study, pseudocirrhosis occurred in the presence of liver metastases and was associated with a poor prognosis. HER2+ patients with pseudocirrhosis had a better prognosis than other subtypes, but we did not identify other significant predictors of survival. Chemotherapy was not a prerequisite for pseudocirrhosis development, although the majority of patients had received at least one line of chemotherapy before pseudocirrhosis was diagnosed. [ABSTRACT FROM AUTHOR]

Simple Summary: The vaginal microbiome may play a role in racial disparities in ovarian cancer; there is evidence suggesting that it differs according to race and contributes to inflammation by producing or consuming compounds that can shape how ovarian cancer progresses. Our cross-sectional study aimed to investigate the extent to which chemical compounds, or metabolites, from vaginal fluid, also differ by race, and whether these metabolites are linked to systemic inflammation. Our study of 20 White and 16 Black patients identified 1 out of 99 metabolites, arachidonoylcarnitine (C20:4), as occurring at lower levels in Black and higher levels in White patients with ovarian cancer. More than one-third of vaginal fluid metabolites considered showed correlations with biomarkers of systemic inflammation. Our findings suggest that vaginal fluid metabolites likely differ by race, and may play an important role in inflammatory processes, which may be relevant to racial differences in ovarian cancer outcomes. These pilot findings have the potential to improve our understanding of biological mechanisms underlying racial disparities in ovarian cancer but need verification with larger sample sizes. The vaginal microbiome differs by race and contributes to inflammation by directly producing or consuming metabolites or by indirectly inducing host immune response, but its potential contributions to ovarian cancer (OC) disparities remain unclear. In this exploratory cross-sectional study, we examine whether vaginal fluid metabolites differ by race among patients with OC, if they are associated with systemic inflammation, and if such associations differ by race. Study participants were recruited from the Ovarian Cancer Epidemiology, Healthcare Access, and Disparities Study between March 2021 and September 2022. Our study included 36 study participants with ovarian cancer who provided biospecimens; 20 randomly selected White patients and all 16 eligible Black patients, aged 50–70 years. Acylcarnitines (n = 45 species), sphingomyelins (n = 34), and ceramides (n = 21) were assayed on cervicovaginal fluid, while four cytokines (IL-1β, IL-10, TNF-α, and IL-6) were assayed on saliva. Seven metabolites showed >2-fold differences, two showed significant differences using the Wilcoxon rank-sum test (p < 0.05; False Discovery Rate > 0.05), and 30 metabolites had coefficients > ±0.1 in a Penalized Discriminant Analysis that achieved two distinct clusters by race. Arachidonoylcarnitine, the carnitine adduct of arachidonic acid, appeared to be consistently different by race. Thirty-eight vaginal fluid metabolites were significantly correlated with systemic inflammation biomarkers, irrespective of race. These findings suggest that vaginal fluid metabolites may differ by race, are linked with systemic inflammation, and hint at a potential role for mitochondrial dysfunction and sphingolipid metabolism in OC disparities. Larger studies are needed to verify these findings and further establish specific biological mechanisms that may link the vaginal microbiome with OC racial disparities. [ABSTRACT FROM AUTHOR]

Simple Summary: Upfront surgery with adjuvant capecitabine is the only curative treatment for hilar cholangiocarcinoma. Unfortunately, most patients do not present with resectable disease and are treated with a combination of locoregional therapy and systemic therapy. This review will summarize existing literature and ongoing clinical trials focused on the multidisciplinary care of hilar cholangiocarcinoma. Cholangiocarcinoma (CCA) is a rare malignancy of the intrahepatic and extrahepatic biliary ducts. CCA is primarily defined by its anatomic location: intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma. Hilar cholangiocarcinoma (HC) is a subtype of extrahepatic cholangiocarcinoma that arises from the common hepatic bile duct and can extend to the right and/or left hepatic bile ducts. Upfront surgery with adjuvant capecitabine is the standard of care for patients who present with early disease and the only curative therapy. Unfortunately, most patients present with locally advanced or metastatic disease and must rely on systemic therapy as their primary treatment. However, even with current systemic therapy, survival is still poor. As such, research is focused on developing targeted therapies and multimodal strategies to improve overall prognosis. This review discusses the work-up and management of HC focused on the most up-to-date literature and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Drugs used to treat cancer are most often very toxic. Taking their high doses may adversely affect the patient's health, as a result of which the therapy, instead of helping, harms. An example of such a drug is 6-mercaptopurine, described in this paper. Due to these negative properties, it is necessary to create such systems that would release the drug in a controlled manner only in the vicinity of diseased tissues. In this work, a drug carrier was prepared that releases the drug only in the acidic environment of cancer, due to which healthy tissues will not be exposed to it. Systems that release the drug only in an acidic environment have not been described before and the application potential of such a carrier is very large. Hydroxy double salts are layered materials that are considered to be biocompatible. For this reason, research has been initiated on the possibility of their use in drug delivery. Despite their use for several types of drugs, their potential for controlled release of mercaptopurine (MERC) has not been studied. In this work, the synthesized hydroxy double salt (HDS) material was used as a carrier for this drug for the first time. The effectiveness of HDS synthesis has been proven by such techniques as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Based on the FT-IR and energy-dispersive X-ray spectroscopy (EDS) results, the effectiveness of drug sorption was proven. The exact amount of drug retained was determined by the UV-Vis technique. The obtained results indicate that the drug is evenly distributed on the surface of the carrier, which is important during the controlled delivery of drugs. In the most important stage of the research, the effectiveness of drug release in response to changes in the pH of the environment was proven. The drug is not released into an environment that mimics healthy human tissues. It is released only after contact with the acidic environment that usually surrounds cancer cells. The low cellular toxicity of HDS and significant cytotoxic effect of HDS-MERC were confirmed by in vitro studies on MCF-7 human breast and DU145 prostate cancer cell lines and non-cancerous keratinocytes HaCaT. Interestingly, coupling with the HDS carrier increased the cytotoxic effect of MERC towards DU145 cells. Such an "intelligent" drug carrier for mercaptopurine has not been previously described in the literature. The obtained results indicate its great potential. [ABSTRACT FROM AUTHOR]

Cytostatic and pro-apoptotic effects of selenium steroid derivatives against HeLa cells were determined. The highest cytostatic activity was shown by derivative 4 (GI50 25.0 µM, almost complete growth inhibition after three days of culture, and over 97% of apoptotic and dead cells at 200 µM). The results of our study (cell number measurements, apoptosis profile, relative expression of apoptosis-related APAF1, BID, and mevalonate pathway-involved HMGCR, SQLE, CYP51A1, and PDHB genes, and computational chemistry data) support the hypothesis that tested selenosteroids induce the extrinsic pathway of apoptosis by affecting the cell membrane as cholesterol antimetabolites. An additional mechanism of action is possible through a direct action of derivative 4 to inhibit PDHB expression in a way similar to steroid hormones. [ABSTRACT FROM AUTHOR]

Antimetabolites, especially 5-fluorouracil, are commonly used clinically to treat breast, colon, and other cancers. However, their side effects and inefficiency in monotherapy have prompted further searches for new combinations. Thus, the anticancer effect of 5-fluorouracil (5-FU) and the sulforaphane analogue, 4-isoselenocyanato-1-butyl 4′-fluorobenzyl sulfoxide (ISC), were tested in in vitro and in vivo models of triple-negative breast cancer (TNBC) as a new option for this treatment-resistant and aggressive type of breast cancer. A synergic interaction between 5-FU and ISC was observed in the TNBC in vitro model MDA-MB-231 cell line, which led to enhanced antiproliferative effects. The results of in vitro studies were confirmed by in vivo tests, which demonstrated stronger tumor growth inhibition and additive interactions between 5-FU and ISC in the murine TNBC model. Moreover, the results of the body mass and blood analysis showed the safety of the tested combination. The mechanistic study revealed that the combined treatment triggered apoptosis and necrosis, as well as inhibited cell migration. [ABSTRACT FROM AUTHOR]

