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Competing Interests: Conflict of interest All authors declare no conflicts of interest.

In photosystem II (PSII), D1-Tyr246 and D2-Tyr244 are symmetrically located at the binding site of the bicarbonate ligand of the non-heme Fe complex. Here, we investigated the role of the symmetrically arranged tyrosine pair, D1-Tyr246 and D2-Tyr244, in the function of PSII, by generating four chloroplast mutants of PSII from Chlamydomonas reinhardtii: D1-Y246F, D1-Y246T, D2-Y244F, and D2-Y244T. The mutants exhibited altered photoautotrophic growth, reduced PSII protein accumulation, and impaired O 2 -evolving activity. Flash-induced fluorescence yield decay kinetics indicated a significant slowdown in electron transfer from Q A •- to Q B in all mutants. Bicarbonate reconstitution resulted in enhanced O 2 -evolving activity, suggesting destabilization of bicarbonate binding in the mutants. Structural analyses based on a quantum mechanical/molecular mechanical approach identified the existence of a water channel that leads to incorporation of bulk water molecules and destabilization of the bicarbonate binding site. The water intake channels, crucial for bicarbonate stability, exhibited distinct paths in the mutants. These findings shed light on the essential role of the tyrosine pair in maintaining bicarbonate stability and facilitating efficient electron transfer in native PSII., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Tuberous sclerosis complex (TSC)-related skeletal abnormalities are understudied. Awareness of skull thickening in patients with TSC is important from the surgical standpoint because a thick skull might complicate craniotomy. This study aimed to discover if patients with TSC are generally prone to skull thickening by retrospectively investigating the frequency and characteristics of skull thickening in these patients., Methods: Patients with TSC ages 10 to 60 years who underwent magnetic resonance imaging in the neurosurgery, dermatology, or pediatrics clinic between 2010 and 2021 were identified. Two control groups were used for comparison: one with patients with unruptured intracranial aneurysms to serve as control without antiseizure medication exposure and one with non-TSC epilepsy as control with antiseizure medication exposure. In all patients, thickness of frontal, parietal, temporal, and occipital bones was measured at a fixed location of each bone on T2-weighted axial images., Results: Inclusion criteria were fulfilled by 29 patients. Frontal and temporal bones of the TSC group were significantly thicker than those of either control group. Skull thickening was significantly associated with intracerebral calcification, but not with age, sex, or antiseizure medication exposure. Focal skull thickening was associated with the presence of a subcortical calcification., Conclusions: Patients with TSC have skull thickening, which is often linked to intracerebral calcification. The presence of skull thickening may require modification of surgical approach during craniotomy. Skull thickening and the underlying intracerebral calcification likely share a common precipitating factor given their relationship. Future studies are warranted to clarify the genetic underpinnings of this relationship and even broader skeletal abnormalities in TSC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nocardiosis in patients after allogeneic hematopoietic stem cell transplantation (HSCT) is rare, but is associated with a significant mortality risk. Although trimethoprim-sulfamethoxazole (TMP/SMX) remains the cornerstone of nocardiosis treatment, optimal alternative therapies for patients intolerant to TMP/SMX are not well-established. Herein, we report a case of disseminated nocardiosis with bacteremia and multiple lesions in the lungs and brain caused by Nocardia farcinica, in a 60-year-old man who had previously undergone allogeneic HSCT and was receiving immunosuppressants for severe chronic graft-versus-host disease. The patient received atovaquone for the prophylaxis of Pneumocystis pneumonia because of a previous serious allergic reaction to TMP/SMX. The patient was initially treated with imipenem/cilastatin and amikacin, which were later switched to ceftriaxone and amikacin based on the results of antimicrobial susceptibility testing. After switching to oral levofloxacin and a standard dose of minocycline, the patient experienced a single recurrence of brain abscesses. However, after switching to oral moxifloxacin and high-dose minocycline, the patient did not experience any relapses during the subsequent two years and seven months of treatment. In treating nocardiosis with brain abscesses, it is crucial to select oral antibiotics based on the antimicrobial susceptibility test results and pharmacokinetics, especially when TMP/SMX is contraindicated. A combination of oral moxifloxacin and high-dose minocycline could be a promising alternative therapy., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Burkholderia cepacia complex (BCC) encompasses opportunistic pathogen with various clinical manifestations ranging