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Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate; therefore, the development of effective treatments is a priority. The stimulator of interferon genes (STING) pathway enhances tumor immunity by inducing the production of type 1 interferon (IFN) and proinflammatory cytokines and chemokines and promoting the infiltration of cytotoxic T cells. To assess the function of STING on pancreatic tumorigenesis, Ptf1a ER-Cre/+ LSL-Kras G12D/+ p53 loxP/loxP mice (KPC mice) and Ptf1a ER-Cre/+ LSL-Kras G12D/+ p53 loxP/loxP /STING −/− mice (KPCS mice) were generated. However, STING deletion did not affect pancreatic tumorigenesis in mice. Because STING is expressed not only in immune cells but also in cancer-associated fibroblasts (CAFs), we evaluated the STING function in PDAC CAFs. A mouse STING agonist 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA) was administered to KPC mice and CAFs from KPC mice and the resulting immune response was evaluated. DMXAA activated STING in PDAC CAFs in KPC mice, promoting cytotoxic T cell infiltration by secreting proinflammatory cytokines and enhancing tumor immunity. We next generated STING-deficient PDAC cells and subcutaneous tumors in which STING was expressed only in CAFs by performing bone marrow transplantation and assessed the antitumor effect of STING-activated CAFs. The administration of DMXAA to subcutaneous tumors expressing STING only in CAFs sustained the antitumor effect of DMXAA. About half of human PDACs lacked STING expression in the cancer stroma, suggesting that STING activation in PDAC CAFs exerts an antitumor effect, and STING agonists can be more effective in tumors with high than in those with low STING expression in the stroma.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy. Personalized medicine based on genetic mutations is required to improve its prognosis. The PI3K/AKT pathway plays a crucial role in cancer progression. While PI3K inhibitors have been developed for several malignancies, none have been clinically applied to PDAC. PIK3CA encodes the catalytic subunit of Class IA PI3K, and an activating mutation such as E545K and H1047R is oncogenic. In this study, we developed a novel pancreatic cancer mouse model with PIK3CA H1047R mutation, designated Ptf1a cre/+ ; Rosa26-LSL-PIK3CA H1047R :p53 loxP/loxP (PPC) mice. At 150 days of age, PPC mice developed PDAC and AKT was activated in their tumor epithelial cells. We established a pancreatic cancer cell line from PPC mice, and alpelisib, an inhibitor of PI3K p110α, inhibited the proliferation of PPC cells in vitro . Furthermore, PPC cells were subcutaneously transplanted into NOD/SCID mice, and alpelisib significantly reduced the tumor burden of PPC cells. Western blotting upon treatment with alpelisib revealed compensatory activation of ERK in PPC cells. Combination treatment with alpelisib and the MEK inhibitor PD98059 significantly inhibited cell proliferation. These data indicate that PIK3CA mutation may be oncogenic in PDAC and that PI3K inhibitors can be effective against such tumors. Dual inhibition of the PI3K/AKT and MEK/ERK pathways may enhance therapeutic effects in PI3K/AKT-activated pancreatic tumors.

Carotid body tumor is a hypervascular tumor with multiple feeding arteries and unique orientation at the carotid bifurcation. Although resection is a radical therapy for this tumor, complete resection is challenging. Articles reporting carotid body tumor treatment and surgical resection were reviewed including case-control series and review articles. Selected reports were reviewed and discussed focusing on choice of treatment, surgical difficulties and preoperative embolization of feeding arteries. Multiple feeding arteries and adhesion of the tumor to the carotid arterial wall are causes of difficulties in carotid body tumor resection. The effectiveness of preoperative embolization remains controversial due to the varied situations in performing surgical resection among the institutions. However, perfect embolization and resection immediately after embolization reduce blood loss and operative time of surgery for carotid body tumor.

