Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag.

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol).

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including log can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.

Broadly Applicable and Comprehensive Synthetic Method for -Alkyl-Rich Drug-like Cyclic Peptides.

We report a versatile and durable method for synthesizing highly -alkylated drug-like cyclic peptides. This is the first reported method for synthesizing such peptides in parallel with a high success rate and acceptable purity that does not require optimizations for a particular sequence. We set up each reaction condition by overcoming the following issues: (1) diketopiperazine (DKP) formation, (2) insufficient peptide bond formation due to the steric hindrance of the -alkylated amino acid, and (3) instability of highly -alkylated peptides under acidic conditions.

Rare pancreatic metastasis of undifferentiated pleomorphic sarcoma originating from the pelvis: A case report.

Introduction: Undifferentiated pleomorphic sarcoma (UPS) is a reclassification of malignant fibrous histiocytoma by the World Health Organization in 2002. UPS, the most common soft tissue sarcoma reported in adults, mostly recurs as lung disease. Pancreatic metastasis of UPS is extremely rare.

Next Generation Sequencing (NGS) in chromosome translocation 46, XX, t (9; X) (q22; q28) - a case report.

This paper reports the case of a patient who sought assisted reproductive technology (ART) treatment and was referred to pre-implantation genetic diagnosis (PGD) on account of a chromosomal translocation presented with secondary infertility. The patient underwent a highly complex ART treatment and had 14 metaphase II oocytes collected on the day of follicular aspiration. The embryos were taken to extended culture and five were biopsied and vitrified.

Can trophectoderm morphology act as a predictor for euploidy?

Objective: Euploid embryo transfers yield better implantation rates. In Brazil, morphological evaluation is performed to select the best embryos, since genetic analysis is still an expensive procedure. This study aimed to evaluate whether there is an association between trophectoderm morphology and ploidy status.

The impact of high progesterone levels on the day of HCG administration in assisted human reproduction treatments.

Objective: Progesterone is a steroid hormone that acts on the endometrium. It is known for producing physical and mood-related side effects. Few studies have looked into how progesterone levels affect embryo development and quality.

Usefulness of positron emission tomography (PET)/contrast-enhanced computed tomography (CE-CT) in discriminating between malignant and benign intraductal papillary mucinous neoplasms (IPMNs).

Background/objectives: We evaluated the usefulness of positron emission tomography (PET)/contrast-enhanced computed tomography (CE-CT) in discriminating between malignant and benign intraductal papillary mucinous neoplasms (IPMNs).

Methods: PET/CE-CT imaging was conducted on 29 IPMN lesions, which subsequently underwent surgery. Preoperative findings on PET/CE-CT imaging were compared with the histological findings of the resected specimens to determine the diagnostic accuracy of PET/CE-CT imaging for evaluation of the differential diagnosis between benign and malignant IPMNs.

[A case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant 5-FU+CDDP therapy for esophageal cancer].

We present a case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant chemotherapy with 5-FU+CDDP for esophageal cancer. A 52-year-old woman visited another hospital with the complaint of discomfort during swallowing. Upper gastrointestinal endoscopy revealed an ulcerated lesion in the lower thoracic esophagus, which was pathologically diagnosed as squamous cell carcinoma.

Utility of contrast-enhanced FDG-PET/CT in the clinical management of pancreatic cancer: impact on diagnosis, staging, evaluation of treatment response, and detection of recurrence.

Objectives: Fluorodeoxyglucose (FDG)-positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non-CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer.

Methods: Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases.

Solitary fibrous tumor of the pancreas.

A solitary fibrous tumor (SFT) originating in the pancreas is rare. We report a 55-year-old woman with an asymptomatic pancreatic mass incidentally discovered on abdominal ultrasonography. Contrast-enhanced computed tomography (CT) showed a well-demarcated exophytic mass in the pancreatic head with prolonged and delayed enhancement.

Risk factors for metachronous gastric cancer in the remnant stomach after early cancer surgery.

Background: Early gastric cancer patients have a good prognosis after radical resection. However, if the patients have a gastric remnant after the surgery, the risk of metachronous gastric cancer remains. The aim of this study was to clarify the risk factors for metachronous gastric cancer after partial gastrectomy for early gastric cancer.

Primary extranodal non-Hodgkin's lymphoma of the common bile duct manifesting as obstructive jaundice: report of a case.

Primary non-Hodgkin's lymphoma (NHL) of the common bile duct (CBD) manifesting as obstructive jaundice is extremely rare: to our knowledge, only 22 cases of primary NHL arising from the CBD have been reported. The patient in this case report was a 63-year-old man who presented with obstructive jaundice. Abdominal sonography, positron emission tomography, and computed tomography showed a mass with abnormal 18-fluorodeoxyglucose uptake in pancreatic head.

[A case with a linear white matter lesion connecting striatocapsular infarction and old cortical infarction].