In this work, we elucidated some key aspects of the mechanism of action of the cisplatin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare the interactions of Thermus aquaticus (Taq) DNA polymerase with three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP = 5′-(2′-deoxy)-guanosine-triphosphate}, using canonical dGTP as a reference, in the presence of DNA. The goal was to elucidate the binding site interactions between Taq DNA polymerase and the tested nucleotide derivatives, providing valuable atomistic insights. Unbiased molecular dynamics simulations (200 ns for each complex) with explicit water molecules were performed on the four ternary complexes, yielding significant findings that contribute to a better understanding of experimental results. The molecular modeling highlighted the crucial role of a specific α-helix (O-helix) within the fingers subdomain, which facilitates the proper geometry for functional contacts between the incoming nucleotide and the DNA template needed for incorporation into the polymerase. The analysis revealed that complex 1 exhibits a much lower affinity for Taq DNA polymerase than complexes 2–3. The affinities of cisplatin metabolites 2–3 for Taq DNA polymerase were found to be quite similar to those of natural dGTP, resulting in a lower incorporation rate for complex 1 compared to complexes 2–3. These findings could have significant implications for the cisplatin mechanism of action, as the high intracellular availability of free nucleobases might promote the competitive incorporation of platinated nucleotides over direct cisplatin attachment to DNA. The study's insights into the incorporation of platinated nucleotides into the Taq DNA polymerase active site suggest that the role of platinated nucleotides in the cisplatin mechanism of action may have been previously underestimated. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the most prevalent neoplasms worldwide. Capecitabine is an oral fluoropyrimidine widely used to treat colorectal cancer in early and advanced stages. However, it shows high interindividual variability in its effectiveness and safety. This variability may be due to genetic variants in proteins involved in the pharmacokinetics and pharmacodynamics of the drug. Currently, only four variants of the DPYD gene are clinically relevant for the prediction of severe toxicity, and there are no validated predictive biomarkers of capecitabine effectiveness. Therefore, the search of potential predictive genetic biomarkers to personalize and optimize capecitabine therapy remains necessary. The aim of this study was to systematically review the literature published in the last 10 years on the influence of single-nucleotide polymorphisms in the main genes involved in capecitabine pharmacokinetics and pharmacodynamics on therapy outcomes in patients with colorectal cancer. The aim of this systematic review was to provide a comprehensive overview of the literature published in the last decade on the association of single-nucleotide polymorphisms in genes involved in the pharmacodynamic and pharmacokinetic pathways of capecitabine with treatment outcomes among colorectal cancer patients. A systematic search of the literature published in the last 10 years was carried out in two databases (Medline and Scopus) using keywords related to the objective. Quality assessment of the studies included was performed using an assessment tool derived from the Strengthening the Reporting of Genetic Association (STREGA) statement. Thirteen studies were included in this systematic review. Genes involved in bioactivation, metabolism, transport, mechanism of action of capecitabine, DNA repair, and folate cycle were associated with toxicity. Meanwhile, genes related to DNA repair were associated with therapy effectiveness. This systematic review reveals that several SNPs other than the four DPYD variants that are screened in clinical practice could have an impact on treatment outcomes. These findings suggest the identification of future predictive biomarkers of effectiveness and toxicity in colorectal cancer patients treated with capecitabine. However, the evidence is sparse and requires further validation. [ABSTRACT FROM AUTHOR]

Simple Summary: The introduction of venetoclax (VEN) to combination regimens has dramatically changed the paradigm of treatment for acute myeloid leukemia (AML) patients deemed unfit for intensive chemotherapy. Several researchers have reported that this regimen was successfully used as a bridge to potentially curative allogeneic hematopoietic stem cell transplantation (allo-HCT) in AML patients; however, data about clinical outcomes after allo-HCT are still lacking. In this study, we evaluated the post-transplant outcomes of 50 patients who received VEN-hypomethylating agents (HMA) treatment, either as initial therapy for newly diagnosed AML (n = 10) or as a salvage regimen for relapsed/refractory (R/R) AML (n = 40). The probabilities of overall survival, relapse-free survival, cumulative incidence of relapse, and nonrelapse mortality at 1 year were 63.7%, 59.3%, 28.5%, and 12.2%, respectively. Even though 30% of our data were from a second allo-HCT, our results suggest that allo-HCT following VEN-HMA therapy is a safe and effective treatment option. Recently, the combination of VEN-HMA has been shown to achieve durable responses in patients with both newly diagnosed (ND) and R/R-AML. We retrospectively evaluated the post-allo-HCT outcomes of 50 patients who received VEN-HMA therapy. In total, 10 were ND and 40 were R/R and, at the time of HCT, the median age was 53 years. In the ND- and R/R-AML groups, the percentage of patients who achieved CR/CRi or MLFS was 90% and 92.5%, respectively. In all, after a median follow-up of 13.7 months, the probabilities of overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) at 1 year were 63.7%, 59.3%, 28.5%, and 12.2%, respectively. In addition, the cumulative incidences of grade II–IV acute graft-versus-host disease (GVHD) and moderate–severe chronic GVHD at 1 year were 28.4% and 37.4%, respectively. In multivariate analysis, the factors associated with a statistically significant impact on OS were VEN-HMA cycle (p = 0.021), ELN risk group (p = 0.041), and the response to VEN-HMA therapy before allo-HCT (p = 0.003). Although 80% of our patients had R/R-AML and 30% underwent a second allo-HCT, our data still suggest that allo-HCT following VEN-HMA therapy is a safe and effective treatment option. [ABSTRACT FROM AUTHOR]

Nucleoside analogues (NAs) are a family of compounds which include a variety of purine and pyrimidine derivatives, widely used as anticancer and antiviral agents. For their ability to compete with physiological nucleosides, NAs act as antimetabolites exerting their activity by interfering with the synthesis of nucleic acids. Much progress in the comprehension of their molecular mechanisms has been made, including providing new strategies for potentiating anticancer/antiviral activity. Among these strategies, new platinum-NAs showing a good potential to improve the therapeutic indices of NAs have been synthesized and studied. This short review aims to describe the properties and future perspectives of platinum-NAs, proposing these complexes as a new class of antimetabolites. [ABSTRACT FROM AUTHOR]

