A HIF-1α inhibitor combined with palmitic acid and L-carnitine treatment can prevent the fat metabolic reprogramming under hypoxia and induce apoptosis in hepatocellular carcinoma cells.

BACKGROUND: A hypoxic environment often persists within solid tumors, including hepatocellular carcinoma (HCC). Hypoxia-inducible factor-1α (HIF-1α) can accelerate cancer malignancy by inducing hypoxia-dependent expression of various genes. Tumor hypoxia can also induce metabolic reprogramming of fatty acid (FA) metabolism, through which HIF-1α plays an essential role in diminishing fatty acid ß-oxidation (FAO) in hypoxic cancer cells. METHODS: We aimed to investigate potential new drug therapy options for targeting hypoxic cancer cells within HCC tumors, specifically through combining HIF-1α inhibition with palmitic acid (PA) + L-carnitine (LC) treatment to effectively induce apoptosis in hypoxic HCC cells. To test this hypothesis, in vitro and in vivo studies were performed. RESULTS: We first demonstrated that hypoxia-dependent apoptosis was induced by an overload of PA in two HCC cell lines (HepG2 and Hep3B) via excessive production of reactive oxygen species (ROS). Moreover, this observed PA-induced apoptosis was enhanced by HIF-1α knockdown (KD) in these cells under hypoxia. In addition, the combination of PA with FAO activator LC increased FAO activity and led to stronger cell death than PA alone in hypoxic HIF-1α KD cells, specifically through further ROS generation. To clarify the mechanism of hypoxia-induced FA metabolism reprogramming, expression levels of the genes encoding FAO enzymes CPT1A, ACSL1, MCAD, and LCAD, FA transporter CD36, and FA esterification enzymes DGAT and APGAT were analyzed using HIF-1α KD and scramble control (SC) cells. The results suggested that HIF-1α could repress mRNA expression of the FAO-related enzymes and CD36, while it upregulated FA esterification gene expression. This suggested a central role for HIF-1α in hypoxia-induced reprogramming of FA metabolism in HCC cells. Using a nude mouse model, PA administration was found to induce apoptosis from ROS overproduction in HIF-1α KD tumors compared with SC tumors. Additional LC treatment synergistically enhanced the PA-induced apoptosis in HIF-1α KD tumors. Finally, in vivo therapy composed of HIF-1α inhibitor YC-1 with PA + LC could induce ROS-mediated apoptosis in HepG2 tumors without significant toxicity. CONCLUSIONS: A combination therapy of YC-1 with PA + LC may be a unique anti-tumor therapy for targeting hypoxic HCC cells, specifically by ROS overproduction leading to forced FAO activation.

A rare case of inflammatory myofibroblast tumor of the stomach successfully treated by inverted laparoscopic and endoscopic cooperative surgery.

BACKGROUND: An Inflammatory myofibroblastic tumor (IMT) is a rare intermediate malignancy characterized by myofibroblast proliferation and inflammatory cell infiltration. Various organs are the primary sites of origin. However, primary tumors originating in the stomach tend to be extremely rare, making the diagnosis difficult. Herein, we present a case of IMT originating in the stomach that was effectively managed using inverted laparoscopic endoscopic cooperative surgery (LECS). CASE PRESENTATION: A 47-year-old male who was admitted to the hospital because of a submucosal tumor that was discovered during upper gastrointestinal endoscopy. The diameter of the tumor was approximately 20 mm. A KIT-negative gastrointestinal stromal tumor was suspected based on the biopsy findings. Therefore, partial resection of the stomach was performed using inverted laparoscopic and endoscopic cooperative surgery. Histopathological examination revealed collagen fiber proliferation from the submucosal layer to the muscular layer, accompanied by infiltration of spindle-shaped cells, lymphocytes, and numerous inflammatory cells. Immunohistochemistry results were positive for SMA and negative for CD34, desmin, and c-kit. IgG4-positive cells were observed with an IgG4/IgG ratio > 50%, and specific nuclei were positive for ALK. Therefore, IMT was diagnosed. This condition may be difficult to diagnose both before and after surgery because of its rarity and submucosal tumor-like morphology. CONCLUSION: When a submucosal tumor originating in the stomach is observed, IMT should be considered. Partial resection of the stomach with LECS and immunohistochemical diagnosis may be useful.

Laparoscopic surgery for rectal cancer with a coexisting Retzius shunt and inferior mesenteric arteriovenous malformation: A case report.

A coexisting short-circuit from the inferior mesenteric vein (IMV) to the inferior vena cava, known as a Retzius shunt, and arteriovenous malformation (AVM) of the inferior mesentery are extremely rare conditions. We encountered a case of rectal cancer with coexisting Retzius shunt and inferior mesenteric AVM successfully treated with laparoscopic surgery. Contrast computed tomography (CT) in a 62-year-old man with rectal cancer showed multiple dilated veins at the mesenterium of the descending sigmoid colon. These dilated veins were connected between the IMV and the left renal vein. A diagnosis of Retzius shunt was made, and laparoscopic low anterior resection with lymph node dissection was performed. A pathological examination of the colonic mesenterium revealed AVM communicating with the dilated IMV and Retzius shunt. The preoperative evaluation of aberrant vessels by three-dimensional CT is particularly useful for patients with vascular malformations to ensure safe laparoscopic surgery.

