Unanticipated pathological clearance in two cases of clinical T4b dMMR/MSI-h advanced colorectal cancer: the potential of immune checkpoint inhibitors despite positive positron-emission tomography results.

BACKGROUND: The standard treatment for colorectal cancer consists of surgery and chemotherapy, which can be combined to improve outcomes. Immune checkpoint inhibitors (ICI) are a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair (dMMR). However, limited data are available about the use of ICI in the neoadjuvant and conversion settings. Here, we present two cases treated with ICI. CASE PRESENTATION: Case 1: A 75-year-old male with a large, borderline resectable rectal cancer diagnosed as cT4bN1bM0 who underwent neoadjuvant chemotherapy, followed by combination ICI consisting of ipilimumab and nivolumab. After four courses of ICI, the tumor significantly shrank, but positron emission tomography still showed a positive result and R0 resection was performed. Pathological analysis revealed no residual cancer cells. The patient has been monitored without adjuvant chemotherapy, and no recurrences have occurred after one year. Case 2: A 60-year-old male with locally advanced sigmoid colon cancer who received neoadjuvant treatment with pembrolizumab. The tumor partially shrank after three courses, and continued pembrolizumab monotherapy resulted in further tumor shrinkage which still showed positive positron emission tomography. Curative sigmoidectomy with partial resection of the ileum and bladder was performed, and the pathological outcome was pCR. There was no viable tumor in the specimen. The patient has been monitored without adjuvant chemotherapy for six months, and no recurrence has been observed. CONCLUSIONS: The present study reports two cases, including a large, borderline resectable rectal cancer after failure of chemotherapy followed by combination treatment with nivolumab and ipilimumab and one case of sigmoid colon cancer after pembrolizumab treatment, which resulted in pathological complete response. However, it remains unknown whether ICI therapy can replace surgery or diminish the optimal extent of resection, or whether adjuvant chemotherapy is needed after surgery in the case of achieving pCR after ICI therapy. Overall, this case report suggests that ICI before colorectal surgery can be effective and potentially a 'watch-and-wait" strategy could be used for cases in which ICI is effective.

Selection and characterization of aptamers targeting the Vif-CBFß-ELOB-ELOC-CUL5 complex.

The viral infectivity factor (Vif) of human immunodeficiency virus 1 forms a complex with host proteins, designated as Vif-CBFß-ELOB-ELOC-CUL5 (VßBCC), initiating the ubiquitination and subsequent proteasomal degradation of the human antiviral protein APOBEC3G (A3G), thereby negating its antiviral function. While recent cryo-electron microscopy (cryo-EM) studies have implicated RNA molecules in the Vif-A3G interaction that leads to A3G ubiquitination, our findings indicated that the VßBCC complex can also directly impede A3G-mediated DNA deamination, bypassing the proteasomal degradation pathway. Employing the Systematic Evolution of Ligands by EXponential enrichment (SELEX) method, we have identified RNA aptamers with high affinity for the VßBCC complex. These aptamers not only bind to the VßBCC complex but also reinstate A3G's DNA deamination activity by inhibiting the complex's function. Moreover, we delineated the sequences and secondary structures of these aptamers, providing insights into the mechanistic aspects of A3G inhibition by the VßBCC complex. Analysis using selected aptamers will enhance our understanding of the inhibition of A3G by the VßBCC complex, offering potential avenues for therapeutic intervention.

Novel erectile analyses revealed augmentable penile Lyve-1, the lymphatic marker, expression.

Purpose: The pathophysiology of penis extends to erectile dysfunction (ED) to conditions including sexually transmitted diseases (STDs) and cancer. To date, there has been little research evaluating vascular drainage from the penis. We aimed to evaluate penile blood flow in vivo and analyze its possible relationship with the lymphatic maker. Materials and Methods: We established an in vivo system designed to assess the dynamic blood outflow from the corpus cavernosum (CC) by dye injection. To analyze lymphatic characteristics in the CC, the expression of Lyve-1, the key lymphatic endothelium marker, was examined by the in vitro system and lipopolysaccharide (LPS) injection to mimic the inflammatory conditions. Results: A novel cavernography methods enable high-resolution morphological and functional blood drainage analysis. The expression of Lyve-1 was detected along the sinusoids. Furthermore, its prominent expression was also observed after penile LPS injection and in the erectile condition. Conclusions: The current in vivo system will potentially contribute to the assessment of penile pathology from a novel viewpoint. In addition, current analyses revealed inducible Lyve-1 expression for LPS injection and the erection state, which requires further analyses on penile lymphatic system.