Simple Summary: Current treatments for patients with metastatic triple negative breast cancer (TNBC) are generally ineffective. This manuscript shows for the first time that the survival of mice with metastatic TNBC can be markedly increased through dietary manipulation. Our study revealed that the survival of some mice with metastatic TNBC was increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) are manipulated, and the levels of lipids are markedly reduced. The anticancer activity of this non-pharmacological strategy was higher than that of drugs currently used in the treatment of patients with metastatic TNBC. This anticancer strategy also increased the survival of mice with other types of metastatic cancers. Manipulation of AA and lipid levels with artificial diets may be a useful strategy to treat patients with metastatic TNBC and other types of disseminated cancer. Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show for the first time that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were also tested in this model. AA manipulation led to modest improvements in mice survival when the levels of lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Some mice fed the artificial diets as monotherapy lived much longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the second leading cause of cancer deaths, with approximately 15–25% of the primary diagnosis. MicroRNA-92a (miR-92a) is considered one of the most promising biomarkers for colorectal cancer diagnosis; however, at present the diagnostic accuracy of miR-92a for CRC remains inconclusive and the upstream regulatory mechanism is not well understood in CRC development. In this study, we firstly found that serum/plasma miR-92a had better diagnostic efficacy compared to stool samples in CRC through meta-analysis. Additionally, we confirmed that decreased miR-92a expression and secretion take place in CRC cells after knockdown of heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) in vitro. The common peaks of N6-methyladenosine (m6A) and HNRNPA2B1 in proximate miR-92a suggested HNRNPA2B1 mediated miR-92a expression through m6A modification. Thus, we identified that miR-92a derived from blood could be a better noninvasive biomarker, and provide insight into the mechanism of miR-92a in the expression and secretion in CRC. MicroRNA-92a (miR-92a) may serve as a novel promising biomarker in multiple cancers, including colorectal cancer (CRC); however, the diagnostic accuracy and the underlying molecular mechanism of miR-92a in CRC is poorly understood. We first carried out meta-analysis and found that serum/plasma miR-92a yield better diagnostic efficacy when compared to stool samples and CRC tissues, and this finding was validated by our independent study through stool sample. Multiple bioinformatics assay indicated that miR-92a expression was positively correlated with heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) expression and closely related with the clinical characteristics of CRC. Experimental evidence showed that knockdown of HNRNPA2B1 could significantly decrease miR-92a expression and secretion in RKO cells. HNRNPA2B1 mediated miR-92a via m6A RNA modification. These findings indicate that HNRNPA2B1-m6A RNA modification-derived MicroRNA-92a upregulation and section from the local CRC acts a candidate noninvasive serum biomarker in colorectal cancer. Our study provides a novel insight into miR-92a mechanisms in relation to both expression and secretion for CRC diagnosis. [ABSTRACT FROM AUTHOR]

The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. In this study, we aimed to determine the biological function and regulatory mechanism of GMEB2 in CRC. We found that GMEB2 was highly expressed in CRC and significantly promoted the growth of CRC in vitro and in vivo. Mechanistically, GMEB2 acted as a transcription factor to activate ADRM1/NF-κB signalling and was upregulated by YTHDF1 through enhancing its mRNA stability. Our findings suggest that GMEB2 may serve as a new therapeutic target for CRC treatment in the future. Transcription factors are frequently aberrantly reactivated in various cancers, including colorectal cancer (CRC). However, as a transcription factor, the role of GMEB2 in cancer is still unclear, and further studies are needed. Here, we aimed to identify the function and mechanism of GMEB2 in regulating the malignant progression of CRC. GMEB2 was found to be highly expressed in online data analyses. We demonstrated that GMEB2 was markedly upregulated at both the mRNA and protein levels in CRC cells and tissues. GMEB2 knockdown inhibited CRC cell growth in vitro and in vivo. Mechanistically, as a transcription factor, GMEB2 transactivated the ADRM1 promoter to increase its transcription. Rescue experiments showed that ADRM1 downregulation partially reversed the promoting effects of GMEB2 on CRC growth in vitro. Moreover, the GMEB2/ADRM1 axis induced nuclear translocation of NF-κB, thus activating NF-κB signalling. Finally, we further revealed that YTHDF1 recognized and bound to the m6A site on GMEB2 mRNA, which enhanced its stability. Taken together, our findings reveal the crucial role and regulatory mechanism of GMEB2 in CRC for the first time and provide a novel potential therapeutic target for CRC therapy. [ABSTRACT FROM AUTHOR]

The essential oil (EO) from the leaves of Zanthoxylum caribaeum (syn. Chiloperone) (Rutaceae) was studied previously for its acaricidal, antimicrobial, antioxidant, and insecticidal properties. In prior studies, the most abundant compound class found in leaf oils from Brazil, Costa Rica, and Paraguay was terpenoids. Herein, essential oil from the leaves of Zanthoxylum caribaeum (prickly yellow, bois chandelle blanc (FWI), peñas Blancas (Costa Rica), and tembetary hu (Paraguay)) growing in Guadeloupe was analyzed with comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC-TOFMS), and thirty molecules were identified. A comparison with previously published leaf EO compositions of the same species growing in Brazil, Costa Rica, and Paraguay revealed a number of molecules in common such as β-myrcene, limonene, β-caryophyllene, α-humulene, and spathulenol. Some molecules identified in Zanthoxylum caribaeum from Guadeloupe showed some antimetabolic effects on enzymes; the in-depth study of this plant and its essential oil with regard to metabolic diseases merits further exploration. [ABSTRACT FROM AUTHOR]

Simple Summary: There is no clear preference between S-1 and capecitabine in combination with platinum agent as first-line therapy for patients with HER2-negative unresectable advanced or recurrent gastric cancer (GC) with measurable disease. Although a distinguishing use of S-1 versus capecitabine based on histological classification has been studied, the present integrated analysis, using 162 individual participant data of GC patients with measurable disease, is the first to show that S-1 plus cisplatin (SP) achieves deeper tumor shrinkage than capecitabine plus cisplatin (XP), leading a longer overall survival although no differences in response rate or progression-free survival in differentiated GC. On the other hand, in undifferentiated GC, SP consistently showed better clinical results than XP. These findings thus have implications for the choice of oral fluoropyrimidine in the era of first line therapy in combination with oxaliplatin and immune checkpoint inhibitor. It has been suggested that the therapeutic efficacy of S-1 + cisplatin (SP) and capecitabine + cisplatin (XP) may differ depending on the histology of the tumor, but no clear evidence exists. Individual participant data were obtained from three randomized phase II trials in which such patients received either SP (S-1 [40–60 mg twice daily for 21 days] plus cisplatin [60 mg/m2 on day 8], every 5 weeks) or XP (capecitabine [1000 mg/m2 twice daily for 14 days] plus cisplatin [80 mg/m2 on day 1], every 3 weeks). A total of 162 patients were included, with 79 patients in the SP arm and 83 patients in the XP arm. Although there was also no difference between arms in ORR according to histological classification, differentiated tumors showed a significantly better OS (but not PFS) for SP versus XP that was associated with a deeper tumor shrinkage. Undifferentiated tumors showed a consistently better OS, and PFS for SP versus XP, likely because cases without tumor shrinkage tended to be fewer for SP. Our data thus showed that SP was superior to XP in this setting, but there were qualitative differences in therapeutic efficacy dependent on tumor histology. [ABSTRACT FROM AUTHOR]

Inflammatory breast cancer (IBC) is one of the most belligerent types of breast cancer. While various modalities exist in managing/treating IBC, drug delivery using microneedles (MNs) is considered to be the most innovative method of localized delivery of anti-cancer agents. Localized drug delivery helps to treat IBC could limit their adverse reactions. MNs are nothing but small needle like structures that cause little or no pain at the site of administration for drug delivery via layers of the skin. The polyethylene glycol diacrylate (PEGDA) based MNs were fabricated by using three dimensional (3D) technology called Projection Micro-Stereo Lithography (PµSL). The fabricated microneedle patches (MNPs) were characterized and coated with a coating formulation comprising of gemcitabine and sodium carboxymethyl cellulose by a novel and inventive screen plate method. The drug coated MNPs were characterized by various instrumental methods of analysis and release profile studies were carried out using Franz diffusion cell. Coat-and-poke strategy was employed in administering the drug coated MNPs. Overall, the methods employed in the present study not only help in obtaining MNPs with accurate dimensions but also help in obtaining uniformly drug coated MNPs of gemcitabine for treatment of IBC. Most importantly, 100% drug release was achieved within the first one hour only. [ABSTRACT FROM AUTHOR]