[Adult Intussusception Associated with a Low-Grade Appendiceal Mucinous Neoplasm-A Case Report].

A 52-year-old woman patient, who presented with lower abdominal pain, was suspected of having colonic intussusception. An enhanced CT examination indicated that the end of the small intestine or appendix tumor had invaginated into the transverse colon. The CT revealed no evidence of intestinal ischemia, the emergency operation was performed on the following day. After relieving a colonic intussusception, a mass of the appendix was found and we performed laparoscope-assisted ileocolic resection and D3 dissection because of a strong possibility of carcinoma. The patient was discharged 8 days after the surgery and showed no evidence of recurrence for 6 months after the surgery. In postoperative histopathological examination, appendix tumor was diagnosed as a low-grade appendiceal mucinous neoplasm(LAMN). Adult intussusception is a rare disease and most of the cases are caused by malignant lesions, and a treatment strategy for LAMN has not yet been established. We report this case , as there are very few reported cases of adult intussusception caused by LAMN, with a review of the relevant literature.

Intussusception of the cecum due to the acute appendicitis: A case report.

INTRODUCTION AND IMPORTANCE: Intussusception of the cecum due to acute appendicitis is rare condition. PRESENTATION OF CASE: A 17-year-old male patient presented to our hospital with a chief complaint of right lower abdominal pain, which had lasted for two days. Computed tomography (CT) revealed a "target sign" from the cecum to the ascending colon, leading to a diagnosis of cecocolic intussusception. Colonoscopy revealed an erythematous, edematous, and internally distorted cecum in the ascending colon, which was difficult to repair with air insufflation. Laparoscopic surgery was performed to remove the bowel obstruction. Repositioning of the invaginated cecum was difficult due to the presence of a hard and edematous colic wall. Therefore, laparoscopic ileocecal resection was performed to release the obstruction. The pathological diagnosis was appendicitis and abscess within the cecum wall, with no malignant findings. DISCUSSION: In our case, intussusception was considered to have caused thickening of the intestinal wall of the cecum due to inflammation of the appendix, and the thickened area became the leading point. CONCLUSION: Considering that malignancy is a frequent leading point in adult patients with intussusception, a preoperative endoscopic examination is important for minimizing bowel resection.

Laparoscopic Training for Gastrointestinal Surgery Using Japanese Traditional Papercraft Origami.

PURPOSE: The aim of this study is to show the experience and results of laparoscopic training using origami, a Japanese traditional papercraft, and to discuss its usefulness in gastrointestinal surgery. MATERIALS AND METHODS: A laparoscopic training dry box was used. An origami paper crane was folded using laparoscopic instruments. The time to complete the origami crane was measured. RESULTS: Two trainees participated in this study; the total number of origami cranes folded by these trainees was 2000 and 700, respectively. The learning curve gradually improved. According to our experience, this training strengthened mental faculties and was associated with the improvement of hand-eye and left-right coordination, reduction of tremor, acquisition of delicate technique, the ability to distinguish subtle differences in color, ability to respond to trouble. CONCLUSIONS: Laparoscopic training for gastrointestinal surgery using origami may have the potential to improve the technical skills in laparoscopic surgery.

Nutrition-related risk and severe hypoglycemia in older adult outpatients with and without diabetes.

In this study, 17 patients with severe hypoglycemia were assessed for nutrition-related risk using the Geriatric Nutritional Risk Index (GNRI). The results showed that 13 of the 17 patients had nutrition-related risk. Hypoglycemia should be noted in patients with problems on GNRI, with or without diabetes.

On the brink of extinction: a new freshwater amphipod Jesogammarusacalceolus (Anisogammaridae) from Japan.

Freshwater habitats, especially cold springs, are environments in which the risk of extinction faced by organisms remains high due to human activities. To conserve endangered species, it is important to describe and name them. Here, a new, endangered freshwater anisogammarid amphipod species, Jesogammarus (Jesogammarus) acalceolussp. nov., found in a spring in Aomori Prefecture, Japan, is described which is potentially the sole remaining habitat of this species. Both morphological and molecular phylogenetic results strongly support the nesting of the new species within Jesogammarus. Jesogammarus (J.) acalceolussp. nov. is the first species of genus Jesogammarus that was found to lack a calceolus, a sensory organ located on male antenna 2. Thus, the diagnostic criteria for this genus required amendment. A reconstruction of ancestral calceoli, based on a molecular phylogenetic tree, revealed that the common ancestor of Jesogammarus possessed calceoli, which were secondarily lost in J. (J.) acalceolussp. nov. Our results indicate that this new species, which is key to clarifying the evolution of the calceolus, is of high conservation significance.

Increased nutrition-related risk as an independent predictor of the incidence of hypoglycemia in the hospitalized older individuals with type 2 diabetes: a single-center cohort study.