A 65-year-old woman was admitted to our hospital because of the acute onset of right hand weakness and reduction in spontaneous speech. The patient displayed right hemiparesis, subcortical aphasia and impaired executive function. An acute cerebral infarction involving the left basal ganglion (striatocapsular infarction) and an old infarction of the left superior frontal gyrus (Brodmann area 8) were detected on a brain MRI.

Laparoscopic colectomy for colorectal cancer patients with previous abdominal surgery.

Background/aims: Laparoscopic colectomy has been widely accepted as a standard operation for colorectal cancer. The use of this procedure for patients with previous abdominal surgery is now well established. The aim of this study was to evaluate the peri-operative and long-term outcomes of such patients, and to compare them to patients without previous surgery.

Long-term outcome after laparoscopic wedge resection for early gastric cancer.

Background: Laparoscopic wedge resection (LWR) can be applied for the management of early gastric cancer without the risk of lymph node metastasis. Although LWR for early gastric cancer is one of the minimally invasive procedures, its radicality in cancer therapy is controversial. This study aimed to evaluate the long-term outcomes after LWR.

Higher incidence of gastric remnant cancer after proximal than distal gastrectomy.

Background/aims: Proximal gastrectomy has been widely accepted as a standard operation for early stage gastric cancer located in the upper third of the stomach. Therefore, cancer of the distal gastric remnant is now increasing. The aims of this study were to clarify and compare the incidences of gastric remnant cancer after proximal and distal gastrectomy.

Unusual abscesses associated with colon cancer: report of three cases.

Three cases of colon cancer accompanied by unusual abscess formation are reported. Case I : A 77-year-old man was diagnosed with a paracolic abscess formation behind the cecum and a swollen appendix by computed tomography (CT) scan. Case II : An 85-year-old woman was diagnosed with an abscess formation of the right iliopsoas muscle, a swollen appendix, and a thickened right colon wall by CT scan.

Recognition of DNA with assembly of minor groove binders mediated by metal complexation.

Genome-targeting molecules would have broad application as probes in genomic study. We recently developed the ligands (Bpy-H) connecting the Hoechst33258 skeleton for DNA binding and 2,2'-bipyridine for Cu(2+) complexation. It was shown that L-Bpy-H with a long linker exhibited Cu(2+)-mediated assembly on the DNA template having two A(3)T(3) sites in a ratio of 1:2:1 DNA-ligand-Cu(2+).

Discrimination of the length of two remote binding sites by the spacer-linked DNA minor groove binders.

The aim of this study is to develop new recognition molecules for the DNA higher-ordered structure on the basis of new concept of DNA recognition mode. In order to bind two remote binding sites of DNA at the same time, we designed the new bidentate ligands that have two Hoechst 33258 units connected by a spacer. DNA binding affinity of the ligands was evaluated by measuring SPR (surface plasmon resonance).

Equilibrium shift by target DNA substrates for determination of DNA binding ligands.

An equilibrium containing the thiol derivative of Hoechst33258 (Ht-SH), glutathione (G-SH), and the corresponding homo and hetero disulfides was shifted by the addition of the duplex DNA. It was shown from the analysis of the components that the hetero disulfide Ht-SS-G increased by binding with the DNA (CA14) with an A(3)T(3) binding motif for the structure of Hoechst33258, and that the different equilibrium shift was observed in the presence of CT14 with no A(3)T(3) binding motif.

Cu2+ -mediated assembly of the minor groove binders on the DNA template with sequence selectivity.

The ligands (Bpy-H, 5) have been designed to connect the Hoechst33258 skeleton for DNA binding and 2,2'-bipyridine for Cu(2+) complexation. It has been revealed that the new Hoechst ligand long Bpy-H (5L) having a long linker exhibits Cu(2+)-mediated assembly on the DNA template having two A(3)T(3) sites in a selective manner depending on the length of the linker of the ligand as well as on the distance between the two A(3)T(3) sites of DNA. [reaction: see text]

Design of new bidentate ligands constructed of two Hoechst 33258 units for discrimination of the length of two A3T3 binding motifs.

[structure: see text] The aim of this study is to develop bidentate minor-groove binders that bind the double binding motifs cooperatively. The new bidentate ligands (1) have been designed by connecting two Hoechst 33258 units with a polyether linker for cooperative binding with two remote A3T3 sites of DNA. The linker is introduced to the benzimidazole ring so that it is located at the convex side of the Hoechst unit.

Inflammatory pseudotumor of the liver associated with malignant disease: report of two cases and a review of the literature.

Two cases of inflammatory pseudotumor (IPT) of the liver associated with gastrointestinal tract cancer are reported. In addition, the etiological correlation between IPT and abscesses of the liver in cancer patients is discussed. The first patient was a 63-year-old woman who underwent distal gastrectomy and partial hepatectomy under a diagnosis of stomach cancer with liver metastasis.