Catalytic Cleavage of the C-O Bonds in Lignin and Lignin Model Compounds by Metal Triflate Catalysts.

The effective cleavage of C-O bonds in linkages of lignin was one of the significant strategies promoting lignin valorization. Herein, the strategy of C-O bonds cleavage of lignin using metal triflate as the catalyst was developed. The carboxylic acid or alcohol could be used as the nucleophile to stabilize the reactive intermediates formed during the depolymerization of lignin, and the corresponding ester/ether compounds could be obtained. This catalytic system was suitable for the C-O bond cleavage in α-O-4 and ß-O-4 linkages with excellent efficiency. Additionally, reaction conditions were optimized. The reaction mixture was detected by 1 H NMR, and no other byproducts were found. As for treated lignin samples, the cleavage of C-O bonds in linkages was determined by 2D HSQC NMR, the increased content of the phenol hydroxyl group was proved by FT-IR, and the reduced molecular weight was investigated by GPC. Furthermore, multiple phenolic compounds were detected by GC-MS in the reaction mixtures.

2D MOF based-heterostructure with hierarchical architecture as antibacterial wound dressing.

Bacterial infections pose a huge threat to human health due to the inevitable emergency of drug resistance. Metal-organic frameworks (MOFs) consisting of metal ions and organic linkers, as emerging efficient antibacterial material, have the merits of structural flexibility and adjustable physicochemical property. With assistance of photosensitive agents as organic linkers, MOFs have great potential in antibacterial application through photocatalytic therapy by the generation of reactive oxygen species (ROS). However, the limited light use efficiency and short lifespan of ROS are two obstacles for their applications. Inspired by the semiconductor heterostructure in photocatalysis, we rationally design and precisely synthesize MOFs based heterostructures, in which the TiO2 nanoclusters are filled into the pores of Cu-TCPP nanosheets (i.e. TiO2 NCs@Cu-TCPP HSs). And the composite materials possess three-dimensional (3D) hierarchical architectures, which have advantages of large surface area, excellent light-absorbing ability and photocatalytic efficiency. Significantly, this novel material displays >99.99 % antibacterial efficiency against E. coli and S. aureus within 30 min and preserves the excellent antibacterial ability during reusing three times, which is superior to recently reported photocatalystic-based antibacterial materials. Our study provides new insights into the energy band engineering for enhanced antibacterial performance, paving a way for designing advanced clinical wound dressings.

Integrated metabolomics and network pharmacology to reveal the mechanism of areca nut addiction.

As a chewing hobby, areca nut (Areca catechu L.) has become the most common psychoactive substance in the world, besides tobacco, alcohol and caffeinated beverages. Moreover, as a first-class carcinogen designated by International Agency for Research on Cancer, long-term chewing areca nut can result in oral mucosal diseases and even oral cancer. To clarify the potential mechanism of areca nut addiction, an integrated strategy of metabolomics and network pharmacology was adopted in this study. Network pharmacology study indicated that all the key targets related to areca nut addiction could be regulated by arecoline and pointed out the importance of G-protein coupled receptor signalling pathway. Analysis results of mice plasma metabolome and faeces metabolome intervened by arecoline suggested that the component may affect the dopamine system and 5-HT system by regulating phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, primary bile acid biosynthesis, glycerophospholipid metabolism and intestinal flora structure. Moreover, the potential importance of bile acids in formation of addictive behaviour of chewing areca nut was investigated by integrative analysis of the relationships between metabolites and intestinal flora. The study can provide scientific basis for the addiction intervention and treatment of areca nut chewers.

Up Front Unfolded Protein Response Combined with Early Protein Secretion Pathway Engineering in Yarrowia lipolytica to Attenuate ER Stress Caused by Enzyme Overproduction.