BACKGROUND AND AIMS: There are few reports on the association between malnutrition and hypoglycemia. The geriatric nutritional risk index (GNRI) allows risk classification by morbidity and mortality resulting from conditions often associated with malnutrition in older individuals. However, the association between GNRI and hypoglycemia is unclear. This study examined the associations between nutrition-related risk and hypoglycemia among older individuals with type 2 diabetes (T2D) using diabetes medication. METHODS: This single-center historical cohort study included hospitalized patients aged ≥ 65 years with T2D on medication. Nutrition-related risk was assessed using the GNRI and classified into four risk groups. Hypoglycemia and serious hypoglycemia were determined by oral or intravenous glucose intake and blood glucose < 3.9 mmol/L (70 mg/dL) as hypoglycemia, among them blood glucose < 3.0 mmol/L (54 mg/dL) as serious hypoglycemia. Data were recorded at least once during hospitalization. RESULTS: Patients who met the criteria (n = 1.754) were included in the study. The participants median age was 75.0 years. During the study, 81 patients (4.6%) experienced hypoglycemia and 7 patients (0.4%) experienced serious hypoglycemia. Hypoglycemia was observed in patients in the major risk (16.0%), moderate risk (9.7%), low risk (5.2%), and no risk (1.5%) groups (p for trend < 0.001). After adjusting for other risk factors, the hazard ratios of hypoglycemic among people with major, moderate, and low risk were 5.50, 3.86, and 2.55, respectively. CONCLUSIONS: Hypoglycemia increased with increasing nutrition-related risk among older individuals with T2D using diabetes medication. The GNRI is a simple and useful assessment tool in the clinical setting.

Hyperstable De Novo Protein with a Dimeric Bisecting Topology.

Recently, we designed and assembled protein nanobuilding blocks (PN-Blocks) from an intermolecularly folded dimeric de novo protein called WA20. Using this dimeric 4-helix bundle, we constructed a series of self-assembling supramolecular nanostructures including polyhedra and chain-type complexes. Here we describe the stabilization of WA20 by designing mutations that stabilize the helices and hydrophobic core. The redesigned proteins denature with substantially higher midpoints, with the most stable variant, called Super WA20 (SUWA), displaying an extremely high midpoint (Tm = 122 °C), much higher than the Tm of WA20 (75 °C). The crystal structure of SUWA reveals an intermolecularly folded dimer with bisecting U topology, similar to the parental WA20 structure, with two long α-helices of a protomer intertwined with the helices of another protomer. Molecular dynamics simulations demonstrate that the redesigned hydrophobic core in the center of SUWA significantly suppresses the deformation of helices observed in the same region of WA20, suggesting this is a critical factor stabilizing the SUWA structure. This hyperstable de novo protein is expected to be useful as nanoscale pillars of PN-Block components in new types of self-assembling nanoarchitectures.

Retrospective Risk Analysis for Anastomotic Leakage Following Laparoscopic Rectal Cancer Surgery in a Single Institute.

PURPOSE: Anastomotic leakage (AL) is one of the most serious complications after laparoscopic low anterior resection (LALAR) for rectal cancer. The aim of the present study was to investigate the risk factors for AL after LALAR. METHODS: A retrospective study was conducted of 103 patients who underwent LALAR in a single institute between October 2008 and January 2018. Univariate and multivariate analyses were performed to determine the clinicopathological factors associated with AL. RESULTS: The overall incidence of AL was 9.7% (10/103). After anastomosis using the double-stapling technique, a transanal tube was placed in 88 patients (85.4%). A diverting stoma was created in 26 patients (25.2%). The univariate analysis showed that a younger age (P = 0.014), higher stage (P = 0.048), deeper depth of tumor invasion (P = 0.028), larger tumor circumference (P = 0.024), longer operation time (P = 0.015), and early postoperative diarrhea (P = 0.002) were associated with AL. The multivariate logistic regression analysis revealed early postoperative diarrhea (odds ratio [OR] 16.513, 95% confidence interval [CI] 2.393-113.971, P = 0.004) a younger age (10-year increments; OR 0.351, 95% CI 0.147-0.839, P = 0.019), operative time (10-min increments; OR 1.089, 95% CI 1.012-1.172, P = 0.022), and higher stage (OR 10.605, 95% CI 1.279-87.919, P = 0.029) were independent risk factors for AL CONCLUSION: Our findings suggest that tumor progression accompanied by a high stage, long operative time, and insufficient bowel preparation and early postoperative diarrhea due to a large tumor circumference may be risk factors of AL after LALAR for rectal cancer.

[Anal canal basaloid carcinoma with vaginal invasion which was recurrence-free for 5 years postoperatively].

We performed abdomino-perineal resection of the rectum and partial resection of a vagina in a 78-year-old woman on a diagnosis of anal canal basaloid carcinoma with vaginal invasion. We did not perform specific adjuvant therapy pre- or postoperatively, but no recurrence appeared for 5 years. Anal canal basaloid carcinoma is a comparatively rare disorder, and the prognosis is relatively good. It seemed that determination of the indication of postoperative adjuvant therapy will require the accumulation of future further cases and enough appearance with operative methods in the treatment of anal canal basaloid carcinoma.