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are mitochondrial proteins that are thought to be genes which duplicated during evolution and are the causative genes for Parkinson’s disease and amyotrophic lateral sclerosis/frontotemporal lobe dementia, respectively. CHCHD2 forms a heterodimer with CHCHD10 and a homodimer with itself, both of which work together within the mitochondria. Various pathogenic and disease-risk variants have been identified; however, how these mutations cause neurodegeneration in specific diseases remains a mystery. This review focuses on important new findings published since 2019 and discusses avenues to solve this mystery.

We studied the kinetic phenomenon of an airbag impact on eyes with different axial lengths using finite element analysis (FEA) to sequentially determine the physical and mechanical responses of intraocular segments at various airbag deployment velocities. The human eye model we created was used in simulations with the FEA program PAM-GENERIS . The airbag was set to impact eyes with axial lengths of 21.85 mm (hyperopia), 23.85 mm (emmetropia) and 25.85 mm (myopia), at initial velocities of 20, 30, 40, 50 and 60 m/s. The deformation rate was calculated as the ratio of the length of three segments, anterior chamber, lens and vitreous, to that at the baseline from 0.2 ms to 2.0 ms after the airbag impact. Deformation rate of the anterior chamber was greater than that of other segments, especially in the early phase, 0.2-0.4 ms after the impact (P < 0.001), and it reached its peak, 80%, at 0.8 ms. A higher deformation rate in the anterior chamber was found in hyperopia compared with other axial length eyes in the first half period, 0.2-0.8 ms, followed by the rate in emmetropia (P < 0.001). The lens deformation rate was low, its peak ranging from 40% to 75%, and exceeded that of the anterior chamber at 1.4 ms and 1.6 ms after the impact (P < 0.01). The vitreous deformation rate was lower throughout the simulation period than that of the other segments and ranged from a negative value (elongation) in the later phase. Airbag impact on the eyeball causes evident deformation, especially in the anterior chamber. The results obtained in this study, such as the time lag of the peak deformation between the anterior chamber and lens, suggest a clue to the pathophysiological mechanism of airbag ocular injury.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson’s disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

Vernal keratoconjunctivitis (VKC) is a refractory ocular allergic disorder that mainly affects boys. Long-term follow-up has been rarely reported for VKC. We investigated the long-term clinical outcome of VKC to identify relevant clinical features of prognostic value based on follow-up for a median of 70 months. In total, 45 consecutive patients clinically diagnosed with VKC aged 4 to 12 years at onset at the Department of Ophthalmology of Fukuoka University Hospital were included. Patients were treated with immunosuppressive eye drops without simultaneous corticosteroid eye drops, except for the occurrence of exacerbations. Collated variables were gender, age at onset, clinical score of ocular lesions (conjunctival giant papillae, limbal edema and corneal epithelial lesions) at the first visit, and clinical score of atopic dermatitis (AD) at baseline. Cumulative cure rate was estimated using Kaplan-Meier method. A binomial logistic predictive model was used to determine the most reliable clinical predictors of VKC outcome. The observation period ranged from 24 to 188 months, with median of 70 months. Among the 45 cases enrolled, all non-cured cases (14 cases) observed clinically were complicated by AD. Cumulative cure rate was 74.5% and 84.9% at eight- and ten-year follow-up, respectively. Ten-year cumulative cure rates of cases with and without AD were 50.5% and 100%, respectively, and a significant difference was found between these cumulative cure curves. Binomial regression analysis revealed that AD and gender were significantly related to worse outcome, and this binomial regression model had high sensitivity and specificity. This study demonstrated that th eclinical outcomeof VKC might be predicted by several factors that can beobtained in the early clinical phase. Information on the long-term prognosis of VKC patients might play an important role for precision medicine for VKC in childhood.