Conjunctival Chalasis Should Not be Overlooked: Investigation Into Postoperative Ocular Surface Changes in Involutional Blepharoptosis.

BACKGROUND: Involutional blepharoptosis is common among elderly people. The tightening of eyelids postptosis surgery could potentially increase friction between the eyelid and the ocular surface, but this hypothesis has not yet been substantiated by research. The authors explored the relationship between involutional blepharoptosis surgery and friction-related diseases, namely conjunctivochalasis, lid wiper epitheliopathy, and superior limbic keratoconjunctivitis. METHODS: We conducted a prospective study involving 31 patients who underwent levator advancement for involutional blepharoptosis. Both preoperatively and 6 weeks postoperatively, the authors assessed a range of outcome measures, including margin reflex distance-1, 2, tear film break-up time, superficial punctate keratopathy, inferior conjunctivochalasis, upper lid wiper epitheliopathy, and superior limbic keratoconjunctivitis. RESULTS: Conjunctivochalasis was detected in 18 eyes preoperatively and 20 eyes postoperatively. Lid wiper epitheliopathy was detected in 2 eyes preoperatively and in no eyes postoperatively. Superior limbic keratoconjunctivitis was detected in 2 eyes preoperatively and 1 eye postoperatively. From preoperative to postoperative assessments, conjunctivochalasis worsened in 11 eyes (17.2%), and there were no eyes with worsening lid wiper epitheliopathy or superior limbic keratoconjunctivitis. There was a significant worsening of superficial punctate keratopathy in the group with exacerbated conjunctivochalasis compared with the unchanged group (0.72 vs. 0.12, P=0.0222). The superficial petechial keratopathy in the 6 cases in which there was worsening of both conjunctivochalasis and superficial petechial keratopathy were all located inferiorly in the cornea. CONCLUSIONS: Conjunctivochalasis can worsen following ptosis surgery, potentially leading to an increase in inferior superficial punctate keratopathy. When performing involutional blepharoptosis surgery, surgeons should be mindful of the potential implications of friction-related diseases, particularly conjunctivochalasis.

Appropriate Relevancy and Reliability of Real-World Data for the Utilization of Regulatory Submission.

The extraction of data that contribute to regulatory approval from real-world data (RWD) is difficult because of the lack of a standardized data format and extraction methodology. Additionally, when real-world evidence (RWE) is used as an external control group, the similarity between internal and external control data is not evaluated. To investigate the data extraction methodology for the external control data of rare molecular subtypes, we have initiated the "REALISE" study. In this study, we aim to elucidate the "relevance" and "reliability" of RWD/RWE necessary for regulatory approval. As most databases are not designed for regulatory use in the creation phase, we will investigate retrospective methodologies to ensure RWD/RWE reliability. This study will compare the "relevance" and "reliability" of the ARCAD global database, SCRUM-Japan Registry, SCRUM-Japan observational study, and Flatiron Health RWD, and statistically analyze the differences and similarities among the four databases. We will also examine the methodology for extracting sufficiently relevant data from the SCRUM-Japan observational study. Additionally, if the reliability of the RWD/RWE does not reach the required level for regulatory approval, we will examine the methodologies to ensure the "reliability" of the SCRUM-Japan observational study for regulatory approval. The obtained results will be submitted to the "Consultation for Development of Registry" in the Pharmaceuticals and Medical Devices Agency, and we will discuss the standard methodology. The procedures and findings identified in the REALISE study will be organized from the perspectives of "database construction," "data analysis," and "outcome evaluation" and will be issued as "the draft guidelines."

Suctionable Gauze Ball Operated by the Console Surgeon Overcomes Wet Scenes during Robotic Rectal Surgery.