from no symptoms to severe respiratory infections and septicemia. Central nervous system infections caused by BCC are rare. To the best of our knowledge, we present the first reported case of choroid plexitis caused by BCC after severe COVID-19. A 67-year-old woman who had been previously diagnosed with COVID-19 presented with a mild fever and headache. Gadolinium-enhanced T1-weighted brain magnetic resonance imaging showed contrast effects in the right choroid plexus and encapsulated abscess. Gram staining of cerebrospinal fluid revealed the presence of gram-negative rods. Broad-range polymerase chain reaction amplification of 16S ribosomal RNA from the cerebrospinal fluid, followed by sequence analysis, identified BCC; thus, choroid plexitis caused by BCC was diagnosed. After prolonged antimicrobial treatment with a multiantibiotic regimen, the patient recovered completely. This case highlights the importance of long-term therapy with a carefully selected multiantibiotic regimen to achieve complete recovery after BCC infection., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Few reports have analyzed the fusion genes involved in carcinogenesis in the oropharynx, where the incidence of human papillomavirus-associated tumors is relatively low. The aim of this study was to identify novel driver fusion genes in patients with oropharyngeal cancer. The study enrolled fifty-seven patients who were diagnosed with oropharyngeal carcinoma. RNA sequencing data from fresh-frozen specimens were used to identify candidate fusion genes via the JAFFA, arriba, and STAR-Fusion pipelines. Candidate fusion genes were confirmed by direct sequencing. The expression level of a candidate fusion gene was compared to that of tumors without fusion genes. Finally, filtering was performed for driver genes using the annoFuse pipeline. In addition, the VIRTUS pipeline was used to analyze the presence of human papillomavirus in the tumors. We identified 5 (8.8 %) novel potential driver in-frame fusion genes, MKNK2::MOB3A, ICMT::RPS6KA3, ATP1B3::GRK7, CSNK2A1::KIF16B, and FGFR3::MAEA, and 1 (1.8 %) known in-frame fusion gene, FGFR3::TACC3, in 57 patients with pharyngeal carcinoma. Our results suggest that sporadic fusion genes may contribute to tumorigenesis in oropharyngeal carcinomas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katsuhiro Masago reports was provided by Aichi Cancer Center.

Introduction: During the epidemic of the Omicron variant of SARS-CoV-2, nosocomial transmissions from healthcare workers (HCWs) to patients occur frequently. The influence of COVID-19 on hospitalized patients from nursing schools affiliated with the hospitals is a concern but it had not been well studied., Methods: We here describe COVID-19 outbreaks at the nursery school affiliated with an acute-care hospital, during the surges of the Omicron variants on the transmission of SARS-CoV-2 children as well as for the patients who were judged to be the close contacts of patients of COVID-19 by contact investigation by PCR testing., Results: A total of 36 children and five caregivers were diagnosed with COVID-19 during the study period. Of the 206 preschoolers who had close contact with the infected persons, only 16 became positive (7.6%). Secondary transmission from the 36 preschool children to the parents as HCWs occurred in 19 (61%) out of 31 parents. Three hospitalized patients were judged to have unsafe contact with the infected HCWs but this did not result in their infections, making a total of zero transmission from the nursery school to the hospital., Conclusions: Children at the nursery school are potential reservoirs for nosocomial transmissions at the affiliated hospital, but multiple practical measures might have prevented them to occur., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Although segmentectomy is a widely used surgical procedure, lobectomy is the standard procedure for resectable non-small-cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of segmentectomy for NSCLC up to 3 cm in size, including ground-glass opacity (GGO) and predominant GGO., Methods: A multicentre, single-arm, confirmatory phase 3 trial was conducted across 42 institutions (hospitals, university hospitals, and cancer centres) in Japan. Segmentectomy with hilar, interlobar, and intrapulmonary lymph node dissection was performed as protocol surgery for patients with a tumour diameter of up to 3 cm, including GGO and dominant GGO. Eligible patients were those aged 20-79 years with an Eastern Cooperative Oncology Group performance score of 0 or 1 and clinical stage IA tumour confirmed by thin-sliced CT. The primary endpoint was 5-year relapse-free survival (RFS). This study is registered with the University Hospital Medical Information Network Clinical Trials (UMIN000011819), and is ongoing., Findings: A total of 396 patients were registered from Sept 20, 2013, to Nov 13, 2015, of whom 357 underwent segmentectomy. At a median follow-up of 5·4 years (IQR 5·0-6·0), the 5-year RFS was 98·0% (95% CI 95·9-99·1). This finding exceeded the 87% of the pre-set threshold 5-year RFS and the primary endpoint was met. Grade 3 