We studied the kinetic phenomenon of an airbag impact on eyes after trabeculectomy using finite element analysis (FEA), a computerized method for predicting how an object reacts to real-world physical effects and showing whether an object will break, to sequentially determine the responses at various airbag deployment velocities. A human eye model was used in the simulations using the FEA program PAM-GENERIS (Nihon ESI, Tokyo, Japan). A half-thickness incised scleral flap was created on the limbus and the strength of its adhesion to the outer sclera was set at 30%, 50%, and 100%. The airbag was set to hit the surface of the post-trabeculectomy eye at various velocities in two directions: perpendicular to the corneal center or perpendicular to the scleral flap (30° gaze-down position), at initial velocities of 20, 30, 40, 50, and 60 m/s. When the airbag impacted at 20 m/s or 30 m/s, the strain on the cornea and sclera did not reach the mechanical threshold and globe rupture was not observed. Scleral flap lacerations were observed at 40 m/s or more in any eye position, and scleral rupture extending posteriorly from the scleral flap edge and rupture of the scleral flap resulting from extension of the corneal laceration through limbal damage were observed. Even in the case of 100% scleral flap adhesion strength, scleral flap rupture occurred at 50 m/s impact velocity in the 30° gaze-down position, whereas in eyes with 30% or 50% scleral flap adhesion strength, scleral rupture was observed at an impact velocity of 40 m/s or more in both eye positions. An airbag impact of ≥40 m/s might induce scleral flap rupture, indicating that current airbags may induce globe rupture in the eyes after trabeculectomy. The considerable damage caused by an airbag on the eyes of short-stature patients with glaucoma who have undergone trabeculectomy might indicate the necessity of ocular protection to avoid permanent eye damage.

In clinical cases of pancreas divisum, endoscopic retrograde cholangiopancreatography often necessitates cannulation of the pancreatic duct through the minor papilla. Nevertheless, this procedure can be challenging because of the small size of the minor papilla and the difficulty in visualizing the ductal orifice. A new image‐enhanced endoscopy technique called texture and color enhancement imaging (TXI) has been developed, which enhances texture, brightness, and color compared with white‐light imaging, resulting in subtle differences in the surface mucosa. Herein, we describe the case of a 73‐year‐old man with pancreas divisum in whom TXI was useful in identifying the orifice of the minor papilla. He was referred to our hospital with repetitive acute exacerbation of chronic pancreatitis. Since contrast‐enhanced computed tomography revealed a pancreatic stone in the main pancreatic duct, endoscopic retrograde cholangoepancreatography was performed as a therapeutic intervention. Despite the initial difficulty in identifying the orifice of the minor papilla on white‐light imaging, TXI enhanced its visibility successfully, enabling dorsal pancreatic duct cannulation via the minor papilla. Subsequently, endoscopic pancreatic sphincterotomy was performed and a 6Fr plastic stent was placed. Post‐endoscopic therapy, the patient's abdominal pain was relieved. TXI was useful in identifying the minor papilla orifice and led to successful cannulation.

We report a case of massive bleeding from proton pump inhibitor (PPI)‐induced fundic gland polyps (FGPs) that regressed after switching to a histamine‐2 receptor antagonist (H2RA). A 46‐year‐old man with antiphospholipid syndrome had been receiving warfarin and lansoprazole for 4 years. Esophagogastroduodenoscopy (EGD) revealed multiple enlarged, edematous FGPs compared to those observed 3 years earlier. One month later, the patient presented with melena, anemia, and transient loss of consciousness. Laboratory data revealed anemia and a prolonged prothrombin time/international normalized ratio (PT‐INR). Emergency EGD showed refractory oozing from the FGPs caused by insufflation and water jet stimulation. The bleeding was successfully controlled with vitamin K administration. After PT‐INR normalization, no further bleeding occurred, and a follow‐up EGD 3 days later showed no bleeding recurrence. We considered that PPI therapy might lead to recurrent bleeding from the FGPs and switched therapy to an H2RA. Follow‐up EGD at 2 and 6 months revealed gradual and marked regression of the FGPs. This case demonstrates that PPI‐induced FGPs can result in massive bleeding, particularly in patients receiving anticoagulant therapy. Furthermore, FGP regression following the switch to H2RA suggests that H2RA therapy may be an alternative treatment when discontinuation of PPI therapy is not feasible.