Although robotic rectal resections are now widely performed, there are few robotic suction tools that can be easily used by console surgeons. It can therefore be difficult to maintain a clear visual field in the pelvis when there is effusion and bleeding from either a highly advanced cancer or from preoperative cancer treatment. In this report, we introduce our unique surgical technique that uses a soft catheter with a small gauze ball attached, inserted through the assistant port. This simple and inexpensive "instrument" can be used by the console surgeon as a retractor as well as a reliable suction device to secure their view of the operative field in the pelvis. This technique can be used in a narrow surgical field and does not rely on an assistant surgeon, making it potentially applicable to all types of surgery.

[A Case of Transverse Colon Cancer with Gastrointestinal Amyloidosis Prevented from Anastomotic Leakage by Multidimensional Approach].

The patient was a 68-year-old woman who was on hemodialysis due to systemic amyloidosis and nephrotic syndrome. Biopsy revealed amyloid deposition in the stomach, duodenum, and colon. A transverse colon tumor was found on a follow- up CT after the aortic dissection surgery. We performed lower gastrointestinal endoscopy and contrast-enhanced CT and diagnosed transverse colon cancer with gastric wall infiltration(cStage Ⅲc). We considered that transverse colon resection was oncologically sufficient. However, due to concurrent gastrointestinal amyloidosis, which increased the risk of anastomotic leakage we performed laparoscopic extended right hemicolectomy to avoid colon-colon anastomosis with partial gastrectomy. Additionally intraoperative indocyanine green(ICG)fluorescence imaging showed that the fluorescence signal in the small intestinal wall was satisfactory, while it was weak in the colon wall. As a result, we suspected of impaired blood flow of colon wall due to an amyloidosis, so we additionally created a loop ileostomy. It is said that gastrointestinal amyloidosis raises the risk of anastomotic leakage. A case of transverse colon cancer complicated by gastrointestinal amyloidosis in which we successfully prevented anastomotic leakage through a multidimensional evaluation and approach is reported, along with a literature review.

"Role-sharing surgery": a new surgical education system that gives beginner surgeons more chances to operate while ensuring the surgical quality of robotic surgery.

It has been pointed out that robotic surgery is more time-consuming than laparoscopic surgery, and a major challenge for the future is educating young surgeons while maintaining the surgical quality. To solve these problems, we report a role-sharing surgery (RSS) approach in which the surgery is divided into several areas and timetabled, with roles shared by several operators. We performed RSS for 19 standard colorectal cancer surgeries. The surgery was completed within + 28 min of the scheduled operation time, and a beginner robotic surgeon (BRS) was able to perform approximately 66% of the total surgery. There were no statistically significant differences in the short-term outcomes between the RSS and conventional surgery groups. Based on these findings, RSS has the potential to be the best practice for educating BRSs in robotic surgery, the use of which is expected to increase steadily in the future.

A Randomized Control Study in Healthy Adult Smokers to Assess Reduced Exposure to Selected Cigarette Smoke Constituents in Switching to the Novel Heated Tobacco Product DT3.0a.

This was a randomized, controlled, open-label, confinement study to assess change in exposure to selected cigarette smoke constituents in healthy adult cigarette smokers who switched to using a novel heated tobacco product (direct heating tobacco system, platform 3, generation 3, version a [DT3.0a]). Sixty nonmenthol cigarette smokers were randomized into 1 of the 4 study groups in which subjects switched to a nonmenthol type of tobacco stick used with DT3.0a, switched to a nonmenthol tobacco stick used with an in-market heated tobacco product device (THS), continued to smoke nonmenthol cigarettes, or stopped smoking. Furthermore, 30 menthol cigarette smokers were randomized into 1 of the 2 study groups in which subjects switched to a menthol tobacco stick used with DT3.0a (mDT3.0a) or continued to smoke menthol cigarettes. Fifteen biomarkers of exposure to selected harmful and potentially harmful constituents (HPHCs) were measured during the 5-day exposure period, followed by assessment of nicotine pharmacokinetics with the assigned product. Results indicated that switching to DT3.0a, THS, and mDT3.0a showed significant exposure reductions in most of the selected HPHCs as compared to continuing smoking cigarettes, with reductions being similar in magnitude to reductions observed with smoking cessation. For DT3.0a and mDT3.0a, nicotine pharmacokinetic parameters were not remarkably different from those obtained for cigarettes and the THS except that a longer time to maximum concentration was obtained following use of the mDT3.0a. In conclusion, switching from smoking cigarettes to DT3.0a or THS use reduced exposure to most of the selected HPHCs, and no remarkable differences were observed for the measurements obtained from different flavors of DT3.0a stick.

