Tissue-Resident Memory T Cells in Gastrointestinal Cancers: Prognostic Significance and Therapeutic Implications.

Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response within nonlymphoid tissues. In this review, we summarize the characteristics and functions of Trm cells and discuss their profound implications for patient outcomes in gastrointestinal cancers. Positioned strategically in peripheral tissues, Trm cells have functions beyond immune surveillance, affecting tumor progression, prognosis, and response to immunotherapy. Studies indicate that Trm cells are prognostic markers and correlate positively with enhanced survival. Their presence in the tumor microenvironment has sparked interest in their therapeutic potential, particularly with respect to immune checkpoint inhibitors, which may improve cancer treatment. Understanding how Trm cells work will not only help to prevent cancer spread through effective treatment but will also contribute to disease prevention at early stages as well as vaccine development. The role of Trm cells goes beyond just cancer, and they have potential applications in infectious and autoimmune diseases. This review provides a thorough analysis of Trm cells in gastrointestinal cancers, which may lead to personalized and effective cancer therapies.

Significance of signal recognition particle 9 nuclear translocation: Implications for pancreatic cancer prognosis and functionality.

Signal recognition particles (SRPs) are essential for regulating intracellular protein transport and secretion. Patients with tumors with high SRP9 expression tend to have a poorer overall survival. However, to the best of our knowledge, no reports have described the relationship between SRP9 localization and prognosis in pancreatic cancer. Thus, the present study aimed to investigate this relationship. Immunohistochemical staining for SRP9 using excised specimens from pancreatic cancer surgery cases without preoperative chemotherapy or radiotherapy showed that SRP9 was preferentially expressed in the nucleus of the cancerous regions in some cases, which was hardly detected in other cases, indicating that SRP9 was transported to the nucleus in the former cases. To compare the prognosis of patients with SRP9 nuclear translocation, patients were divided into two groups: Those with a nuclear translocation rate of >50% and those with a nuclear translocation rate of ≤50%. The nuclear translocation rate of >50% group had a significantly better recurrence­free survival than the nuclear translocation rate of ≤50% group (P=0.037). Subsequent in vitro experiments were conducted; notably, the nuclear translocation rate of SRP9 was reduced under amino acid­deficient conditions, suggesting that multiple factors are involved in this phenomenon. To further study the function of SRP9 nuclear translocation, in vitro experiments were performed by introducing SRP9 splicing variants (v1 and v2) and their deletion mutants lacking C­terminal regions into MiaPaCa pancreatic cancer cells. The results demonstrated that both splicing variants showed nuclear translocation regardless of the C­terminal deletions, suggesting the role of the N­terminal regions. Given that SRP9 is an RNA­binding protein, the study of RNA immunoprecipitation revealed that signaling pathways involved in cancer progression and protein translation were downregulated in nuclear­translocated v1 and v2. Undoubtedly, further studies of the nuclear translocation of SRP9 will open an avenue to optimize the precise evaluation and therapeutic control of pancreatic cancer.

Fat and proteolysis due to methionine, tryptophan, and niacin deficiency leads to alterations in gut microbiota and immune modulation in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is one of the intractable diseases. Nutritional components associated with IBD have been identified, and it is known that excessive methionine intake exacerbates inflammation, and that tryptophan metabolism is involved in inflammation. Analysis of the gut microbiota has also progressed, where Lactobacillus regulate immune cells in the intestine and suppress inflammation. However, whether the methionine and tryptophan metabolic pathways affect the growth of intestinal Lactobacillus is unknown. Here we show how transient methionine, tryptophan, and niacin deficiency affects the host and gut microbiota in mouse models of colitis (induced by dextran sodium sulfate) fed a methionine-deficient diet (1K), tryptophan and niacin-deficient diet (2K), or methionine, tryptophan, and niacin-deficient diet (3K). These diets induced body weight decrease and 16S rRNA analysis of mouse feces revealed the alterations in the gut microbiota, leading to a dramatic increase in the proportion of Lactobacillus in mice. Intestinal RNA sequencing data confirmed that the expression of several serine proteases and fat-metabolizing enzymes were elevated in mice fed with methionine, tryptophan, and niacin (MTN) deficient diet. In addition, one-carbon metabolism and peroxisome proliferator-activated receptor (PPAR) pathway activation were also induced with MTN deficiency. Furthermore, changes in the expression of various immune-related cytokines were observed. These results indicate that methionine, tryptophan, and niacin metabolisms are important for the composition of intestinal bacteria and host immunity. Taken together, MTN deficiencies may serve as a Great Reset of gut microbiota and host gene expression to return to good health.