Raltitrexed is a classical antifolate drug with antimetabolite and anticancer properties. In this research, we provide its detailed antitrypanosomal inhibition against six Trypanosoma species and investigate its potential mode of action. Molecular dynamics (MD) simulations and in silico analyses were used to track the binding strength and stability. Raltitrexed showed broad-spectrum trypanocidal actions against Trypanosoma brucei brucei GUTat3.1, T. b. rhodesiense IL1501, T. b. gambiense IL1922, T. evansi Tansui, T. equiperdum IVM-t1 and T. congolense IL3000. The estimated IC50 was found to be in the range of 5.18–24.13 µg/mL, indicating inhibition of Trypanosoma in the low micromolar range. Although the co-crystallized ligand had robust hydrogen bonding and lipophilic characteristics, its docking score was only −4.6 compared to raltitrexed's −7.78, indicating strong binding with T. brucei dihydrofolate reductase-thymidylate synthase (TbDHFR-TS). MD simulations support the strong binding of raltitrexed with TbDHFR-TS evidenced by low root mean square deviation (RMSD), low residues fluctuations, a tight radius of gyration (ROG) and an average of 3.38 ± 1.3 hydrogen bonds during 50 ns MD simulation. The prospective extended spectrum of raltitrexed against Trypanosoma species grants further research for the synthesis of raltitrexed derivatives and repurposing against other protozoa. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relapse or are refractory to chemotherapy despite the low frequency of TP53 mutations. The nucleolar stress response is one of the mechanisms that activate P53 by ribosomal protein L11 (RPL11). We hypothesized that the lack of nucleolar stress response is related to chemoresistance and relapse in some pediatric BCP-ALL cases. We revealed that clinical BCP-ALL therapeutics, such as 6-mercaptopurine, methotrexate, daunorubicin, and cytarabine, induced the nucleolar stress response, and its treatment susceptibility was dependent on the nucleolar stress response. Furthermore, we observed decreased RPL11 expression at relapse in seven children with BCP-ALL in comparison to that at onset. Our findings provide new insights into the anti-leukemia mechanism in BCP-ALL and multidrug resistance and relapse via the nucleolar stress response, suggesting that the nucleolar stress response may be a potential therapeutic strategy to predict chemosensitivity and improve chemoresistance in pediatric BCP-ALL. Approximately 20% of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relapse or are refractory to chemotherapy despite the low frequency of TP53 mutations. The nucleolar stress response is a P53-activating mechanism via MDM2 inhibition by ribosomal protein L11 (RPL11). We analyzed the role of the nucleolar stress response using BCP-ALL cell lines and patient samples by drug sensitivity tests, Western blotting, and reverse transcription polymerase chain reaction. We revealed that the nucleolar stress response works properly in TP53 wild-type human BCP-ALL cell lines. Next, we found that 6-mercaptopurine, methotrexate, daunorubicin, and cytarabine had anti-leukemic effects via the nucleolar stress response within BCP-ALL treatment. Comparing the samples at onset and relapse in children with BCP-ALL, RPL11 mRNA expression decreased at relapse in seven of nine cases. Furthermore, leukemia cells with relapse acquired resistance to these four drugs and suppressed P53 and RPL11 expression. Our findings suggest that the nucleolar stress response is a novel anti-leukemia mechanism in BCP-ALL. As these four drugs are key therapeutics for BCP-ALL treatment, dysfunction of the nucleolar stress response may be related to clinical relapse or refractoriness. Nucleolar stress response may be a target to predict and improve the chemotherapy effect for pediatric BCP-ALL. [ABSTRACT FROM AUTHOR]

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Several novel therapies are being developed to improve the management of patients with myelodysplastic syndromes. They include drugs aimed at improving hematopoiesis and differentiation of myeloid precursors, hypomethylating agents, several compounds that target intracellular molecular pathways, and immunotherapies. In this review article, we discuss how the novel drugs may address the several unmet needs of lower- and higher-risk patients. Myelodysplastic syndromes (MDS) are a very heterogeneous disease, with extremely variable clinical features and outcomes. Current management relies on risk stratification based on IPSS and IPSS-R, which categorizes patients into low (LR-) and high-risk (HR-) MDS. Therapeutic strategies in LR-MDS patients mainly consist of erythropoiesis stimulating agents (ESAs), transfusion support, and luspatercept or lenalidomide for selected patients. Current unmet needs include the limited options available after treatment failure, and the consequent transfusion burden with several hospital admissions and poor quality of life. Therapeutic approaches in HR-MDS patients are aimed at changing the natural course of the disease and hypometylating agents (HMA) are the first choice. The only potentially curative treatment is allogeneic stem cell transplant (allo-HCT), restricted to a minority of young and fit candidates. Patients unfit for or those that relapse after the abovementioned options harbor an adverse prognosis, with limited overall survival and frequent leukemic evolution. Recent advances in genetic mutations and intracellular pathways that are relevant for MDS pathogenesis are improving disease risk stratification and highlighting therapeutic targets addressed by novel agents. Several drugs are under evaluation for LR and HR patients, which differ by their mechanism of action, reported efficacy, and phase of development. This review analyzes the current unmet clinical needs for MDS patients and provides a critical overview of the novel agents under development in this setting. [ABSTRACT FROM AUTHOR]

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Adjuvant chemotherapy regimens tegafur/gimeracil/oteracil (S-1) and capecitabine plus oxaliplatin (CAPOX) have predominated, owing to evidence of their remarkable oncologic outcomes, however, there has been a lack of studies on the difference in efficacy between the two regimens. We conducted pairwise meta-analyses comparing the efficacy of S-1 and CAPOX regimens for overall survival (OS) and disease-free survival (DFS) in stage II or III gastric cancer patients. In all stages (stages II and III), the five-year OS was not different between the two regimens (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.78–1.17; p = 0.56). Additionally, the five-year DFS was not different at any stage (HR 1.00, 95% CI 0.85–1.18; p = 0.21). The present meta-analysis showed that five-year OS and DFS for stage II or III gastric cancer patients were comparable between the S-1 and CAPOX adjuvant chemotherapy regimens. Background: Adjuvant chemotherapy (AC) regimens tegafur/gimeracil/oteracil (S-1) and capecitabine plus oxaliplatin (CAPOX) have predominated, however, there has been a lack of studies on their differences in efficacy. Methods: We conducted pairwise meta-analyses comparing the efficacy of S-1 and CAPOX regimens for overall survival (OS) and disease-free survival (DFS) in stage II or III GC patients. Results: Three studies were enrolled and analyzed using a forest plot for meta-analysis. Two of them were propensity score matching studies, and the remaining one was a retrospective observational study. In all stages, the five-year OS was not different between the two regimens (HR 0.96, 95% CI 0.78–1.17; p = 0.56). Additionally, the 5-year DFS was not different at any stage (HR 1.00, 95% CI 0.85–1.18; p = 0.21). After omitting the retrospective observational study, the five-year OS (HR 1.40, 95% CI 0.53–3.73) and DFS (HR 1.41, 95% CI 0.57–3.44) of S-1 tended to be better in stage II, and the five-year OS (HR 0.81, 95% CI 0.56–1.16) and DFS (HR 0.85, 95% CI 0.63–1.13) of CAPOX tended to be better in stage III, without statistical significance. Conclusions: In the present meta-analysis, the five-year OS and DFS for stage II or III GC patients were comparable between S-1 and CAPOX regimens as AC. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of several antiHuman Epidermal Growth Factor Receptor 2 (HER2) treatments over the last few years has improved the landscape of HER2-positive breast cancer. Despite this, relapse is still the main issue in HER2-positive breast cancer. The reasons for therapeutic failure lie in the heterogeneity of the disease itself, as well as in the drug resistance mechanisms. In this review, we intended to understand the milestones that have had an impact on this disease up to their implementation in clinical practice. In addition, understanding the underlying molecular biology of HER2-positive disease is essential for the optimization and personalization of the different treatment options. For this reason, we focused on two relevant aspects, which are triple-positive disease and the role that modulation of the immune response might play in treatment and prognosis. Despite the improvement achieved by the introduction of HER2-targeted therapy, up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown a significant improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). In ER+ HER2+ patients, target therapies such as phosphoinositide-3-kinase (PI3K) pathway inhibition or cyclin-dependent kinases 4/6 blocking may be effective in controlling downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies. Multiple trials have explored these strategies with some promising results, and probably, in the next years conclusive results will succeed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents such as HER-2 therapy plus checkpoint inhibitors, or new vaccines approaches have been investigated in this setting, with promising but controversial results obtained to date. [ABSTRACT FROM AUTHOR]