or 4 early postoperative complications occurred in seven patients (2%), but no grade 5 treatment-related deaths occurred., Interpretation: Segmentectomy should be considered as part of standard treatment for patients with predominantly GGO NSCLC with a tumour size of 3 cm or less in diameter, including GGO even if it exceeds 2 cm., Funding: National Cancer Centre Research and Development Fund and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests KA, AH, HI, TK, HK, TMiy, RN, YO, MO, JO, YT, and SW report research funding from the National Cancer Center Research and Development Fund by the National Cancer Center and Practical Research for Innovative Cancer Control Fund by Japan Agency for Medical Research and Development. HF reports lecture fees from Chugai Pharmaceuticals, outside of the submitted work. MW reports honoraria from Nihon Medi-Physics outside of the submitted work. MTs reports research funding from Boehringer-Ingelheim Japan and commissioned research for clinical trials from MSD, Astrazeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Eli Lilly Japan, Novartis, and BMG; lecture fees from Johnson & Johnson Japan, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, MSD, Bristol-Myers Squibb, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical, Daiichi-Sankyo, and Novartis, outside of the submitted work; is on the advisory board of AstraZeneca, Chugai Pharmaceutical, MSD, Novartis, and Eli Lilly, outside of the submitted work; and also is on the committee of Japan Lung Cancer Society and Japanese Association of Chest Surgery, Cancer Net Japan, Japanese Organization for Research, and Treatment of Cancer, outside of the submitted work. TMim reports research funding from the Japan Society for the Promotion of Science KAKENHI (grant number 20K09177) by the Japan Society for Promotion of Science, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: At craniotomy, the dura shrinks due to the drying effect of illumination and air exposure, rendering its primary closure difficult. When the opening is narrow, it can be patched with autologous grafts. However, tissue harvesting and meticulous suturing take time. As the cost-effectiveness of using dural substitutes is poor, we developed a new technique that involves dural scratching for the primary closure of dural openings., Methods: We applied our technique because in 53 adults who underwent supratentorial craniotomy we encountered difficulties with the primary closure of a dural opening 5 mm or less in width. With a scalpel, we placed several fine scratches parallel to the edge of the opening on the surface of the dura, taking care not to perforate the deep layer. This relieved dural tension and the tissue was stretched enough to permit closing with sutures., Results: Our technique achieved primary dural closure in 46 of 53 patients (87%) who primarily had undergone narrow supratentorial craniotomies. The other 7 additionally required small autologous grafts to patch narrow residual openings at the intersection of the durotomy. There were no procedure-related complications such as cerebrospinal fluid leakage and persistent headache due to tension of the closed dura., Conclusions: Dural scratching is simple, safe, requires no special instrumentation, facilitates primary closure of the shrunken dura by stretching, and reduces the need for patch grafting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The distribution of floating plastic debris around the Kuroshio Current which transports plastics from the coastal waters of Asian countries to North Pacific subtropical gyre, was investigated in 2014. The mean abundance and weight of plastic debris on the sea surface were 100,376 counts/km 2 and 446.16 g/km 2 , respectively. Intensive plastic accumulation was observed in the frontal area between the northern edge of the Kuroshio and coastal waters off Shikoku, while a relatively higher abundance in the south of Kuroshio was generally associated with anticyclonic mesoscale eddies. Such an accumulation resulted from the eddy-Kuroshio interactions which are specifically associated with the offshore non-large meandering Kuroshio path. Overall, white, fragmented, small-sized (≤1 mm) particles with polyethylene and polypropylene polymers were dominant. In the southern area of Kuroshio, the contribution of polystyrene and larger-sized plastic was higher, suggesting a rapid influx of fresh particles from western Japan to offshore by the northwest monsoon., Competing Interests: Declaration of competing interest The authors declare no competing interests regarding the work described in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The emergence of the Alpha variant of novel coronavirus 2019 (SARS-CoV-2) is a concerning issue but their clinical implications have not been investigated fully., Methods: We conducted a nested case-control study to compare severity and mortality caused by the Alpha variant (B.1.1.7) with the one caused by the wild type as a control from December 2020 to March 2021, using whole-genome sequencing. 