Engineering the yeast Yarrowia lipolytica as an efficient host to produce recombinant proteins remains a longstanding goal for applied biocatalysis. During the protein overproduction, the accumulation of unfolded and misfolded proteins causes ER stress and cell dysfunction in Y. lipolytica. In this study, we evaluated the effects of several potential ER chaperones and translocation components on relieving ER stress by debottlenecking the protein synthetic machinery during the production of the endogenous lipase 2 and the E. coli ß-galactosidase. Our results showed that improving the activities of the non-dominant translocation pathway (SRP-independent) boosted the production of the two proteins. While the impact of ER chaperones is protein dependent, the nucleotide exchange factor Sls1p for protein folding catalyst Kar2p is recognized as a common contributor enhancing the secretion of the two enzymes. With the identified protein translocation components and ER chaperones, we then exemplified how these components can act synergistically with Hac1p to enhance recombinant protein production and relieve the ER stress on cell growth. Specifically, the yeast overexpressing Sls1p and cytosolic heat shock protein Ssa8p and Ssb1p yielded a two-fold increase in Lip2p secretion compared with the control, while co-overexpressing Ssa6p, Ssb1p, Sls1p and Hac1p resulted in a 90% increase in extracellular ß-galp activity. More importantly, the cells sustained a maximum specific growth rate (µmax) of 0.38 h-1 and a biomass yield of 0.95 g-DCW/g-glucose, only slightly lower than that was obtained by the wild type strain. This work demonstrated engineering ER chaperones and translocation as useful strategies to facilitate the development of Y. lipolytica as an efficient protein-manufacturing platform.

Installing xylose assimilation and cellodextrin phosphorolysis pathways in obese Yarrowia lipolytica facilitates cost-effective lipid production from lignocellulosic hydrolysates.

BACKGROUND: Yarrowia lipolytica, one of the most charming chassis cells in synthetic biology, is unable to use xylose and cellodextrins. RESULTS: Herein, we present work to tackle for the first time the engineering of Y. lipolytica to produce lipids from cellodextrins and xylose by employing rational and combinatorial strategies. This includes constructing a cellodextrin-phosphorolytic Y. lipolytica by overexpressing Neurospora crassa cellodextrin transporter, Clostridium thermocellum cellobiose/cellodextrin phosphorylase and Saccharomyces cerevisiae phosphoglucomutase. The effect of glucose repression on xylose consumption was relieved by installing a xylose uptake facilitator combined with enhanced PPP pathway and increased cytoplasmic NADPH supply. Further enhancing lipid production and interrupting its consumption conferred the obese phenotype to the engineered yeast. The strain is able to co-ferment glucose, xylose and cellodextrins efficiently, achieving a similar µmax of 0.19 h-1, a qs of 0.34 g-s/g-DCW/h and a YX/S of 0.54 DCW-g/g-s on these substrates, and an accumulation of up to 40% of lipids on the sugar mixture and on wheat straw hydrolysate. CONCLUSIONS: Therefore, engineering Y. lipolytica capable of assimilating xylose and cellodextrins is a vital step towards a simultaneous saccharification and fermentation (SSF) process of LC biomass, allowing improved substrate conversion rate and reduced production cost due to low demand of external glucosidase.

WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

Impact of concomitant cardiovascular medications on overall survival in patients with liver cirrhosis.

OBJECTIVES OF THE ARTICLE: Liver cirrhosis is the end-stage liver disease associated with poor prognosis and cardiovascular comorbidity could significantly impact mortality of cirrhotic patients. We conducted a large, retrospective study to investigate the survival impact of cardiovascular co-medications in patients with liver cirrhosis. MATERIALS AND METHODS: A study-specific R package was processed on the local databases of partner institutions within the Observational Health Data Sciences and Informatics consortium, namely Columbia University, New York City (NYC), USA and Ajou University School of Medicine (AUSOM), South Korea. Patients with cirrhosis diagnosed between 2000 and 2020 were included. Final analysis of the anonymous survival data was performed at Medical Faculty Mannheim, Heidelberg University. RESULTS: We investigated a total of 32,366 patients with liver cirrhosis. Our data showed that administration of antiarrhythmics amiodarone or digoxin presented as a negative prognostic indicator (p = 0.000 in both cohorts). Improved survival was associated with angiotensin-converting enzyme inhibitor ramipril (p = 0.005 in NYC cohort, p = 0.075 in AUSOM cohort) and angiotensin II receptor blocker losartan (p = 0.000 in NYC cohort, p = 0.005 in AUSOM cohort). Non-selective beta blocker carvedilol was associated with a survival advantage in the NYC (p = 0.000) cohort but not in the AUSOM cohort (p = 0.142). Patients who took platelet inhibitor clopidogrel had a prolonged overall survival compared to those without (p = 0.000 in NYC cohort, p = 0.003 in AUSOM cohort). CONCLUSION: Concomitant cardiovascular medications are associated with distinct survival difference in cirrhotic patients. Multidisciplinary management is needed for a judicious choice of proper cardiovascular co-medications in cirrhotic patients.