Trypanosoma brucei, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt Acanthamoeba sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target T. brucei. We found that CHT/ERGT inhibited cell growth in vitro, yielding EC50 values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered T. brucei cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with T. brucei, doubling their survival time following daily treatment for 8–10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper we perform an introduction about pregnancy-associated cancer (PAC) and transplacental passage of antineoplastic agents. Furthermore, we describe therapeutic use and potential toxic effects of chemotherapeutic drug (alkylating agents, antimetabolites agents, anthracyclines, topoisomerase inhibitors, antimitotic agents, actinomycin-D, bleomycin) and targeted agents during pregnancy. This manuscript may be a useful and practical guide for the management of PAC, which is a challenge for clinicians that have to consider alike maternal benefits and fetal potential risks correlated to the antineoplastic treatment. The incidence of PAC is relatively infrequent among pregnant women. However, it has gradually increased in recent years, becoming a challenging area for clinicians that should take into account in the same way maternal benefits and fetal potential risks correlated to the antineoplastic treatment. None of the antineoplastic drugs is completely risk-free during the pregnancy, the timing of exposure and transplacental transfer properties influence the toxicity of the fetus. Despite the lack of guidelines about the management of PAC, several studies have described the use and the potential fetal and neonatal adverse events of antineoplastic drugs during pregnancy. We provide a review of the available literature about the transplacental passage and fetal effects of chemotherapy and targeted agents, to guide the clinicians in the most appropriate choices for the management of PAC. [ABSTRACT FROM AUTHOR]

The cancer xenograft model in which human cancer cells are implanted in a mouse is one of the most used preclinical models to test the efficacy of novel cancer drugs. However, the model is imperfect; animal models are ethically burdened, and the imperfect efficacy predictions contribute to high clinical attrition of novel drugs. If microfluidic cancer-on-chip models could recapitulate key elements of the xenograft model, then these models could substitute the xenograft model and subsequently surpass the xenograft model by reducing variation, increasing sensitivity and scale, and adding human factors. Here, we exposed HCT116 colorectal cancer spheroids to dynamic, in vivo-like, concentrations of oxaliplatin, including a 5 day drug-free period, on-chip. Growth inhibition on-chip was comparable to existing xenograft studies. Furthermore, immunohistochemistry showed a similar response in proliferation and apoptosis markers. While small volume changes in xenografts are hard to detect, in the chip-system, we could observe a temporary growth delay. Lastly, histopathology and a pharmacodynamic model showed that the cancer spheroid-on-chip was representative of the proliferating outer part of a HCT116 xenograft, thereby capturing the major driver of the drug response of the xenograft. Hence, the cancer-on-chip model recapitulated the response of HCT116 xenografts to oxaliplatin and provided additional drug efficacy information. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgical resection is the only potentially curative treatment for pancreatic cancer, and its indication relies on precise imaging criteria and on patients' operability. Chemotherapy is recommended, except for patients a with very short life expectancy. We sought to provide real-world information on the management and outcomes of pancreatic cancer. Among patients with a surgically resectable tumor, only half of those aged 75–84 and none after 85 actually underwent resection, even though the prognosis following pancreatectomy in elderly patients was similar to that in younger patients. Patients' refusal of chemotherapy increased from 7% before 75 years to 73% after 85 years. These results underline the need to develop guidelines for the management of elderly patients with pancreatic cancer and to generalize geriatric assessments. Background: Our objective was to describe real-world patterns of care and outcomes in pancreatic cancer. Methods: 912 patients diagnosed with pancreatic cancer from 2014 to 2017 were registered by the population-based cancer registry of Burgundy (France). Progression-free and net survival were estimated. Results: at diagnosis, 52% of tumors were associated with metastases. Among the 20% of patients fulfilling resectability criteria, half of those aged 75–84 years and none of those ≥85 years actually underwent resection. Age was not associated with 3-year observed survival in patients who underwent resection. Overall, 77% of patients aged <75 years, 55% of those aged 75–84 years and 8% of those ≥85 years received chemotherapy. Among patients who were offered chemotherapy, 73% of those aged ≥85 years refused. Chemotherapy toxicity was higher with Gemcitabine_Oxaliplatin/Gemcitabine_Abraxane and FOLFIRINOX than with Gemcitabine alone. Patients resected after induction FOLFIRINOX and those treated with adjuvant Gemcitabine presented the lowest risk of progression. Three-year net survival was 35% in patients with non-metastatic resectable tumors and under 10% for other patients. Conclusions: Only half of patients aged 75–84 years with a resectable tumor actually underwent resection. Two thirds of patients aged ≥85 years refused chemotherapy, thus underlining the need to expand geriatric assessments. [ABSTRACT FROM AUTHOR]

Simple Summary: The capecitabine/temozolomide (CAPTEM) regimen has proven activity in pancreatic neuroendocrine tumors (NETs); however, data are limited in NETs of the small bowel. To observe whether this regimen has activity in this patient population, we conducted a retrospective study of all patients with small bowel NETs treated with this regimen at our institution. We found that response rates were poor among patients with low-intermediate grade tumors but higher among patients with high-grade disease. Our findings suggest that the CAPTEM regimen should be reserved for patients with higher-grade small bowel NETs. The capecitabine/temozolomide regimen has significant activity in pancreatic NETs; however, data are limited in NETs of the small bowel (midgut). A retrospective study of all patients with metastatic midgut NETs seen at Moffitt Cancer Center between January 2008 and June 2019 treated with CAPTEM was conducted. 32 patients with proven or suspected well-differentiated primary small bowel NETs (excluding duodenum) were identified. 6 patients were found to have a radiographic response (19%), 5 of whom had high-grade disease. Only one patient among 23 with low/intermediate-grade disease responded (4%), whereas the response rate for patients with high-grade disease was 56%. Among patients with low/intermediate-grade disease, 44% discontinued due to poor tolerability. The CAPTEM regimen appears to have an activity in patients with high-grade small bowel NETs and is largely inactive in patients with low/intermediate-grade tumors. [ABSTRACT FROM AUTHOR]