28-day mortality and other clinically important outcomes were evaluated., Results: Infections caused by the Alpha variant were associated with an increase in the use of oxygen (43.4% vs 26.3%. p = 0.017), high flow nasal cannula (21.2% vs 4.0%, p = 0.0007), mechanical ventilation (16.2% vs 6.1%, p = 0.049), ICU care (30.3% vs 14.1%, p = 0.01) and the length of hospital stay (17 vs 10 days, p = 0.031). More patients with the Alpha variant received medications such as dexamethasone. However, the duration of each modality did not differ between the 2 groups. Likewise, there was no difference in 28-day mortality between the 2 groups (12% vs 8%, p = 0.48), even after multiple sensitivity analyses, including propensity score analysis., Conclusion: The Alpha variant was associated with a severe form of COVID-19, compared with the non-Alpha wild type, but might not be associated with higher mortality., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered a potential conflict of interest., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Preoperative identification of the carotid bifurcation (CB) location and plaque and stenosis distal end of the cervical internal carotid artery in relation to bony structures is essential for carotid endarterectomy (CEA). However, for patients with contrast contraindications, cervical 3-dimensional computed tomography angiography (3D-CTA) is unavailable. In this study, we created fusion images of magnetic resonance angiography (MRA), black-blood (BB) magnetic resonance imaging (MRI), and CT to determine if these noncontrast agent images are superior to 3D-CTA for preoperative CEA planning., Methods: The fusion images showed vascular structures obtained by MRA, plaque observed by BB-MRI, and bone structures shown by CT. Spatial localization accuracy was verified by directly overlaying contrast-enhanced 3D-CTA images on the fusion images. We validated this technique in 50 patients with unilateral ICA stenosis, 28 of whom underwent CEA. The 2D-distance CB MRA-CTA (the 2D distance difference between CB MRA and CB CTA perpendicular to the long axis of the carotid artery) was measured. We also compared the findings of the fusion image regarding the CB location and plaque distal end with the operative findings., Results: The median 2D distance CB MRA-CTA was 1 mm. CB MRA was located distal and proximal to CB CTA in 21and 29 patients, respectively. The CB location and fusion-image plaque were consistent with the intraoperative findings in all CEA patients., Conclusions: Fusion images created from MRA, BB-MRI, and noncontrast CT were feasible as an alternative to 3D-CTA for patients with contrast contraindications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: This study assessed the clinicopathological background of early-stage KRAS-mutated non-small-cell lung cancer and analyzed the biological process of KRAS-mutated tumor using an RNA sequencing procedure., Patients and Methods: We used a cohort of consecutive series of 179 surgically resected early-stage non-small-cell lung cancers harboring KRAS mutations and analyzed the clinicopathological features, including the KRAS genotypes, affecting the recurrence-free survival and prognosis. Consequently, we performed RNA sequencing to determine the gene expression profiles of nineteen KRAS-mutated non-small-cell cancers., Results: The most common KRAS genotype was p.G12C (57; 31.8%). A high p-stage (hazard ratio [HR], 4.181; P < 0.0001) and solid predominant adenocarcinoma histology (HR, 2.343; P = 0.0076) were significant independent prognostic factors for the recurrence-free survival. A high p-stage (HR, 3.793; P < 0.0001), solid predominant adenocarcinoma histology (HR, 2.373; P = 0.0147), and KRAS p.G12V genotype (HR, 1.975; P = 0.0407) were significant independent prognostic factors for the overall survival. A gene expression analysis of the two factors revealed the p.G12V genotype to be closer to those of stem cells, and the traits of e an enhanced fatty acid and amino acid metabolism. as well as And a solid predominant phenotype were shown to an acquired a trait that can withstand hypoxia and the effect of prostaglandin-endoperoxide synthase., Conclusion: The KRAS p.G12V genotype and solid predominant adenocarcinoma phenotype may be independent predictive factors of a poor clinical course in resected early-stage non-small-cell lung cancers, possibly due to the differentiation tendency observed in stem cells, the trait of an enhanced fatty acid and amino acid metabolism, and the effect of prostaglandin-endoperoxide synthase., (Copyright © 2022. Published by Elsevier Inc.)

Concurrent EGFR mutation and ROS1 rearrangement is a rare event in early-stage non-small-cell lung cancer. In addition, a co-occurring de novo EGFR T790M mutation in such a case is extremely rare. We encountered a 72-year-old woman who developed 3 early-stage lung lesions synchronously, one each harboring EGFR L858R, ROS1 rearrangement, and EGFR L858R and de novo T790M. These three nodules were pathologically time-matched lepidic predominant adenocarcinoma with small invasive lesions, which may reflect the concept of field cancerization with driver mutations., (Copyright © 2022. Published by Elsevier Inc.)