Xylobiose treatment strengthens intestinal barrier function by regulating claudin 2 and heat shock protein 27 expression in human Caco-2 cells.

BACKGROUND: Xylobiose, a non-digestible disaccharide, largely contributes to the beneficial physiological effects of xylooligosaccharides. However, there is insufficient evidence to assess the direct effect of xylobiose on intestinal barrier function. Here, we investigated the intestinal barrier function in human intestinal Caco-2 cells treated with xylobiose. RESULTS: In total, 283 genes were upregulated and 256 genes were downregulated in xylobiose-treated Caco-2 cells relative to the controls. We focused on genes related to intestinal barrier function, such as tight junction (TJ) and heat shock protein (HSP). Xylobiose decreased the expression of the TJ gene Claudin 2 (CLDN2) and increased the expression of the cytoprotective HSP genes HSPB1 and HSPA1A, which encode HSP27 and HSP70, respectively. Immunoblot analysis confirmed that xylobiose suppressed CLDN2 expression and enhanced HSP27 and HSP70 expression. A quantitative reverse transcription-PCR and promoter assays indicated that xylobiose post-transcriptionally regulated CLDN2 and HSPB1 levels. Additionally, selective inhibition of phosphatidyl-3-inositol kinase (PI3K) inhibited xylobiose-mediated CLDN2 expression, whereas HSP27 expression induced by xylobiose was sensitive to the inhibition of PI3K, mitogen-activated protein kinase kinase and Src. CONCLUSION: The results of the present study reveal that xylobiose suppresses CLDN2 and increases HSP27 expression in intestinal Caco-2 cells via post-transcriptional regulation, potentially strengthening intestinal barrier integrity; however, these effects seem to occur via different signaling pathways. Our findings may help to assess the physiological role of xylobiose. © 2023 Society of Chemical Industry.

Phase Ib/II Study of a Liposomal Formulation of Eribulin (E7389-LF) plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase Ib.

Purpose: To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen. Experimental Design: Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m2 plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m2 plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D. Results: Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg2 every 3 weeks (n = 6), E7389-LF 2.1 mg/m2 every 3 weeks (n = 6), E7389-LF 1.1 mg/m2 every 2 weeks (n = 7), E7389-LF 1.4 mg/m2 every 2 weeks (n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m2 every 3 weeks, 1 at 1.1 mg/m2 every 2 weeks, and 1 at 1.4 mg/m2 every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3-4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%. Conclusions: E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks. Significance: This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling.

Effects of aerosols from heated tobacco products with flavors on the discoloration of bovine tooth enamel.

OBJECTIVES: This in vitro study assessed the potential of tooth discoloration by aerosols generated from three heated tobacco products (HTPs) with different specifications: in-direct heating tobacco system platform 1.0a (IT1.0a), in-direct heating tobacco system platform 2.0a (IT2.0a), and direct heating tobacco system platform 3.0a (DT3.0a). In addition, three flavor types (regular, menthol, and berry menthol) were selected for each HTP to characterize the effect of flavor types on tooth discoloration. MATERIAL AND METHODS: Six bovine tooth samples were exposed directly to aerosols generated from one pack of each HTP: 350 puffs for IT1.0a, 325 puffs for IT2.0a, and 220 puffs for DT3.0a. Six bovine tooth samples were also exposed to air (350 puffs) and smoke generated from one pack of cigarettes (160 puffs) as negative and positive controls, respectively. The color of each tooth sample was measured before and after exposure. The overall color changes were assessed using overall color differences (ΔE) calculated according to the Commission International de I'Eclairage color system. A one-way analysis of variance followed by Tukey's post hoc test was used to compare ΔE among bovine tooth samples exposed to air, cigarette smoke, and aerosols generated from each HTP. RESULTS: ΔE values for tooth samples exposed to air and aerosols generated from the three HTPs (IT1.0a, IT2.0a, and DT3.0a) were significantly lower than ΔE value for tooth samples exposed to cigarette smoke. ΔE values obtained with DT3.0a were significantly higher than those obtained with air-exposed control samples. However, ΔE values obtained with IT1.0a and IT2.0a were not significantly different from that obtained with air-exposed control samples. No HTPs showed significant differences in ΔE values among the three flavor types. CONCLUSIONS: This study showed that HTP aerosols reduce tooth discoloration potential compared with cigarette smoke, regardless of flavor types, and the tooth discoloration potential of the product may depend on product specifications.