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

Pharmacokinetic enhancers (boosters) are compounds used in combination with a primary therapeutic agent (drug) and are not used for their direct effects on the disease but because they enhance or restore the activity of the primary agent. Hence, in certain cases, they represent an indispensable escort for enzyme-labile drugs. Pharmacokinetic enhancers can exert their activity on different ways. In the most common case, they inhibit enzymes such as human cytochrome P450 enzymes in the liver or other organs and, thereby, block or reduce undesired metabolism and inactivation of the primary drug. In this review, an overview will be given on the therapeutically most important classes of pharmacokinetic enhancers like β-lactamase inhibitors, inhibitors of CYP (cytochrome P450) enzymes in HIV therapy and hepatitis C, boosters for fluoropyrimidine-type anticancer agents, compounds utilized for enabling therapy of Parkinson's disease with levodopa, and others. Inhibitors of efflux pumps in both pathogenic bacteria and tumor cells will be addresses shortly. [ABSTRACT FROM AUTHOR]

With the clear need for better cancer treatment, naturally occurring molecules represent a powerful inspiration. Recently, curcumin has attracted attention for its pleiotropic anticancer activity in vitro, especially against colorectal and prostate cancer cells. Unfortunately, these encouraging results were disappointing in vivo due to curcumin's low stability and poor bioavailability. To overcome these issues, herein, the synthesis of eight new pyrimidine-curcumin derivatives is reported. The compounds were fully characterized ( 1 H/ 13 C NMR (Nuclear Magnetic Resonance), LC-MS (Liquid Chromatography-Mass Spectrometri), UV-Vis spectroscopy), particularly their acid/base behavior; overall protonation constants were estimated, and species distribution, as a function of pH, was predicted, suggesting that all the compounds are in their neutral form at pH 7.4. All the compounds were extremely stable in simulated physiological media (phosphate-buffered saline and simulated plasma). The compounds were tested in vitro (48 h incubation treatment) to assess their effect on cell viability in prostate cancer (LNCaP and PC3) and colorectal cancer (HT29 and HCT116) cell lines. Two compounds showed the same anti-proliferative activity as curcumin against HCT116 cells and improved cytotoxicity against PC3 cells.

Acyclovir (ACV) and penciclovir (PNV) have been commonly used during the last few decades as potent antiviral agents, especially for the treatment of herpes virus infections. In the present research their binding properties with human serum albumin (HSA) were studied using different advanced spectroscopic and in-silico methods. The interactions between ACV/PNV and HSA at the three investigated temperatures revealed a static type of binding. Extraction of the thermodynamic parameters of the ACV-HSA and PNV-HSA systems from the measured spectrofluorimetric data demonstrated spontaneous interactions with an enthalpy change (ΔH0) of -1.79 ± 0.29 and -4.47 ± 0.51 kJ.mol-1 for ACV and PNV, respectively. The entropy change (ΔS0) of 79.40 ± 0.95 and 69.95 ± 1.69 J.mol-1·K-1 for ACV and PNV, respectively, hence supported a potential contribution of electrostatic binding forces to the ACV-HSA and PNV-HSA systems. Putative binding of ACV/PNV to HSA, using previously reported site markers, showed that ACV/PNV were bound to HSA within subdomains IIA and IIIA (Sudlow sites I and II). Further confirmation was obtained through molecular docking studies of ACV-HSA and PNV-HSA binding, which confirmed the binding site of ACV/PNV with the most stable configurations of ACV/PNV within the HSA. These ACV/PNV conformers were shown to have free energies of -25.61 and -22.01 kJ.mol-1 for ACV within the HSA sites I and II and -22.97 and -26.53 kJ.mol-1 for PNV in HSA sites I and II, with hydrogen bonding and electrostatic forces being the main binding forces in such conformers. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Platelets have been demonstrated to be vital in cancer epithelial-mesenchymal transition (EMT), an important step in metastasis. Markers of EMT are associated with chemotherapy resistance. However, the association between the development of chemoresistance, EMT, and the contribution of platelets to the process, is still unclear. Here we report that platelets regulate the expression of (1) human equilibrative nucleoside transporter 1 (hENT1) and (2) cytidine deaminase (CDD), markers of gemcitabine resistance in pancreatic cancer. Human ENT1 (hENT1) is known to enable cellular uptake of gemcitabine while CDD deactivates gemcitabine. Knockdown experiments demonstrate that Slug, a mesenchymal transcriptional factor known to be upregulated during EMT, regulates the expression of hENT1 and CDD. Furthermore, we demonstrate that platelet-derived ADP and ATP regulate Slug and CDD expression in pancreatic cancer cells. Finally, we demonstrate that pancreatic cancer cells express the purinergic receptor P2Y12, an ADP receptor found mainly on platelets. Thus ticagrelor, a P2Y12 inhibitor, was used to examine the potential therapeutic effect of an ADP receptor antagonist on cancer cells. Our data indicate that ticagrelor negated the survival signals initiated in cancer cells by platelet-derived ADP and ATP. In conclusion, our results demonstrate a novel role of platelets in modulating chemoresistance in pancreatic cancer. Moreover, we propose ADP/ATP receptors as additional potential drug targets for treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Solute Carrier (SLC) transporters are a large superfamily of transmembrane carriers involved in the regulated transport of metabolites, nutrients, ions and drugs across cellular membranes. A subset of these solute carriers play a significant role in the cellular uptake of many cancer therapeutics, ranging from chemotherapeutics such as antimetabolites, topoisomerase inhibitors, platinum-based drugs and taxanes to targeted therapies such as tyrosine kinase inhibitors. SLC transporters are co-expressed in groups and patterns across normal tissues, suggesting they may comprise a coordinated regulatory circuit serving to mediate normal tissue functions. In cancer however, there are dramatic changes in expression patterns of SLC transporters. This frequently serves to feed the increased metabolic demands of the tumor cell for amino acids, nucleotides and other metabolites, but also presents a therapeutic opportunity, as increased transporter expression may serve to increase intracellular concentrations of substrate drugs. In this review, we examine the regulation of drug transporters in cancer and how this impacts therapy response, and discuss novel approaches to targeting therapies to specific cancers via tumor-specific aberrations in transporter expression. We propose that among the oncogenic changes in SLC transporter expression there exist emergent vulnerabilities that can be exploited therapeutically, extending the application of precision medicine from tumor-specific drug targets to tumor-specific determinants of drug uptake. [ABSTRACT FROM AUTHOR]

Paenibacillus sp. TKU042, a bacterium isolated from Taiwanese soil, produced α-glucosidase inhibitors (aGIs) in the culture supernatant when commercial nutrient broth (NB) was used as the medium for fermentation. The supernatant of fermented NB (FNB) showed stronger inhibitory activities than acarbose, a commercial anti-diabetic drug. The IC50 and maximum α-glucosidase inhibitory activities (aGIA) of FNB and acarbose against α-glucosidase were 81 μg/mL, 92% and 1395 μg/mL, 63%, respectively. FNB was found to be strongly thermostable, retaining 95% of its relative activity, even after heating at 100 °C for 30 min. FNB was also stable at various pH values. Furthermore, FNB demonstrated antioxidant activity (IC50 = 2.23 mg/mL). In animal tests, FNB showed remarkable reductions in the plasma glucose of ICR (Institute of Cancer Research) mice at a concentration of 200 mg/kg. Combining FNB and acarbose enhanced the effect even more, with an added advantage of eliminating diarrhea. According to HPLC (High-performance liquid chromatography) fingerprinting, the Paenibacillus sp. TKU042 aGIs were not acarbose. All of the results suggest that Paenibacillus sp. TKU042 FNB could have potential use as a health food or to treat type 2 diabetes. [ABSTRACT FROM AUTHOR]