Estimating the elapsed time after death of a corpse immersed in freshwater is often challenging owing to body temperature changes and the degree of postmortem lividity, and the tissues used for this assessment deteriorate drastically as the postmortem period progresses. In this study, assuming a corpse was immersed in freshwater, we analyzed changes in the amount of deposits on the enamel surface of teeth since the time of immersion using an electron probe microanalyzer. We calculated a regression equation for estimating the time of immersion in water (the time after death). We considered this approach would be useful to estimate the time after death even in rotting and skeletonized corpses from which only limited information could be obtained. This study was undertaken according to a previously reported method that used a regression equation for estimating the time after death of bodies found in a seawater area., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Background: Despite holding soft tissue away from high-speed drills during surgery, tissue can unexpectedly wrap around the drill shaft. We performed experiments to examine what precipitates such mishaps., Methods: In a windless environment, a Signature Drill System (Stryker) featuring a 4-mm diameter coarse diamond or cutting bit was placed parallel to a suspended strip of polypropylene. The distance between the end of the strip and the drill shaft or bits was 4 or 8 mm. In another experiment, we placed the drill horizontally 10 mm above the top of dry-ice fog. The maximum drill speed was 75,000 rpm, and the horizontal motion of the polypropylene strip and the vertical motion of the dry-ice fog were recorded by a video camera., Results: In the experiments, the strip parallel to the vertical shaft and the dry-ice fog were pulled toward the shaft; the higher the revolving drill speed, the faster its motion. On the other hand, in experiments where the end of the strip was next to either bit, no such motion was observed., Conclusions: The pulling force generated by revolving high-speed drill shafts may result in tissue wraparound even when soft tissue is held away from the shaft., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation., Methods: We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer., Results: One patient (6.2%) had a BRAF p.V600E and p.K601&#95;W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect., Conclusions: The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Chronic subdural hematomas (CSDHs) with narrow or multilayered hematomas must be accurately localized for burr hole drainage. We present a simple alternative localization method using conventional computed tomography (CT) scans acquired for the initial diagnosis and a commercially available carpenter's square (CS)., Methods: Using our novel method, we localized 77 narrow or multilayered CSDHs. A single burr hole site on the thickest portion of narrow hematomas or on the site allowing access to both the isolated superficial layer and the deep layer of multilayered hematomas was identified on axial CT images; the image was parallel to the orbitomeatal line (OML). On the target CT slice, the level from the OML and from the surface of the forehead to the intended burr hole (sagittal distance) was measured. The OML and the level of the CT target slice were marked using the CS. Then, the CS was placed at the marked target level; the 2 edges of the CS were situated on the frontal and temporal scalp and parallel to the OML and the sagittal line. The sagittal distance was then marked., Results: All burr holes reached the CSDHs. The mean deviation of the burr holes was 4.7 mm inferior and 1.4 mm anterior to the intended site. In 65 instances (84.4%), a deviation within 10 mm was observed in both the superoinferior and the anteroposterior directions., Conclusions: Our simple and inexpensive method can localize narrow or multilayered CSDHs with acceptable accuracy and increases the efficiency of routine clinical work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Adoptive cancer immunotherapy can induce objective clinical efficacy in patients with advanced cancer; however, a sustained response is achieved in a minority of cases. The persistence of infused T cells is an essential determinant of a durable therapeutic response. Antitumor T cells undergo a genome-wide remodeling of the epigenetic architecture upon repeated antigen encounters, which inevitably induces progressive T-cell differentiation and the loss of longevity. In this study, we identified PR domain zinc finger protein 1 (PRDM1) ie, Blimp-1, as a key epigenetic gene associated with terminal T-cell differentiation. The genetic knockout of PRDM1 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) supported the maintenance of an early memory phenotype and polyfunctional cytokine secretion in repeatedly stimulated chimeric antigen receptor (CAR)-engineered T cells. PRDM1 disruption promoted the expansion of less differentiated memory CAR-T cells in vivo, which enhanced T-cell persistence and improved therapeutic efficacy in multiple tumor models. Mechanistically, PRDM1-ablated T cells displayed enhanced chromatin accessibility of the genes that regulate memory formation, thereby leading to the acquisition of gene expression profiles representative of early memory T cells. PRDM1 knockout also facilitated maintaining an early memory phenotype and cytokine polyfunctionality in T-cell receptor-engineered T cells as well as tumor-infiltrating lymphocytes. In other words, targeting PRDM1 enabled the generation of superior antitumor T cells, which is potentially applicable to a wide range of adoptive cancer immunotherapies., (© 2022 by The American Society of Hematology.)