Trehalose metabolism targeting as a novel strategy to modulate acid tolerance of yeasts and its application in food industry.

Some spoilage yeasts are able to develop resistance to commonly used weak-acid preservatives. We studied the trehalose metabolism and its regulation in Saccharomyces cerevisiae in response to propionic acid stress. We show interruption of trehalose synthetic pathway caused the mutant hypersensitive to the acid stress, while its overexpression conferred acid-tolerance to yeast. Interestingly, this acid-tolerance phenotype was largely independent of trehalose but relied on the trehalose synthetic pathway. We demonstrate trehalose metabolism played a vital role in regulation of glycolysis flux and Pi/ATP homeostasis in yeast during acid-adaptation, and the PKA and TOR signaling pathways were involved in regulating trehalose synthesis at transcriptional level. This work confirmed the regulatory function of trehalose metabolism and improved our understanding of molecular mechanism of acid-adaptation of yeast. By exemplifying trehalose metabolism interruption limited the growth of S. cerevisiae exposed to weak acids, and trehalose pathway overexpression conferring acid-resistance to Yarrowia lipolytica enhanced citric acid production, this work provides new insights into the development of efficient preservation strategies and robust organic acid producers.

The Bioaccessibility of Yak Bone Collagen Hydrolysates: Focus on Analyzing the Variation Regular of Peptides and Free Amino Acids.

The lack of a bioaccessibility test for yak bone collagen hydrolysates (YBCH) limits their development as functional foods. In this study, simulated gastrointestinal digestion (SD) and absorption (SA) models were utilized to evaluate the bioaccessibility of YBCH for the first time. The variation in peptides and free amino acids was primarily characterized. There was no significant alteration in the concentration of peptides during the SD. The transport rate of peptides through the Caco-2 cell monolayers was 22.14 ± 1.58%. Finally, a total of 440 peptides were identified, more than 75% of them with lengths ranging from 7 to 15. The peptide identification indicated that about 77% of the peptides in the beginning sample still existed after the SD, and about 76% of the peptides in the digested YBCH could be observed after the SA. These results suggested that most peptides in the YBCH resist gastrointestinal digestion and absorption. After the in silico prediction, seven typical bioavailable bioactive peptides were screened out and they exhibited multi-type bioactivities in vitro. This is the first study to characterize the changes in peptides and amino acids in the YBCH during gastrointestinal digestion and absorption, and provides a foundation for analyzing the mechanism of YBCH's bioactivities.

Rapidly analyzing of ingredients during chewing and processing of areca nut using feature-based molecular networking.

As a traditional herbal medicine and food in China and many other Asian countries, the areca nut (Areca catechu L.) is not only widely used for the treatment of various diseases, but also popular as a chewing hobby. However, as a first-class carcinogen designated by IARC, clinical studies have shown that long-term chewing of areca nut is associated with oral mucosal diseases and even oral cancer. Moreover, the incidence of these diseases varies regionally, suggesting that it may be related to edible methods in different regions. In this study, UPLC-Q-TOF-MSE was combined with feature-based molecular networking to systematically characterise the chemical ingredients of areca nut. Based on these results, the ingredients of different edible parts and edible methods was rapidly compared. The compositional changes during the production process were also analysed. The obtained results provide a foundation for the scientific utilisation of areca nut.

Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer.

Radiotherapy is an important component of current treatment options for colorectal cancer (CRC). It is either applied as neoadjuvant radiotherapy to improve local disease control in rectal cancers or for the treatment of localized metastatic lesions of CRC. DNA double-strand breaks (DSBs) are the major critical lesions contributing to ionizing radiation (IR)-induced cell death. However, CRC stem cells promote radioresistance and tumor cell survival through activating cell-cycle checkpoints to trigger the DNA damage response (DDR) and DNA repair after exposure to IR. A promising strategy to overcome radioresistance is to target the DDR and DNA repair pathways with drugs that inhibit activated cell-cycle checkpoint proteins, thereby improving the sensitivity of CRC cells to radiotherapy. In this review, we focus on the preclinical studies and advances in clinical trials of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), WEE1 and poly (ADP-ribose) polymerase 1 (PARP1) kinase inhibitors in CRC. Importantly, we also discuss the selective radiosensitization of CRC cells provided by synthetic lethality of these inhibitors and the potential for widening the therapeutic window by targeting the DDR and DNA repair pathways in combination with radiotherapy and immunotherapy.