High N6-methyladenosine-activated TCEAL8 mRNA is a novel pancreatic cancer marker.

N6-methyladenosine (m6A) is an RNA modification involved in RNA processing and widely found in transcripts. In cancer cells, m6A is upregulated, contributing to their malignant transformation. In this study, we analyzed gene expression and m6A modification in cancer tissues, ducts, and acinar cells derived from pancreatic cancer patients using MeRIP-seq. We found that dozens of RNAs highly modified by m6A were detected in cancer tissues compared with ducts and acinar cells. Among them, the m6A-activated mRNA TCEAL8 was observed, for the first time, as a potential marker gene in pancreatic cancer. Spatially resolved transcriptomic analysis showed that TCEAL8 was highly expressed in specific cells, and activation of cancer-related signaling pathways was observed relative to TCEAL8-negative cells. Furthermore, among TCEAL8-positive cells, the cells expressing the m6A-modifying enzyme gene METTL3 showed co-activation of Notch and mTOR signaling, also known to be involved in cancer metastasis. Overall, these results suggest that m6A-activated TCEAL8 is a novel marker gene involved in the malignant transformation of pancreatic cancer.

RN7SL1 may be translated under oncogenic conditions.

RN7SL1 (RNA component of signal recognition particle 7SL1), a component of the signal recognition particle, is a non-coding RNA possessing a small ORF (smORF). However, whether it is translated into peptides is unknown. Here, we generated the RN7SL1-Green Fluorescent Protein (GFP) gene, in which the smORF of RN7SL1 was replaced by GFP, introduced it into 293T cells, and observed cells emitting GFP fluorescence. Furthermore, RNA-seq of GFP-positive cells revealed that they were in an oncogenic state, suggesting that RN7SL1 smORF may be translated under special conditions.

Revealing neuropilin expression patterns in pancreatic cancer: From single­cell to therapeutic opportunities (Review).

Pancreatic cancer, one of the most fatal types of human cancers, includes several non-epithelial and stromal components, such as activated fibroblasts, vascular cells, neural cells and immune cells, that are involved in different cancers. Vascular endothelial cell growth factor 165 receptors 1 [neuropilin-1 (NRP-1)] and 2 (NRP-2) play a role in the biological behaviors of pancreatic cancer and may appear as potential therapeutic targets. The NRP family of proteins serve as co-receptors for vascular endothelial growth factor, transforming growth factor ß, hepatocyte growth factor, fibroblast growth factor, semaphorin 3, epidermal growth factor, insulin-like growth factor and platelet-derived growth factor. Investigations of mechanisms that involve the NRP family of proteins may help develop novel approaches for overcoming therapy resistance in pancreatic cancer. The present review aimed to provide an in-depth exploration of the multifaceted roles of the NRP family of proteins in pancreatic cancer, including recent findings from single-cell analysis conducted within the context of pancreatic adenocarcinoma, which revealed the intricate involvement of NRP proteins at the cellular level. Through these efforts, the present study endeavored to further reveal their relationships with different biological processes and their potential as therapeutic targets in various treatment modalities, offering novel perspectives and directions for the treatment of pancreatic cancer.

RNA methylation in inflammatory bowel disease.

RNA modifications, including the renowned m6A, have recently garnered significant attention. This chemical alteration, present in mRNA, exerts a profound influence on protein expression levels by affecting splicing, nuclear export, stability, translation, and other critical processes. Although the role of RNA methylation in the pathogenesis and progression of IBD and colorectal cancer has been reported, many aspects remain unresolved. In this comprehensive review, we present recent studies on RNA methylation in IBD and colorectal cancer, with a particular focus on m6A and its regulators. We highlight the pivotal role of m6A in the pathogenesis of IBD and colorectal cancer and explore the potential applications of m6A modifications in the diagnosis and treatment of these diseases.