Background: Histologic subtyping offers some prognostic value in lung adenocarcinoma. We thus hypothesized that histologic subtypes may be useful for risk stratification of brain metastasis (BM). In this study, we aimed to investigate the impact of histologic subtypes on the risk for BM in patients with resected lung adenocarcinoma., Patients and Methods: Of 1099 consecutive patients who had undergone curative-intent surgery (2000-2014), 448 patients who had undergone complete resection for lung adenocarcinoma were included in this study. Correlated clinical variables and BM-free survival were analyzed., Results: Micropapillary predominance was significantly associated with higher risk of BM after complete resection in univariate analyses (P < .001). In addition, multivariate analyses showed that micropapillary predominance was an independent risk factor for BM (hazard ratio = 2.727; 95% confidence interval, 1.260-5.900; P = .011), along with younger age and advanced pathologic stage. Unlike the other subtypes, an increase in the percentage of the micropapillary subtype was positively correlated with an increase in BM frequency. Patients with micropapillary adenocarcinoma showed significantly poorer brain metastasis-free survival compared with those with non-micropapillary adenocarcinoma (3 years, 78.2% vs. 95.6%; 5 years, 67.3% vs. 94.3%; P < .001)., Conclusion: The current study demonstrated a significant correlation between micropapillary subtype and higher risk of BM in patients with resected lung adenocarcinoma. This routine histologic evaluation of resected adenocarcinoma may provide useful information for the clinician when considering postoperative management in patients with lung adenocarcinoma. Histologic subtyping offer some prognostic value in lung adenocarcinoma. Because brain metastasis is critical and often refractory to systemic chemotherapy, early detection is clinically important to achieve effective local treatment. We retrospectively analyzed the association between histologic subtypes and occurrence of brain metastasis and found a significant association between micropapillary predominance and higher risk for brain metastasis. Our findings may be relevant when considering postoperative management., (Copyright © 2021. Published by Elsevier Inc.)

Background: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive lung adenocarcinoma. However, the clinical course and prognostic outcomes following IMA resection, particularly postoperative recurrence, remain unclear., Methods: We pathologically reevaluated 1362 lung adenocarcinoma resections performed at our institution, categorizing cases into the IMA group (72 cases) and non-IMA group (1290 cases). The IMA group was further classified into pneumonia and nodular types based on preoperative computed tomography., Results: Overall, the IMA group had lower carcinoembryonic antigen levels (3 vs 8 ng/mL; P < .01), fewer lymph node metastasis (4% vs 24%; P < .01), and more KRAS mutations (56% vs 7%; P < .01) than the non-IMA group. Although postoperative recurrence rates did not differ between both groups (32% vs 27%; P = 0.35), lung recurrence occurred more frequently in the IMA group (83% vs 17%; P < .01). Propensity score-matched pair analysis showed that the IMA group had fewer lymph node metastasis (3% vs 35%; P < .01), more KRAS mutations (56% vs 9%; P < .01), and higher intrapulmonary recurrence rate (84% vs 31%; P < .01) than the non-IMA group. The 5-year overall survival rates did not differ between both groups (74% vs 81%; P = 0.26). However, among patients with intrapulmonary recurrence, those in the IMA group had significantly worse prognosis than those in the non-IMA group (35% vs 77%; P < .01)., Conclusions: Intrapulmonary recurrence, which induced significantly worse prognosis, was more likely to occur in the IMA than non-IMA group., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Temperature is generally considered to be the primary factor controlling the nitrogen removal rate (NR) in nitrate (NO 3 - )-rich submerged sediments. Temperature stimulates both sediment oxygen (O 2 ) respiration, to create anaerobic conditions, and microbial photosynthetic activity, to provide the organic carbon required for denitrification and expand the uppermost aerobic layer, i.e., the O 2 penetration depth (OPD). The OPD serves as a diffusion barrier for NO 3 - to the underlying anaerobic layer for denitrification. The complex effects of O 2 and temperature on the NR are unclear under field conditions with a wide range of temperatures and O 2 suppliers. This study aimed to determine the combined effects of O 2 and temperature on the NR in an NO 3 - -rich, riparian ex-paddy wetland ("yatsu" environment) under long-term bare soil conditions. We used three years of field monitoring with occasional O 2 microprofile measurements from undisturbed submerged soil cores. We observed vertical supersaturated O 2 concentration plateaus up to 4.2 mm depth, which confirmed the presence of underground O 2 producers, i.e., photosynthetic microorganisms forming habitat in the soil, and very large OPDs of up to 42.9 mm. A multiple regression analysis showed that temperature and dissolved O 2 concentration in the flooded water were the key positive and negative influences, respectively, on the NR (332 kg N ha -1  year -1 on average), in association with the total N input. Microbial photosynthesis appeared to