Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary ...colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.
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•Inter- and intra-metastatic immune infiltrates are heterogeneous in colorectal cancer•T cell densities from metastases increase following anti-EGFR treatment•Immunoscore (IS) outperforms PDL1 staining in metastatic biopsy diagnostic accuracy•IS and TB score from the least-infiltrated metastasis are most survival associated
Van den Eynde et al. quantify immune cell types in metastases and primary colorectal tumors. They show that high Immunoscore (IS) associates with fewer metastases, that anti-EGFR treatment significantly increases T cell density in the core of metastases, and that the predictive accuracy of IS better than PDL1.
The ever-increasing demand for storing renewable energy sources calls for novel battery technologies that are of sustainably low levelized energy cost. Research into battery chemistry has evolved to ...a stage where a plethora of choices based on earth-abundant elements can be compared during their development. One of the emerging candidates is the nonaqueous potassium-ion battery. K-ion’s unique properties as a charge carrier have aroused intense interest in exploring high-performing cathode and anode materials for this battery. Rapid progress has been made, where leading candidates of electrodes have been proposed, i.e., hard carbon as anode and Prussian white analogues as cathode. In this new battery technology’s infancy, it is our opinion that the focus should be given to potentially scalable, inexpensive electrode materials and the understanding of their cycle-life-property correlations. It may be the ultralong cycle life that differentiates potassium-ion batteries from sodium-ion batteries in the future market.
Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent ...flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy.
Synopsis
pHLIP-based sorting of acid-exposed cancer cells from 3D spheroids identifies tetraploidy and DDR as hallmarks of tumor acidosis. Drugs targeting ATM and ATR preferentially inhibit growth of acid-exposed cancer cells and sensitize them to chemotherapy.
Acid-exposed cancer cells undergo tetraploidy and trigger a DNA Damage Response (DDR).
Both ATM and ATR pathways are activated in response to acidic pH
e
.
Growth of acid-exposed cancer cells is hampered by ATM and ATR inhibitors.
DDR inhibitors sensitize resistant acid-exposed cancer cells to 5-FU.
pHLIP-based sorting of acid-exposed cancer cells from 3D spheroids identifies tetraploidy and DDR as hallmarks of tumor acidosis. Drugs targeting ATM and ATR preferentially inhibit growth of acid-exposed cancer cells and sensitize them to chemotherapy.
Dual-ion batteries are known for anion storage in the cathode coupled to cation incorporation in the anode. We flip the sequence of the anion/cation-storage chemistries of the anode and the cathode ...in dual-ion batteries (DIBs) by allowing the anode to take in anions and a cation-deficient cathode to host cations, thus operating as a reverse dual-ion battery (RDIB). The anion-insertion anode is a nanocomposite having ferrocene encapsulated inside a microporous carbon, and the cathode is a Zn-insertion Prussian blue, Zn3Fe(CN)62. This unique battery configuration benefits from the usage of a 30 m ZnCl2 “water-in-salt” electrolyte. This electrolyte minimizes the dissolution of ferrocene; it raises the cation-insertion potential in the cathode, and it depresses the anion-insertion potential in the anode, thus widening the full cell’s voltage by 0.35 V compared with a dilute ZnCl2 electrolyte. RDIBs provide a configuration-based solution to exploit the practicality of cation-deficient cathode materials in aqueous electrolytes.
Although the concept of enhanced recovery after surgery was introduced more than 20 years ago, its implementation in daily practice still remains difficult.
This article addresses bottlenecks and ...barriers to the development of enhanced recovery programme (ERP). Barriers to the implementation are multifactorial and are raised by the different actors of these programmes: surgeons, anaesthetists, nurses, patients. Solutions and steps that must be respected to succeed in introducing ERP in an hospital are proposed.
Large-scale implementation of ERP continues to face mainly lack of trust and communication. Solutions exist and are based particularly on team work and interdisciplinary collaboration.
Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier ...function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.
Asymmetric α-arylation of amino acids Leonard, Daniel J; Ward, John W; Clayden, Jonathan
Nature (London),
10/2018, Letnik:
562, Številka:
7725
Journal Article
Recenzirano
Odprti dostop
Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and ...bioactivity and as precursors of medicinally important compounds
. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods
, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging
. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules
. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N'-arylurea adduct
of an imidazolidinone derivative
of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.
To date, tremendous efforts of the battery community are devoted to batteries that employ Li+, Na+, and K+ as charge carriers and nonaqueous electrolytes. However, aqueous batteries hold great ...promise for stationary energy storage due to their inherent low cost and high safety. Among metal batteries that use aqueous electrolytes, zinc metal batteries are the focus of attention. In this study, iron as an anode candidate in aqueous batteries is investigated because iron is undoubtedly the most earth‐abundant and cost‐effective metal anode. Reversible iron plating/stripping in a FeSO4 electrolyte is demonstrated on the anode side and reversible topotactic (de)insertion of Fe2+ in a Prussian blue analogue cathode is showcased. Furthermore, it is revealed that LiFePO4 can pair up with the iron metal anode in a hybrid cell, delivering stable performance as well.
The plating/stripping reversibility of an iron metal anode is demonstrated, which can pair with a Fe‐based Prussian blue as the cathode in a full‐cell configuration with a FeSO4 solution as the electrolyte. The iron metal anode can couple with the LiFePO4 cathode to form an aqueous hybrid battery as well.
Background
This study aimed to review the authors’ 16-year experience with transanal endoscopic microsurgery (TEM). Mortality, morbidity, recurrence rate, and functional outcome were assessed. New ...indications and technical improvements are presented.
Methods
From November 1991 to August 2008, 123 patients (72 men and 51 women; median age, 68 years; range, 21–91 years) underwent TEM for excision of 105 adenomas with low- or high-grade dysplasia, 9 invasive adenocarcinomas (5 curative and 4 palliative resections), 2 neuroendocrine tumors, and 2 extramucosal lesions. Five additional patients had excisional biopsies, allowing staging after previous endoscopic resection. Most of the resections were full-thickness rectal resections using electrocautery or, more recently, the Harmonic scalpel. The latest mucosectomies were performed using the endoscopic submucosal dissection (ESD) technique. In addition, nontumoral indications included pelvic abscess (7 patients) and rectal strictures, which were either anastomotic or chemical. Pelvic abscesses were drained transrectally, whereas rectal stenoses were treated by strictureplasty. Foreign object retrieval and collagen plug placement for anal fistulas were performed using TEM in three patients.
Results
No mortality occurred. One intraoperative rectal perforation required conversion to laparotomy. The postoperative complications included one pneumoperitoneum, which was treated medically, and one rectal perforation requiring Hartmann’s procedure. In the polyp subgroup, six patients (6/91, 7%) experienced local recurrence. Pelvic abscesses were successfully treated, and stenosis did not recur after strictureplasty. Anorectal manometry showed functional alterations without significant clinical impact.
Conclusions
The findings showed TEM to be a safe and effective procedure for local excision of rectal lesions with a low recurrence rate and minimal consequences in terms of anorectal function. In addition, TEM proved to be feasible and effective for pelvic abscess drainage and rectal stenosis treatment. New technologies such as the Harmonic scalpel and ESD increase the precision already offered by this approach.
Concentrated potassium acetate as a water-in-salt electrolyte provides a wide potential window from −1.7 to 1.5 V vs Ag/AgClKCl sat.. It facilitates the reversible operation of KTi2(PO4)3, an anode ...of potassium-ion batteries, that otherwise only functions in nonaqueous electrolytes.
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