Microbial metabolite n-butyrate upregulates intestinal claudin-23 expression through SP1 and AMPK pathways in mouse colon and human intestinal Caco-2 cells.

AIMS: Regulation of the intestinal barrier is closely related to intestinal microbial metabolism. This study investigated the role of intestinal microflora in the regulation of the tight junction (TJ) barrier in epithelial cells, focusing on the microbial metabolite n-butyrate, a major short-chain fatty acid, using mice and human intestinal Caco-2 cells. MATERIALS AND METHODS: Whole transcriptome analysis with RNA sequencing and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were performed in the colon of germ-free (GF) and specific pathogen-free (SPF) mice. Claudin-23 expression was examined by qRT-PCR, immunoblotting, and immunofluorescence in Caco-2 cells treated with n-butyrate. Luciferase reporter assay was performed to examine the effect of n-butyrate on claudin-23 transcriptional activity. The siRNA targeting the transcription factor SP1 and pharmacological inhibitor of AMPK were used in combination. TJ permeability was examined in canine kidney MDCKII cells stably expressing human claudin-23. KEY FINDINGS: Cldn23 mRNA expression was downregulated in the colon of GF mice (0.6-fold) compared to that in SPF mice. n-Butyrate upregulated claudin-23 mRNA (1.7-fold) and protein (2.1-fold) expression as well as increased the transcriptional activity (15-fold) of CLDN23 in Caco-2 cells. The n-butyrate-mediated increase in claudin-23 expression and transcriptional activity was reduced by inhibition of SP1 and AMPK. Exogenously expressed human claudin-23 in MDCKII cells did not affect TJ permeability to ions and macromolecules. SIGNIFICANCE: n-Butyrate regulates intestinal claudin-23 expression through the SP1 and AMPK pathways. This mechanism may be involved in the beneficial effects of n-butyrate-mediated intestinal homeostasis.

Imprinting Spatial Helicity Structure of Vector Vortex Beam on Spin Texture in Semiconductors.

We present the transfer of the spatially variant polarization of topologically structured light to the spatial spin texture in a semiconductor quantum well. The electron spin texture, which is a circular pattern with repeating spin-up and spin-down states whose repetition rate is determined by the topological charge, is directly excited by a vector vortex beam with a spatial helicity structure. The generated spin texture efficiently evolves into a helical spin wave pattern owing to the spin-orbit effective magnetic fields in the persistent spin helix state by controlling the spatial wave number of the excited spin mode. By tuning the repetition length and azimuthal angle, we simultaneously generate helical spin waves with opposite phases by a single beam.

Spontaneous regression of advanced transverse colon cancer with deficient mismatch repair: a case report.

BACKGROUND: Spontaneous regression (SR) of cancer occurs in 1 in 60,000-100,000 patients. This phenomenon has been reported in almost all cancer types, most commonly neuroblastoma, renal cell carcinoma, malignant melanoma, and lymphoma/leukemia. However, SR in colorectal cancer (CRC) is extremely rare, particularly in advanced cases. Hence, this report describes a very rare case of spontaneous regression of advanced transverse colon cancer. CASE PRESENTATION: A 76-year-old female with anemia was diagnosed with a type II well-differentiated adenocarcinoma in the middle transverse colon. Two months later, a second colonoscopy examination was performed for preoperative marking, and it revealed tumor shrinkage and a shift to type 0-IIc morphology. Endoscopic tattooing was then performed, followed by a laparoscopic partial resection of the transverse colon with D3 lymph node dissection. However, the resected specimen contained no tumor, and colonoscopy showed no tumor remnants in the remaining colon. Histopathological examination revealed mucosal regeneration and a mucus nodule in between the submucosal and muscular layers, with no cancer cells detected. Immunohistochemical analysis revealed the loss of MutL homolog 1 (MLH1) and postmeiotic segregation increased 2 (PMS2) expression in the cancer cells of biopsied specimens, suggesting deficient mismatch repair (dMMR). The patient continues to be followed up until 6 years postoperatively, and no recurrence has been observed. In this study, we also reviewed similar reported cases of spontaneous regression of cancer involving dMMR. CONCLUSION: This study presents a rare case of spontaneous regression of advanced transverse colon cancer wherein dMMR is strongly involved. However, further accumulation of similar cases is needed to elucidate this phenomenon and to develop new treatment strategies for CRC.