Elasticity of the Forearm Flexor-Pronator Muscles as a Risk Factor for Medial Elbow Injuries in Young Baseball Players: A Prospective Cohort Study of 314 Players.

BACKGROUND: Young baseball players with medial elbow injuries are known to have high forearm flexor-pronator muscle elasticity; however, the causal relationship between forearm muscle elasticity and the occurrence of medial elbow injuries remains unclear. PURPOSE/HYPOTHESIS: The purpose of this study was to determine whether the forearm flexor-pronator muscle elasticity is a risk factor for medial elbow injury in young baseball players. It was hypothesized that high flexor carpi ulnaris (FCU) elasticity would be a risk factor for medial elbow injuries. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Young baseball players (aged 9-12 years) with no history of elbow injuries underwent examination during which the strain ratios (SRs) of the pronator teres, flexor digitorum superficialis, and FCU muscles were measured using ultrasound strain elastography as an index of elasticity. Additionally, the participants completed a questionnaire assessing age, height, weight, months of experience as a baseball player, position in baseball, number of training days per week, number of throws per day, and elbow pain during throwing; then the range of motion of the shoulder and hip internal/external rotation were measured. One year after the baseline measurements, the occurrence of new medial elbow injuries was evaluated. Multivariate logistic regression analysis was subsequently conducted to determine risk factors for medial elbow injuries. Cutoff points for significant SR values obtained from the multivariate logistic regression analysis were calculated using the receiver operating characteristic curve. RESULTS: Of the 314 players, 76 (24.2%) were diagnosed with medial elbow injury. Multivariate logistic regression analysis showed that a 0.1 increase in the SR of the FCU muscle (odds ratio [OR], 1.211; 95% CI, 1.116-1.314) and number of throws per day (OR, 1.012; 95% CI, 1.001-1.022) were significantly associated with medial elbow injuries. Receiver operating characteristic curve analyses revealed that the optimal cutoff for the SR of the FCU muscle was 0.920 (area under the curve, 0.694; sensitivity, 75.0%; specificity, 56.7%). CONCLUSION: Increased FCU elasticity is a risk factor for medial elbow injury. Evaluation of the FCU elasticity may be useful in identifying young baseball players at high risk of medial elbow injuries and may facilitate prevention of medial elbow injury. As shown by the results of multivariate logistic regression analysis, FCU elasticity itself may be useful in identifying young baseball players at high risk of elbow injuries. However, we believe that other factors, such as the number of pitches per day, need to be considered to improve its accuracy.

Drug Discovery and Development of miRNA-Based Nucleotide Drugs for Gastrointestinal Cancer.

Short non-coding RNAs, miRNAs, play roles in the control of cell growth and differentiation in cancer. Reportedly, the introduction of miRNAs could reduce the biologically malignant behavior of cancer cells, suggesting a possible use as therapeutic reagents. Given that the forced expression of several miRNAs, including miR-302, results in the cellular reprograming of human and mouse cells, which is similar to the effects of the transcription factors Oct4, Sox2, Klf4, and c-Myc, this suggests that the selective introduction of several miRNAs will be able to achieve anti-cancer effects at the epigenetic and metabolic levels. In this review article, we bring together the recent advances made in studies of microRNA-based therapeutic approaches to therapy-resistant cancers, especially in gastrointestinal organs.

Role of RNA methylation in the regulation of pancreatic cancer stem cells (Review).

Pancreatic cancer stem cells (CSCs) play a key role in the initiation and progression of pancreatic adenocarcinoma (PDAC). CSCs are responsible for resistance to chemotherapy and radiation, and for cancer metastasis. Recent studies have indicated that RNA methylation, a type of RNA modification, predominantly occurring as m6A methylation, plays an important role in controlling the stemness of cancer cells, therapeutic resistance against chemotherapy and radiation therapy, and their overall relevance to a patient's prognosis. CSCs regulate various behaviors of cancer through cell-cell communication by secreting factors, through their receptors, and through signal transduction. Recent studies have shown that RNA methylation is involved in the biology of the heterogeneity of PDAC. The present review provides an update on the current understanding of RNA modification-based therapeutic targets against deleterious PDAC. Several key pathways and agents that can specifically target CSCs have been identified, thus providing novel insights into the early diagnosis and efficient treatment of PDAC.