remain active regardless of the season, providing O 2 to increase OPD and partly suppress the NR; however, photosynthesis has increased the soil C content and appears to have positively contributed to a sustained NR during the 20 years of bare soil conditions. Our results suggest that temporal no vegetation-shade (bare soil) conditions with periodic weed cutting is recommended to effectively remove N from the watershed, while maintaining high temperatures and soil organic C in yatsu environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We report a structure-based biological approach to identify the proton-transfer pathway in photosystem II. First, molecular dynamics (MD) simulations were conducted to analyze the H-bond network that may serve as a Grotthuss-like proton conduit. MD simulations show that D1-Asp61, the H-bond acceptor of H 2 O at the Mn 4 CaO 5 cluster (W1), forms an H-bond via one water molecule with D1-Glu65 but not with D2-Glu312. Then, D1-Asp61, D1-Glu65, D2-Glu312, and the adjacent residues, D1-Arg334, D2-Glu302, and D2-Glu323, were thoroughly mutated to the other 19 residues, i.e., 114 Chlamydomonas chloroplast mutant cells were generated. Mutation of D1-Asp61 was most crucial. Only the D61E and D61C cells grew photoautotrophically and exhibit O 2 -evolving activity. Mutations of D2-Glu312 were less crucial to photosynthetic growth than mutations of D1-Glu65. Quantum mechanical/molecular mechanical calculations indicated that in the PSII crystal structure, the proton is predominantly localized at D1-Glu65 along the H-bond with D2-Glu312, i.e., pK a (D1-Glu65) > pK a (D2-Glu312). The potential-energy profile shows that the release of the proton from D1-Glu65 leads to the formation of the two short H-bonds between D1-Asp61 and D1-Glu65, which facilitates downhill proton transfer along the Grotthuss-like proton conduit in the S 2 to S 3 transition. It seems possible that D1-Glu65 is involved in the dominant pathway that proceeds from W1 via D1-Asp61 toward the thylakoid lumen, whereas D2-Glu312 and D1-Arg334 may be involved in alternative pathways in some mutants., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The number of patients with a history of clipping of recurrent aneurysms after coil embolization has increased. The aim of this article was to report the feasibility of CT angiography using a commercial metal artifact reduction algorithm (Smart Metal Artifact Reduction [MAR]) for patients who underwent clipping of recurrent aneurysms after coil embolization., Methods: Six cases of clipping of recurrent aneurysms after coil embolization were examined with CT angiography using MAR between 2015 and 2018 at a single institution. Conventional CT angiography and three-dimensional digital subtraction angiography data were compared, and depiction of the status of treated aneurysms using MAR was estimated., Results: Conventional CT angiography was unable to depict the status of treated aneurysms in the patients with a history of clipping of recurrent aneurysms after coil embolization because of metal artifacts. With MAR, metal artifacts were greatly reduced, and the status of treated aneurysms was able to be depicted, although depiction was inferior to three-dimensional digital subtraction angiography., Conclusions: For patients with a history of clipping of recurrent aneurysms after coil embolization, CT angiography using MAR is feasible, although further development of imaging techniques is needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Thrombosed cerebral aneurysm (TCA) can cause cerebral infarction. However, treatment of cerebral infarction due to embolism from TCA is controversial because of the risk of rupture, and no consensus has been established for the treatment of patients with this condition., Case Description: A 75-year-old woman suffered left hemiparesis. Computed tomography (CT) showed a high-density round mass in the right sylvian fissure, which was suspected to be a nonruptured TCA. Magnetic resonance (MR) angiography and CT angiography demonstrated an aneurysm in the distal part of the right middle cerebral artery with poor opacification of most of the aneurysm, suggesting partial thrombosis. Diffusion-weighted MR imaging revealed high intensity in the right frontal lobe, in a distribution distal to the aneurysm. The diagnosis was cerebral infarction due to embolism from a partially thrombosed aneurysm. She was treated with antithrombotic therapy. On day 4, she suddenly became comatose. CT and CT angiography revealed subarachnoid hemorrhage (SAH) and enlarged opacification in the aneurysm, respectively. She underwent neck clipping of the aneurysm, but her neurologic improvement was poor. TCA causing ischemic stroke followed by SAH is extremely rare, with only 4 previous reported cases. All patients had received antithrombotic therapies, and most aneurysms had ruptured within a few days after starting antithrombotic therapy. The outcomes were extremely poor., Conclusions: We suggest that antithrombotic therapy might be avoided for these patients. Early surgical treatment without antithrombotic therapy is recommended to prevent aneurysm rupture and recurrent distal embolism from the TCA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In recent years, blooms of toxic Alexandrium ostenfeldii strains have been reported from around the world. In 2013, the species formed a red tide in a shallow lagoon in western