Elevated Preoperative Serum Vascular Endothelial Growth Factor Does Not Predict Poor Outcomes in Curatively Resected Non-metastatic Colorectal Cancer Treated Without Neoadjuvant Therapy.

BACKGROUND/AIM: Vascular endothelial growth factor (VEGF) influences colorectal cancer (CRC) progression and is a key target in the treatment for metastatic CRC. However, the oncological impact of preoperative circulating VEGF in non-metastatic CRC (non-mCRC) has not been clearly elucidated. Herein, we have investigated the prognostic significance of elevated preoperative serum VEGF concentration in curatively resected non-mCRC without neoadjuvant therapy. PATIENTS AND METHODS: A total of 474 patients with pStage I-III CRC who underwent curative resection without neoadjuvant therapy were included. The relationship between preoperative serum VEGF concentration and clinicopathologic characteristics, overall survival (OS), and recurrence-free survival (RFS) were investigated. RESULTS: The median follow-up duration was 47.4 months. No significant relationship between preoperative VEGF and clinicopathologic characteristics including tumor markers, pStage, and lymphovascular invasion was identified; however, VEGF values were wide-ranged in every pStage. Patients were categorized into four groups as follows: VEGF < median, median to 75th percentile, 75th percentile to 90th percentile, and ≥90th percentile. A tendency for a difference in 5-year OS (p=0.064) and RFS (p=0.089) was observed among the groups; however, OS and RFS were not correlated with VEGF elevation. In multivariate analyses, VEGF ≥90th percentile was paradoxically associated with better RFS. CONCLUSION: Preoperative elevated serum VEGF concentration was associated with neither worse clinicopathological characteristics nor worse long-term outcomes in curatively resected non-mCRC. The prognostic value of preoperative circulating VEGF in initially resectable non-mCRC remains limited.

Partially hydrolyzed guar gum upregulates heat shock protein 27 in intestinal Caco-2 cells and mouse intestine via mTOR and ERK signaling.

BACKGROUND: The intestinal epithelium acts as a barrier against harmful luminal materials, thus preventing intestinal diseases and maintaining intestinal health. Heat shock protein 27 (HSP27) promotes intestinal epithelial integrity under both physiological and stressed conditions. The effects of partially hydrolyzed guar gum (PHGG) on HSP27 expression in intestinal Caco-2 cells and mouse intestines were investigated. RESULTS: The present study showed that PHGG upregulated HSP27 expression in Caco-2 cells without upregulating Hspb1, the gene encoding HSP27. Feeding PHGG increased HSP25 expression in epithelial cells of the small intestine of mice. Inhibition of protein translation using cycloheximide suppressed PHGG-mediated HSP27 expression, indicating that PHGG upregulated HSP27 via translational modulation. Signaling inhibition of the mechanistic target of rapamycin (mTOR) and phosphatidyl 3-inositol kinase reduced PHGG-mediated HSP27 expression, whereas mitogen-activated protein kinase kinase inhibition by U0126 increased HSP27 expression, irrespective of PHGG administration. PHGG increases mTOR phosphorylation and reduces extracellular signal-regulated protein kinase (ERK) phosphorylation. CONCLUSION: PHGG-mediated translation of HSP27 in intestinal Caco-2 cells and mouse intestine via the mTOR and ERK signaling pathways may promote intestinal epithelial integrity. These findings help us better understand how dietary fibers regulate the physiological function of the intestines. © 2023 Society of Chemical Industry.

Ensemble averaging for categorical variables: Validation study of imputing lost data in 24-h recorded postures of inpatients.