Multifaced roles of desmoplastic reaction and fibrosis in pancreatic cancer progression: Current understanding and future directions.

Desmoplastic reaction is a fibrosis reaction that is characterized by a large amount of dense extracellular matrix (ECM) and dense fibrous stroma. Fibrotic stroma around the tumor has several different components, including myofibroblasts, collagen, and other ECM molecules. This stromal reaction is a natural response to the tissue injury process, and fibrosis formation is a key factor in pancreatic cancer development. The fibrotic stroma of pancreatic cancer is associated with tumor progression, metastasis, and poor prognosis. Reportedly, multiple processes are involved in fibrosis, which is largely associated with the upregulation of various cytokines, chemokines, matrix metalloproteinases, and other growth factors that promote tumor growth and metastasis. Fibrosis is also associated with immunosuppressive cell recruitment, such as regulatory T cells (Tregs) with suppressing function to antitumor immunity. Further, dense fibrosis restricts the flow of nutrients and oxygen to the tumor cells, which can contribute to drug resistance. Furthermore, the dense collagen matrix can act as a physical barrier to block the entry of drugs into the tumor, thereby further contributing to drug resistance. Thus, understanding the mechanism of desmoplastic reaction and fibrosis in pancreatic cancer will open an avenue to innovative medicine and improve the prognosis of patients suffering from this disease.

[A Case of Conversion Surgery for Gallbladder Cancer with Para-Aortic Lymph Node Metastasis].

The study presents the case of a 71-year-old woman who visited a nearby hospital for epigastric pain and weight loss. A CT scan showed a mass in the gallbladder, and the CEA level was high, so she was referred to our hospital for further investigation. Abdominal US, CT, and MRI suggested gallbladder cancer with para-aortic metastasis, and the histological findings on the EUS-FNA confirmed the diagnosis. Since surgical resection was not indicated, chemotherapy was performed(gemcitabine plus cisplatin). After 10 courses of chemotherapy, CT and MRI showed downsizing of para-aortic lymph nodes, and no accumulation of FDG was found on FDG-PET. Confirming the downstaging of cancer, conversion surgery, comprising an extended cholecystectomy and a lymph node resection, was performed. The pathological diagnosis showed no lymph node metastasis. No recurrence was observed after 12 months of surgery. Initially, unresectable gallbladder cancer with para-aortic lymph node metastasis was indicated to be compatible with preoperative chemotherapy and conversion surgery.

Pure Laparoscopic Donor Left Hepatectomy Reduces Postoperative Analgesic Use and Pain Scale.

BACKGROUND: Many recent reports have described the efficacy and safety of pure laparoscopic donor hepatectomy (PLDH). Here we investigated the extent to which this technique could reduce patients' experienced pain. METHODS: Among donor left hepatectomy procedures performed between July 2011 and November 2022, we retrospectively analyzed 20 open donor hepatectomy (ODH), 20 laparoscopy-assisted donor hepatectomy (LADH), and 5 PLDH cases. We compared these 3 procedures regarding the total amount of postoperative analgesic use (narcotics and non-narcotics) and the first date when the donor was completely pain-free, as evaluated by the patients using a pain scale. RESULTS: Total postoperative fentanyl use did not significantly differ among the 3 procedures: median (range), ODH, 0.5 mg (0-2 mg); LADH 1.2 mg (0-7 mg); PLDH, 0.5 mg (0-3.5; P = .172). The percentage of patients who completely discontinued analgesics on postoperative day (POD) 5 was significantly higher for PLDH (80%) than for ODH (35%) or LADH (20%) (P = .041). The day when 50% of donors were completely pain-free on a pain scale was POD9 for ODH, POD11 for LADH, and POD5 for PLDH, significantly shorter in the PLDH group (P = .004). CONCLUSION: At our institution, we found that PLDH was a useful technique for postoperative pain management compared with PDH and LADH. Our results suggest that PLDH effectively reduces the duration of postoperative analgesia use. Further studies are warranted as the number of PLDH cases gradually increases.