Simple Summary: Organ preservation is becoming a topic of great interest for rectal cancer. Radiotherapy, often in association with chemotherapy, is playing a major role in achieving tumor sterilization and long-term local control. In order to achieve this goal, a high dose (>70 Gy) of radiotherapy is necessary. To avoid radiation toxicity of such a high dose, an endocavitary approach using contact X-ray 50 kV brachytherapy (CXB) is an attractive method. Historical series and two randomized trials in Europe give good evidence of the merit of CXB. The selection of early tumors is a key prognostic factor to achieve good results. A planned organ preservation treatment using CXB followed by chemoradiotherapy can be proposed to patients with T2–T3 a–b < 3 cm in diameter. At 3 years, the chance of local control should be close to 90% with good bowel function. Rectal adenocarcinoma is a quite radioresistant tumor. In order to achieve non-operative management (NOM) radiotherapy plays a major role. Targeted radiotherapy aiming at high precision 3D radiotherapy uses stereotactic image-guided external beam radiotherapy machines. To further safely increase the tumor dose, endocavitary brachytherapy (ECB) is an original approach. There are two different ways to perform such an ECB: contact X-ray brachytherapy (CXB) using a 50 kV X-ray generator with an X-ray tube positioned under eye guidance into the rectal cavity and high-dose-rate brachytherapy (HDRB) using iridium-192 sources positioned into the rectal cavity under image guidance. This study focused on CXB. CXB uses a small mobile generator that produces 50 kV X-rays with limited penetration. This technique is well adapted to accessible tumors of limited size and especially needs a high dose rate (≥15 Gy/minutes) for rectal tumors. It is performed on an ambulatory basis. A total dose between 80–110 Gy is delivered in 3–4 fractions over 3 to 6 weeks into a small volume (5 cm3). CXB was pioneered in the 1970s by Papillon using the Philips RT 50TM. Since 2009, the Papillon P50TM has been used in 11 institutions in Europe. The OPERA Phase III trial tested the hypothesis that a CXB boost (90 Gy/3 fr) compared to an EBRT boost (9 Gy/5 fr) for T2–T3 ab < 5 cm and N0–N1 < 8 mm will increase the 3-year organ preservation (OP) rate when combined with 45 Gy/5 weeks with concomitant capecitabine. Out of more than 300 patients with tumors < 3 cm (1962–1992), Papillon reported a long-term local control close to 85%. Similar results were published in Europe and USA at that time. The Lyon R96-2 Phase III trial (2004) demonstrated that, when combined with preoperative EBRT, a CXB boost (90 Gy/3 fr) significantly increased the rate of clinical complete response (cCR) and sphincter preservation, with some patients having OP at 10 years. With more than 2000 patients treated in Europe (2010–2020) using the Papillon 50TM, organ preservation appears possible in close to 80% of cases in selected early T2–T3. The OPERA trial closed after 141 inclusions (2015–2020) after an independent data monitoring committee recommendation because of promising results. At the 2-year follow-up (blinded data), the rate of cCR and OP were 77% and 72%, respectively, for the 141 tumors, and for T < 3 cm (61 pts), they were 86% and 85%, respectively, with good bowel function. The final results should be available in 2022. Organ preservation using NOM appears to be a promising approach for rectal cancer. A CXB boost with chemoradiotherapy in selected early T2–T3 could become an attractive option to achieve a planned OP. This approach should be proposed to well-informed patients after discussion in an MDT. [ABSTRACT FROM AUTHOR]

Simple Summary: Leptomeningeal metastases represent an unmet need due to the lack of effective therapy and poor survival. The tyrosine kinase inhibitor, neratinib, has demonstrated promising activity against brain metastases from HER2-positive breast cancer, as reported by the TBCRC and NALA trials, thus suggesting a potential activity also in leptomeningeal metastases when associated with capecitabine. The aim of the study was to investigate the efficacy and tolerability of neratinib in association with capecitabine in leptomeningeal metastases from heavily-pretreated breast cancer patients who failed multiple lines of treatment. Primary endpoints were 6-month overall survival and intracranial progression-free survival. Secondary endpoints were the responses assessed by whole CNS MRI performed every 8 weeks, neurological improvement, and safety. We obtained a median overall survival of 10 months, an intracranial progression-free survival of 4 months, neurological improvement and stable disease on an MRI lasting 6.5 months in six patients (60%). These preliminary findings suggest a potential activity of this treatment in LM from HER2-positive breast cancer that needs to be further investigated in larger datasets. Background: Leptomeningeal metastasis is a neurological complication from HER2-positive breast cancer with a poor prognosis and limited treatment options. This study has evaluated the activity of neratinib in association with capecitabine in 10 patients with LM from HER2-positive BC after the failure of multiple lines of treatment, including trastuzumab-based therapy, within a compassionate program, and a comparison was made with a historical control group of 10 patients. Methods: Patients aged ≥ 18 years with histological diagnosis of primary HER2-positive BC, either amplified or mutated, and newly-diagnosed LM were enrolled. Coexistence of BM that has or has not received radiotherapy, as well as prior chemotherapy, hormone therapy, or monoclonal HER2-targeting antibodies or antibody–drug conjugates, were allowed, with the exclusion of lapatinib. Results: Six-months OS was 60% with a median OS of 10 months (95% CI: 2.00–17.0). Three-month intracranial PFS was 60% with a median intracranial PFS of 4.0 months (95% CI: 2.00–6.0). The neurological benefit was observed in 70% of patients with a median duration of neurological response of 6.5 months. The best radiological response was stable disease in 60% of patients. Conclusions: This small series shows that the combination of neratinib and capecitabine is a safe treatment in LM from heavily pretreated HER2-positive BC with clinical efficacy in some patients and is worth investigating in a larger study. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton pump inhibitors are frequently used in cancer patients to alleviate some symptoms, epigastric pain or heartburn. However, acid suppression decreases the absorption of some oral-targeted anticancer treatments (tyrosine kinase inhibitors, CDK4/6 inhibitors) and induces changes in the gut microbiome. Recent data are showing that these interactions have important clinical impacts and medical oncologists and patients must be aware of these possible interactions. Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician. [ABSTRACT FROM AUTHOR]

Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis. [ABSTRACT FROM AUTHOR]

Pseudomonas syringae is pathogenic in a wide variety of plants, causing diseases with economic impacts. Pseudomonas syringae pathovars produce several toxins that can function as virulence factors and contribute to disease symptoms. These virulence factors include antimetabolite toxins, such as tabtoxin, phaseolotoxin and mangotoxin, which target enzymes in the pathways of amino acid metabolism. The antimetabolite toxins are generally located in gene clusters present in the flexible genomes of specific strains. These gene clusters are typically present in blocks of genes that appear to be integrated into specific sites in the P. syringae core genome. A general overview of the genetic organization and biosynthetic and regulatory functions of these genetic traits of the antimetabolite toxins will be given in the present work. [ABSTRACT FROM AUTHOR]

Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: For many years, patients with breast cancer and brain metastases were excluded from participation in clinical trials. It was believed that anticancer drugs could not cross the blood–brain barrier. However, recent evidence strongly suggests that some drugs can act against brain metastases, with the greatest intracranial response rate reported in the case of capecitabine, neratinib plus capecitabine, trastuzumab deruxtecan and tucatinib plus trastuzumab and capecitabine. In this article, we discuss the achievements in systemic therapy of breast cancer patients with brain metastases. We stress on the newest clinical trial results which indicate tremendous progress in HER2-positive breast cancer. On the other hand, in patients with triple-negative breast cancer or hormone-receptor-positive brain metastases, much fewer compounds were discovered. Based on the presented results, patients with active brain metastases should be routinely included in clinical trials with novel agents. Brain metastases are detected in 5% of patients with breast cancer at diagnosis. The rate of brain metastases is higher in HER2-positive and triple-negative breast cancer patients (TNBC). In patients with metastatic breast cancer, the risk of brain metastases is much higher, with up to 50% of the patients having two aggressive biological breast cancer subtypes. The prognosis for such patients is poor. Until recently, little was known about the response to systemic therapy in brain metastases. The number of trials dedicated to breast cancer with brain metastases was scarce. Our review summarizes the current knowledge on this topic including very significant results of clinical trials which have been presented very recently. We focus on the intracranial response rate of modern drugs, including new antibody–drug conjugates, HER2- targeted tyrosine kinase inhibitors and other targeted therapies. We highlight the most effective and promising drugs. On the other hand, we also suggest that further efforts are needed to improve the prognosis, especially patients with TNBC and brain metastases. The information contained in this article can help oncologists make treatment-related decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is considered incurable, and most cases are detected in the advanced stages. Establishing a new, effective interventional treatment for advanced pancreatic cancer is a pressing issue. Pretreatment with gemcitabine had a restraining effect on the homologous DNA recombination repair (HRR) of DNA crosslinking, inhibiting the function of Rad51, of which expression is found to be increased in pancreatic cancer. The aim of our prospective study was to assess the potential value of the arterial administration of DNA crosslinking agents after intravenous administration of low-dose gemcitabine for patients with advanced pancreatic cancer. We confirmed, among forty-five patients with unresectable advanced pancreatic cancer, that a patient subgroup of locally advanced pancreatic cancer (LAPC, 10 patients) who underwent these treatment courses successively more than twice in the first 6 months had 33 months of overall survival, 31 months of local progression free survival, and a complete response of 40%. This treatment can be a new treatment option for LAPC. (1) Background: Pretreatment by Rad51-inhibitory substances such as gemcitabine followed by arterial chemotherapy using antineoplastic agents causing DNA crosslink might be more beneficial for patients with locally advanced pancreatic cancers than conventional treatments. The efficacy of arterial administration of DNA crosslinking agents with pretreatment of intravenous low-dose gemcitabine for patients with unresectable locally advanced or metastatic pancreatic cancer (LAPC or MPC) is evaluated. (2) Methods: A single-arm, single-center, institutional review board-approved prospective study was conducted between 2005 and 2015. Forty-five patients (23 LAPC, 22 MPC) were included. Patients received a weekly low dose of gemcitabine intravenously for three weeks followed by arterial administration of mitomycin C and epirubicin hydrochloride at tumor-supplying arteries on the fifth or sixth week. This treatment course was repeated at 1.5-to-2-month intervals. Overall survival (OS), local progression-free survival (LPFS), and therapeutic response were evaluated. LAPC or MPC were divided according to treatment compliance, excellent or poor (1 or 2), to subgroups L1, L2, M1, and M2. (3) Results: OS of LAPC and MPC were 23 months and 13 months, respectively. The OS of LAPC with excellent treatment compliance (subgroup L1, 10 patients) was 33 months with 31 months of LPFS, and four patients (40%) had a complete response (CR). The OS of the L1 subgroup was significantly longer than those of other subgroups L2, M1, and M2, which were 17 months, 17 months, and 8 months, respectively. As Grade 3 adverse effects, severe bone marrow suppression, interstitial pneumonitis, and hemolytic uremic syndrome were observed in six (13.0%), three (6.5%), and three (6.5%) patients, respectively. (4) Conclusions: Arterial DNA crosslinking with the systemic restraint of homologous recombination repair can be a new treatment option for LAPC. [ABSTRACT FROM AUTHOR]

Simple Summary: This research suggests a new potential therapeutic approach to pancreatic ductal adenocarcinoma to improve drug effectiveness and overcome drug resistance. A double actively targeted gemcitabine delivery system, consisting of polymeric micelles, was developed by microfluidic technique to ensure a narrow size distribution, a good colloidal stability, and drug-encapsulation efficiency for the selective and controlled release of the loaded drug, in response to the pH variations and uPAR expression in tumors. In vitro studies assessed that the release of the drug in the acidic environment was higher than in the neutral one, and that the pH-responsive and uPAR-targeted polymeric micelles enhanced the antitumor properties of gemcitabine in models resembling the pancreatic tumor microenvironment. Pancreatic ductal adenocarcinoma (PDAC) represents a great challenge to the successful delivery of the anticancer drugs. The intrinsic characteristics of the PDAC microenvironment and drugs resistance make it suitable for therapeutic approaches with stimulus-responsive drug delivery systems (DDSs), such as pH, within the tumor microenvironment (TME). Moreover, the high expression of uPAR in PDAC can be exploited for a drug receptor-mediated active targeting strategy. Here, a pH-responsive and uPAR-targeted Gemcitabine (Gem) DDS, consisting of polymeric micelles (Gem@TpHResMic), was formulated by microfluidic technique to obtain a preparation characterized by a narrow size distribution, good colloidal stability, and high drug-encapsulation efficiency (EE%). The Gem@TpHResMic was able to perform a controlled Gem release in an acidic environment and to selectively target uPAR-expressing tumor cells. The Gem@TpHResMic displayed relevant cellular internalization and greater antitumor properties than free Gem in 2D and 3D models of pancreatic cancer, by generating massive damage to DNA, in terms of H2AX phosphorylation and apoptosis induction. Further investigation into the physiological model of PDAC, obtained by a co-culture of tumor spheroids and cancer-associated fibroblast (CAF), highlighted that the micellar system enhanced the antitumor potential of Gem, and was demonstrated to overcome the TME-dependent drug resistance. In vivo investigation is warranted to consider this new DDS as a new approach to overcome drug resistance in PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer (PDAC) is a deadly disease, exacerbated by obesity, which lacks effective therapeutic interventions. Most PDAC has a limited response to immune- and chemotherapy. Treating PDAC is made additionally challenging by the rapid emergence of muscle wasting and cachexia, which predict poor response to several therapies. We have found that dietary supplementation with β-hydroxy-β-methylbutyrate promotes immunosurveillance in PDAC tumors and protects muscle. This dietary supplement has the potential to be an important adjuvant in PDAC therapy, opening the doors to immunotherapy response. Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, and effective therapies for PDAC are currently lacking. Moreover, PDAC is promoted and exacerbated by obesity, while cachexia and sarcopenia are exceptionally common comorbidities that predict both poor survival and treatment response. Managing PDAC with immunotherapies has thus far proven ineffective, partly due to the metabolically hostile tumor microenvironment. β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine commonly used as a dietary supplement to boost muscle growth and immune function, may be an attractive candidate to augment PDAC therapy. We therefore sought to test the hypothesis that HMB would enhance antitumor immunity while protecting mouse muscle mass. Control and diet-induced obese C57BL/6 male mice bearing subcutaneously injected Panc02 tumors were supplemented with 1% HMB and treated with or without 50 mg/kg gemcitabine (n = 15/group). HMB was associated with reduced muscle inflammation and increased muscle fiber size. HMB also reduced tumor growth and promoted antitumor immunity in obese, but not lean, mice, independent of the gemcitabine treatment. Separately, in lean tumor-bearing mice, HMB supplementation promoted an anti-PD1 immunotherapy response (n = 15/group). Digital cytometry implicated the decreased abundance of M2-like macrophages in PDAC tumors, an effect that was enhanced by anti-PD1 immunotherapy. We confirmed that HMB augments M1-like macrophage (antitumor) polarization. These preclinical findings suggest that HMB has muscle-sparing and antitumor activities against PDAC in the context of obesity, and that it may sensitize otherwise nonresponsive PDAC to immunotherapy. [ABSTRACT FROM AUTHOR]