Second Cancer After Additive Chemotherapy in Patients With Colon Cancer.

BACKGROUND: Additive chemotherapeutic treatment of UICC-stage -III / IV colon cancer with fluorouracil, leucovorin and oxaliplatin is widely accepted as current standard of treatment after R0-resection. However, as patients.. survival is increasing, long-term side effects of chemotherapeutic agents such as second cancer development are becoming increasingly important. PATIENTS: We therefore investigated a total of 2 856 Patients with UICC-stage III / IV colon cancer, 223 of whom (7.8%) had developed a subsequent second cancer. RESULTS: Median follow-up was 73.2 months (range 209.9 months, 95%-CI 69.8-76.9). Most frequent second cancers were prostate cancer (18.4%), colon cancer (16.1%), breast cancers (8.1%), lung cancer (8.1%), rectal cancer (4.9%) and uterine cancer (4.9%). However, in comparison to non-treated patients this did not represent a significantly increased risk for subsequent second cancer in patients after treatment with additive chemotherapy. Of interest, our data suggest a significantly decreased second cancer rate in patients treated with FOLFOX compared to FUFOL for additive treatment. CONCLUSIONS: Second cancer development was not increased after additive chemotherapy for colon cancer, which is a novel aspect in the ongoing discussions on reduction of adjuvant treatment to 3 months or treatment of lymph node negative patients. Novelty and Impact Statement To our knowledge, this is the first population-based study analyzing second cancer development after additive chemotherapy in patients with UICC III-IV colon cancer. The results have an important impact on the surveillance and long-term follow-up of cancer patients.

Sequential Geriatric Assessment in Older Patients with Colorectal Cancer during Chemotherapy: Subgroup Analysis of a Prospective, Multicenter Study EpiReal 75.

INTRODUCTION: Colorectal cancer (CRC) is a disease of older patients, but evidence-based guidelines for chemotherapy in older patients are scarce. Geriatric assessment (GA) evaluates a patient's functional status (FS) and helps in decision-making when choosing chemotherapy for older patients. However, the change of FS during chemotherapy is rarely studied as GA is mostly performed once instead of sequentially. METHODS: We performed a subgroup analysis of a prospective, multicenter study EpiReal 75. Patients aged ≥75 years with gastrointestinal malignancy prior to initiation of chemotherapy or receiving palliative chemotherapy were screened. We defined geriatric core assessments including the Eastern Cooperative Oncology Group score, Barthel's activities of daily living (ADL) scale, Lawton's instrumental activities of daily living (IADL) scale, and G-8 questionnaire, which were performed at baseline and repeated every 3 months. Quality of life (QoL) assessed by QLQ-C30 questionnaire was also re-evaluated every 3 months. We defined any deterioration in any of the geriatric parameters as unstable in the corresponding function. RESULTS: 28 patients with CRC were enrolled between April 2014 and December 2018. 20 patients were evaluable for statistical analysis with a mean age of 78.5 years (range, 75-88). Most patients received chemotherapy in palliative setting. During 3 months of chemotherapy, 25% of patients became more dependent as measured by ADL or IADL. During a median follow-up of 15 months, patients with unstable ADL or IADL had a significantly shorter overall survival (OS) than those with stable ADL or IADL (plogrank = 0.0055 and 0.0253, respectively), without a significant difference in progression-free survival (PFS). Also, unstable IADL correlated with a deterioration in aspects of QoL such as role functioning and emotional functioning (p = 0.0189 and 0.0239, respectively). 20% of patients experienced treatment-related grade 3 adverse events (AEs), no grade 4-5 AEs occurred. CONCLUSION: Sequential GA revealed changes in FS in older patients with CRC receiving chemotherapy. A deterioration of FS during chemotherapy did not influence PFS but had a negative impact on OS and QoL. It is therefore important to maintain FS in older patients with cancer, and regular performance of geriatric core assessments should be encouraged in the clinical practice.

Microbiome-metabolomics insights into the feces of high-fat diet mice to reveal the anti-obesity effects of yak (Bos grunniens) bone collagen hydrolysates.