Increased Medial Elbow Torque Is Associated With Ball Velocity Rather Than a History of Medial Elbow Injuries in Youth Baseball Pitchers.

PURPOSE: This study compared medial elbow torque in youth baseball pitchers with and without a history of medial elbow injuries to determine the relationship between medial elbow torque during pitching and having a history of medial elbow injuries. METHODS: We recruited 171 youth baseball pitchers aged 9 to 12 years old. The exclusion criteria included current pain with pitching, history of surgery on the tested extremity, or osteochondritis dissecans of the humeral capitellum. The participants were grouped into 3 groups: injury <1-year, injury >1-year, and control, based on ultrasonographic abnormalities of the elbow and the presence of elbow pain. Pitchers pitched 3 fastballs while wearing a sensor sleeve that recorded the medial elbow torque, arm speed, and shoulder rotation. Ball velocity was measured using a radar gun. RESULTS: The final analysis included 164 pitchers. Thirty were assigned to the injury <1-year group, 34 to the injury >1-year group, and 100 to the control group. The medial elbow torque was significantly greater in the injury <1-year group compared with the control group (18.6 ± 3.6 Nm vs 16.2 ± 4.8 Nm, P = .023). A multiple regression analysis revealed that ball velocity (B = 0.282, P < .001) and body weight (B = -0.224, P < .001) were significantly associated with medial elbow torque, but not with the history of medial elbow injuries. CONCLUSIONS: Increased medial elbow torque was associated with greater ball velocity regardless of the history of medial elbow injuries. Youth baseball pitchers with a history of medial elbow injuries within one year had greater medial elbow torque during pitching; however, having a history of medial elbow injuries was not an independent factor in increasing medial elbow torque. Limiting the ball velocity can reduce medial elbow torque and may prevent elbow injuries in youth baseball pitchers. LEVEL OF EVIDENCE: Level II, prospective comparative prognostic investigation with the patients enrolled at different time point.

Perioperative fluid management influences complication rates and length of hospital stay in the enhanced recovery after surgery (ERAS) protocol for patients with colorectal cancer.

PURPOSE: To evaluate the efficacy and safety of the enhanced recovery after surgery (ERAS) protocol and quantify the impact of each ERAS item on postoperative outcomes. METHODS: We used a generalized linear model to compare 289 colorectal cancer patients treated with the ERAS protocol between June, 2015 and April, 2021, with 99 colorectal cancer patients treated with the conventional colorectal surgery pathway between April, 2014 and June, 2015. RESULTS: The median length of hospital stay (LOHS) was significantly shorter in the ERAS group, at 9 days (range 3-104 days) vs. 14 days (range 4-44 days) (p < 0.001), but the complication rates (Clavien-Dindo grade 2 or more) were similar (16.6% vs. 22.2%; p = 0.227). However, in the ERAS group, the higher the compliance with ERAS items, the lower the complication rate and LOHS (both p < 0.001). Multiple regression analysis demonstrated that "Discontinuation of continuous intravenous infusion on POD1" and "Avoidance of fluid overload" were significantly associated with the LOHS (p < 0.001 and p = 0.008). CONCLUSION: The ERAS protocol is safe and effective for elective colorectal cancer surgery, and compliance with the ERAS protocol contributes to shorter LOHS and fewer complications. Items related to perioperative fluid management had a crucial impact on these outcomes.

Emerging roles of long noncoding and circular RNAs in pancreatic ductal adenocarcinoma.

An international project on the human genome revealed that various RNAs (e.g., messenger RNAs, microRNAs, and long noncoding RNAs [lncRNAs] and their subclass circular RNA [circRNA)) are involved in the pathogenesis of different human diseases, including cancer. Recent studies have highlighted the critical roles of lncRNAs and circRNA in pancreatic ductal adenocarcinoma (PDAC), especially in the epithelial-mesenchymal transition, a phenomenon regulating cancer metastasis. Growing research in this field has indicated that the tertiary structure of lncRNAs supposedly regulates biological function via RNA-RNA or RNA-protein associations, aiding early diagnosis and therapy selection for various diseases, including cancer. Here we describe the emerging roles of ncRNAs in PDAC and highlight how these ncRNAs can be used to detect and control this intractable cancer.