Acceleration sensors are widely used in consumer wearable devices and smartphones. Postures estimated from recorded accelerations are commonly used as features indicating the activities of patients in medical studies. However, recording for over 24 h is more likely to result in data losses than recording for a few hours, especially when consumer-grade wearable devices are used. Here, to impute postures over a period of 24 h, we propose an imputation method that uses ensemble averaging. This method outputs a time series of postures over 24 h with less lost data by calculating the ratios of postures taken at the same time of day during several measurement-session days. Whereas conventional imputation methods are based on approaches with groups of subjects having multiple variables, the proposed method imputes the lost data variables individually and does not require other variables except posture. We validated the method on 306 measurement data from 99 stroke inpatients in a hospital rehabilitation ward. First, to classify postures from acceleration data measured by a wearable sensor placed on the patient's trunk, we preliminary estimated possible thresholds for classifying postures as 'reclining' and 'sitting or standing' by investigating the valleys in the histogram of occurrences of trunk angles during a long-term recording. Next, the imputations of the proposed method were validated. The proposed method significantly reduced the missing data rate from 5.76% to 0.21%, outperforming a conventional method.

Phase I Study of the Liposomal Formulation of Eribulin (E7389-LF): Results from the Advanced Gastric Cancer Expansion Cohort.

PURPOSE: In the dose-expansion part of this open-label, phase I study, we explored the efficacy and safety of E7389-LF (liposomal formulation of eribulin) in Japanese patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with advanced gastric cancer who had been previously treated with ≥2 lines of chemotherapy received E7389-LF 2.0 mg/m2 every 3 weeks (the previously determined maximum tolerated dose, the primary objective of Study 114). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), and safety; exploratory objectives included disease control rate (DCR) and clinical benefit rate (CBR), as well as pharmacodynamic measurements of serum biomarkers. RESULTS: As of June 24, 2021, 34 patients were enrolled and treated (10 from the original dose-expansion cohort, expanded to include 24 additional patients). Six patients had partial responses, for an ORR of 17.6% [95% confidence interval (CI), 6.8-34.5], and the median PFS was 3.7 months (95% CI, 2.7-4.8). The DCR was 79.4% (95% CI, 62.1-91.3), and the CBR was 32.4% (95% CI, 17.4-50.5). Overall, 32 patients (94.1%) experienced treatment-related adverse events, and 26 patients (76.5%) experienced grade ≥3 events, most commonly neutropenia (41.2%) and leukopenia (29.4%). Of the 8 endothelial cell/vasculature markers tested in this study, 7 were significantly increased among patients treated with E7389-LF; these changes were generally consistent regardless of best overall response. CONCLUSIONS: E7389-LF 2.0 mg/m2 every 3 weeks was tolerable and showed preliminary activity for the treatment of patients with gastric cancer.

AZD6738 promotes the tumor suppressive effects of trifluridine in colorectal cancer cells.

Ataxia telangiectasia and Rad3­related (ATR) is a kinase that repairs DNA damage. Although inhibitors that selectively target ATR have been developed, their effectiveness in colorectal cancer has not been widely reported. The present study hypothesized that anticancer agents that effectively act in the S phase before the G2/M checkpoint may be ideal agents for concomitant use with ATR inhibitors, which act at the G2/M checkpoint. Therefore, the present study examined the combined effects of AZD6738, an ATR inhibitor, and trifluridine (FTD), which acts in the S phase and has a high DNA uptake rate. In vitro cell viability assays, flow cytometry and western blotting were performed to evaluate cell viability, and changes in cell cycle localization and protein expression. The results revealed that in colorectal cancer cells, the combination of AZD6738 and FTD inhibited cell viability, cell cycle arrest at the G2/M checkpoint and Chk1 phosphorylation, and increased apoptotic protein expression levels more than that when treated with FTD alone. HT29, a BRAF­mutant cell line known to be resistant to anticancer drugs, was used to induce tumors in vivo. Since FTD does not have sufficient efficacy when administered orally, it was mixed with tipiracil to prevent degradation; this mixture is known as TAS­102. TAS­102 alone exerted minimal tumor suppressive effects; however, when used in combination with AZD6738, tumor suppression was observed, suggesting that AZD6738 may increase the effectiveness of a weakly effective drug. Although ATR inhibitors are effective against p53 mutants, the present study demonstrated that these inhibitors were also effective against the p53 wild­type HCT116 colorectal cancer cell line. In conclusion, combination therapy with AZD6738 and FTD enhanced the inhibition of tumor proliferation in vitro and in vivo. In the future, we aim to investigate the potentiating effect of AZD6738 on 5­fluouracil­resistant cell lines that are difficult to treat.