In this study, a twelve-week intervention was conducted to investigate the anti-obesity effects of yak bone collagen hydrolysates (YBCH) on mice with a high-fat diet. The obesity-associated phenotypes of mice were detected and the feces of mice were jointly analyzed by 16S rRNA gene sequencing and untargeted metabolomics. Results indicated that supplementation with YBCH could ameliorate the obesity-associated phenotypes of mice, especially with the medium dose (MD) and high dose (HD) of YBCH. Compared with the high-fat diet control (HC) group, the ratio of Firmicutes and Bacteroidetes in the fecal microbiota of the low dose (LD), MD, and HD groups was separately decreased by 29.83 %, 70.85 %, and 75.70 %. Lachnospiraceae and Muribaculaceae were the key bacteria for the YBCH intervention, which might be attributed to their different substrate preferences. The joint analysis of the 16S rRNA gene sequencing and untargeted metabolomics suggested that the anti-obesity effects of YBCH might be achieved by up-regulating the arginine and proline metabolism and down-regulating the aromatic amino acids metabolism via the gut microbiota.

Predicting response to neoadjuvant chemoradiotherapy in rectal cancer: from biomarkers to tumor models.

Colorectal cancer (CRC) is a major contributor to cancer-associated morbidity worldwide and over one-third of CRC is located in the rectum. Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is commonly applied to treat locally advanced rectal cancer (LARC). In this review, we summarize current and novel concepts of neoadjuvant therapy for LARC such as total neoadjuvant therapy and describe how these developments impact treatment response. Moreover, as response to nCRT is highly divergent in rectal cancers, we discuss the role of potential predictive biomarkers. We review recent advances in biomarker discovery, from a clinical as well as a histopathological and molecular perspective. Furthermore, the role of emerging predictive biomarkers derived from the tumor environment such as immune cell composition and gut microbiome is presented. Finally, we describe how different tumor models such as patient-derived cancer organoids are used to identify novel predictive biomarkers for chemoradiotherapy (CRT) in rectal cancer.

Integrated metabolomics and network pharmacology approach to reveal immunomodulatory mechanisms of Yupingfeng granules.

Systems biology is an approach that employs modern biological techniques and methods to combine the overall regulation of the body by Chinese herbal formulas with systems analysis at the molecular level. In this study, the underlying immunomodulatory mechanisms of yupingfeng granules (YPFG) were investigated based on the integration of metabolomics and network pharmacology methods. Selected routine peripheral blood indicators, body weight, and organ indices related to immunity were firstly measured in order to evaluate the effects of YPFG in cyclophosphamide-induced immunocompromised rats. Plasma metabolomics analyses were carried out by UPLC-Q-TOF-MS combined with a multivariate data analysis. Our study indicates that the potential regulatory mechanism was related to bile acid and glycerophospholipid metabolism, involving the regulation of 11 metabolites, including 8 bile acids, 1 phosphatidylserine, and 2 phosphatidylethanolamines. By means of network pharmacology, the compound-target network between potential active components of YPFG and immune dysregulation was constructed, which releated to estrogen receptor, PPAR, MAPK, PI3K-Akt, JNK signaling pathways, and ubiquitin-mediated protein degradation. The immunomodulatory effect of YPFG may be exerted through regulating lipid metabolism, then bile acid metabolism and inflammation were affected. Biological verification was also performed on cyclophosphamide-induced immunocompromised BALB/c mice. Flavonoid and saponin, two types of compounds in YPFG, were found to be the major active ingredients in the immunomodulatory effects of YPFG, and these components may regulate the abnormal metabolism of bile acids by enhancing the expression of FXR and LXRα. This work elucidated active ingredients, potential biomarkers, and mechanisms of action in the immunoregulatory effects of YPFG from the perspective of systems biology, which provides a scientific basis for its precise clinical medication.

Method for rapidly discovering active components in Yupingfeng granules by UPLC-ESI-Q-TOF-MS.