Evaluating Neoadjuvant Chemotherapy for Lower Esophageal Squamous Cell Carcinoma by Measuring Esophageal Wall Thickness.

BACKGROUND/AIM: The aim of this study was to evaluate the efficacy of preoperative chemotherapy for stage II-III esophageal squamous cell carcinoma based on an objective computed tomography method. PATIENTS AND METHODS: A total of 82 patients who underwent preoperative chemotherapy followed by surgery for advanced esophageal squamous cell carcinoma from January 2006 to June 2019 were included. Treatment effect was evaluated by measuring the esophageal wall thickness before and after neoadjuvant chemotherapy using contrast-enhanced thoracoabdominal computed tomography. The percentage decrease in esophageal wall thickness was calculated using the following formula: reduction (%)=(wall thickness before preoperative chemotherapy - wall thickness after preoperative chemotherapy)/(wall thickness before preoperative chemotherapy)×100. We demonstrated the efficacy of this measurement method and then analyzed which patient factors might affect the treatment effect. RESULTS: Receiver operating characteristic analysis showed the percentage tumor reduction to be a good predictor of histological therapeutic effect (grade ≥2) (area under the curve=0.727). In the multivariate analysis, tumor location (lower versus upper esophagus) was identified as an independent factor associated with tumor reduction (odds ratio=0.15; 95% confidence interval=0.03-0.79; p=0.025). CONCLUSION: We demonstrated an association between the reduction of esophageal wall thickness in the tumoral area and the histological therapeutic effect of chemotherapy. Secondary analysis showed poorer tumor reduction in patients with lower esophageal cancer than in those with upper esophageal cancer.

Pancreatic Cancer Research beyond DNA Mutations.

Pancreatic ductal adenocarcinoma (PDAC) is caused by genetic mutations in four genes: KRAS proto-oncogene and GTPase (KRAS), tumor protein P53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homolog 4 (SMAD4), also called the big 4. The changes in tumors are very complex, making their characterization in the early stages challenging. Therefore, the development of innovative therapeutic approaches is desirable. The key to overcoming PDAC is diagnosing it in the early stages. Therefore, recent studies have investigated the multifaced characteristics of PDAC, which includes cancer cell metabolism, mesenchymal cells including cancer-associated fibroblasts and immune cells, and metagenomics, which extend to characterize various biomolecules including RNAs and volatile organic compounds. Various alterations in the KRAS-dependent as well as KRAS-independent pathways are involved in the refractoriness of PDAC. The optimal combination of these new technologies is expected to help treat intractable pancreatic cancer.

High elasticity of the flexor carpi ulnaris and pronator teres muscles is associated with medial elbow injuries in youth baseball players.

OBJECTIVES: The purpose of the present study was to measure the elasticities of the forearm flexor-pronator muscles in youth baseball players and examine their relationships with medial elbow injuries. METHODS: We examined the strain ratios (SR) of the flexor digitorum superficialis (FDS), flexor carpi ulnaris (FCU), and pronator teres (PT) in 89 youth baseball players with medial epicondylar fragmentation (injury group) and in 142 healthy baseball players (control group). An index of muscle elasticity was determined using ultrasound strain elastography. The SR of each muscles was compared between the injury and control groups, and the SR of the both side arms was compared within group. Moreover, multivariable logistic regression analyses were conducted to examine the association of forearm muscle elasticity with medial elbow injuries. RESULTS: The SR of the FCU and PT of the throwing arm were significantly higher in the injury group than in the control group (both P < .001). In the injury group, the SR of the FCU was higher in the throwing arm than in the non-throwing arm (P < .001), but no difference was noted for the PT. Multivariable logistic regression analyses showed that a 0.1 increase of the SR of the FCU of the throwing arm (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.14-1.48) and PT of the throwing arm (OR 1.41, 95% CI 1.19-1.67) and the non-throwing arm (OR 1.31, 95% CI 1.12-1.54) was significantly associated with an increased prevalence of medial elbow injuries. CONCLUSION: High elasticities of the FCU of the throwing arm and PT of both the arms were observed in individuals with medial elbow injuries, and were associated with increased prevalence of medial elbow injuries. These findings may be characteristic of medial elbow injuries in youth baseball players.