Yupingfeng granules (YPFG) were isolated from a traditional Chinese medicine (TCM) formulation composed of three herbs (Astragali Radix, Atractylodis Macrocephalae Rhizoma, and Saposhnikoviae Radix). This formulation is used in TCM to tonify qi, and it can help strengthen exterior and reduce sweating. Nevertheless, the active components of YPFG remain unclear. In this study, the chemical constituents of YPFG were systematically characterized by ultra-performance liquid chromatography coupled with electrospray ionization/ quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS). Fifty-eight compounds, namely, 20 flavonoids, 19 saponins, nine organic acids, four volatile coumarins, three lactones, one alkaloid, and two other components, were identified. In addition, the constituents of YPFG with the potential for in vivo bioactivities following oral administration were investigated in Sprague-Dawley rats. Thirteen compounds, namely, 11 flavonoid-related and 2 saponin-related components, were detected in rat plasma. After enriching flavonoids and saponins in YPFG by extraction, the extracts and YPFG were administrated to immunosuppressed rats, respectively. Plasma samples were analyzed by UPLC-ESI-Q-TOF-MS, and principal component analysis (PCA) confirmed that the extracts had similar effects to YPFG. This method could discover active ingredients in YPFG quickly and provide a scientific basis for quality control and mechanism research.

Cancer-Associated Mutations in Normal Colorectal Mucosa Adjacent to Sporadic Neoplasia.

INTRODUCTION: Colorectal cancer arises in a multistep process of carcinogenesis from normal mucosa. The earliest precursor might be a morphologically inconspicuous precancerous field, harboring cancer-associated mutations. METHODS: We systematically analyzed genetic alterations in 77 tissue samples from 30 patients with sporadic colorectal neoplasms (18 large adenomas and 12 adenocarcinomas) and matched adjacent normal mucosa (N = 30), as well as normal rectal tissue (N = 17). We profiled mutations associated with colorectal cancer by targeted sequencing of 46 genetic loci using 157 custom amplicons and a median depth of 42,655 reads per loci. RESULTS: Multiple mutations were found in colorectal neoplasms, most frequently in APC, KRAS, and TP53. In a subgroup of 11 of 30 patients, alterations were also detected in non-neoplastic mucosa. These mutations were divergent from those in matched neoplasms. The total alteration count and the allele frequency of mutations were higher in neoplasms compared with those in adjacent tissues. We found that younger patients (≤70 years) are less likely affected by mutations in non-neoplastic mucosa than older patients (>70 years, P = 0.013), although no association was found for other variables, including type, location and differentiation of neoplasia, and previous history of polyps. DISCUSSION: Our data show that cancer-associated mutations can be found in non-neoplastic tissues in a subgroup of patients with colorectal neoplasms. Further studies are needed to specify the risk of occurrence and recurrence of neoplasia in this patient population.

Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure.

In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.

Modeling spatial access to cervical cancer screening services in Ondo State, Nigeria.

BACKGROUND: Women in low- and middle-income countries (LMIC) remain at high risk of developing cervical cancer and have limited access to screening programs. The limits include geographical barriers related to road network characteristics and travel behaviors but these have neither been well studied in LMIC nor have methods to overcome them been incorporated into cervical cancer screening delivery programs. METHODS: To identify and evaluate spatial barriers to cervical cancer prevention services in Ondo State, Nigeria, we applied a Multi-Mode Enhanced Two-Step Floating Catchment Area model to create a spatial access index for cervical cancer screening services in Ondo City and the surrounding region. The model used inputs that included the distance between service locations and population centers, local population density, quantity of healthcare infrastructures, modes of transportation, and the travel time budgets of clients. Two different travel modes, taxi and mini bus, represented common modes of transit. Geocoded client residential locations were compared to spatial access results to identify patterns of spatial access and estimate where gaps in access existed. RESULTS: Ondo City was estimated to have the highest access in the region, while the largest city, Akure, was estimated to be in only the middle tier of access. While 73.5% of clients of the hospital in Ondo City resided in the two highest access zones, 21.5% of clients were from locations estimated to be in the lowest access catchment, and a further 2.25% resided outside these limits. Some areas that were relatively close to cervical cancer screening centers had lower access values due to poor road network coverage and fewer options for public transportation. CONCLUSIONS: Variations in spatial access were revealed based on client residential patterns, travel time differences, distance decay assumptions, and travel mode choices. Assessing access to cervical cancer screening better identifies potentially underserved locations in rural Nigeria that can inform plans for cervical cancer screening including new or improved infrastructure, effective resource allocation, introduction of service options for areas with lower access, and design of public transportation networks.