Japan, which was the first report of the species in the area. To investigate the genetic relatedness of Japanese A. ostenfeldii and global isolates, the full-length SSU, ITS and LSU sequences were determined, and phylogenetic analyses were conducted for isolates from western and northern Japan and from the Baltic Sea. Genotyping and microsatellite sequence comparison were performed to estimate the divergence and connectivity between the populations from western Japan and the Baltic Sea. In all phylogenetic analyses, the isolates from western Japan grouped together with global isolates from shallow and low saline areas, such as the Baltic Sea, estuaries on the east coast of U.S.A. and from the Bohai Sea, China. In contrast, the isolates from northern Japan formed a well-supported separate group in the ITS and LSU phylogenies, indicating differentiation between the Japanese populations. This was further supported by the notable differentiation between the sequences of western and northern Japanese isolates, whereas the lowest differentiation was found between the western Japanese and Chinese isolates. Microsatellite genotyping revealed low genetic diversity in the western Japanese population, possibly explained by a recent introduction to the lagoon from where it was detected. The red tide recorded in the shallow lagoon followed notable changes in the salinity of the waterbody and phytoplankton composition, potentially facilitating the bloom of A. ostenfeldii., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Liposarcoma of the uterine corpus is extremely rare. We performed a laparotomy on a 55-year-old woman with the complaints of abdominal distension and genital bleeding who was found to have a uterine tumor, 17 × 16 cm in diameter. The preoperative diagnosis was a lipoma or lipoleiomyoma of the uterine corpus. However, pathological examination revealed proliferation of mature adipocytes and lipoblast-like atypical cells with small, weakly pleomorphic nuclei and foamy or vacuolated cytoplasm present within a fibrous septum. Immunohistochemistry showed that the tumor cells were focally positive for mouse double minute 2 homolog (MDM2). The final pathological diagnosis was a well-differentiated liposarcoma of International Federation of Gynecology and Obstetrics (FIGO) stage IB (pT1bNxM0). On magnetic resonance imaging (MRI), T1 -weighted and fat-saturated images showed high and low intensity in the tumor, respectively, suggesting that this tumor contained a fat component. The septum inside the tumor had a contrast enhancement on T1-weighted, gadolinium-enhanced imaging. The septum was nonuniformly thickened and partially nodular. In hindsight, these findings may have suggested a well-differentiated liposarcoma in the uterine corpus rather than a lipoma or lipoleiomyoma. Clinicians should be aware of the possibility of a liposarcoma of the uterine corpus when a neoplasm contains adipose tissue and a nonuniformly thickened or partially nodular septum on MRI.

Background: Electromagnetic (EM) navigation has been reported to be a noninvasive and easy-to-use technique. However, the use of metal neurosurgical instruments (e.g., skin hooks, head frames, brain retractors systems) can interfere with the magnetic fields of such systems. We present the freehand technique, a new technique involving the manual manipulation of the emitter of an EM navigation system, which helps to prevent interference caused by metal instruments during surgery., Methods: The AxiEM Electromagnetic StealthStation Navigation System (Medtronic) was used in this study. The emitter was placed in the sterilized surgical field, which allowed it to be moved freely during surgery. When navigation was necessary during the procedure, the assistant held the emitter at an appropriate angle to the sterile surgical field to avoid interference caused by the metal neurosurgical instruments., Results: During surgery involving metal surgical instruments, all of the functions of the EM navigation system were available throughout the procedure. The accuracy of the navigation system was sufficient to allow craniotomy and intradural manipulation to be conducted., Conclusions: During the use of EM navigation systems, the freehand technique with the emitter can prevent interference caused by metal instruments., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Emergence of the T790M point mutation in exon 20 of the epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of this study was to investigate the association between T790M mutation status and the progression patterns during EGFR-TKI treatment., Methods: We reviewed 181 patients with advanced non-small-cell lung cancer harboring EGFR mutation, who were evaluated for T790M mutation status after initial EGFR-TKI failure (gefitinib, erlotinib, or afatinib). We retrospectively investigated the patient characteristics, initial EGFR-TKI response, T790M mutation status, subsequent treatment after initial EGFR-TKIs, timing of re-biopsy, and progression patterns during the EGFR-TKI treatment., Results: After the resistance to the EGFR-TKIs, the T790M mutation was identified in 87 (48%) of 181 patients. Seventy-three (40%) patients had solitary lesion progression, and 108 (60%) had multiple lesion progression during the initial EGFR-TKI treatment. The prevalence of the T790M mutation was significantly greater in patients with solitary lesion progression than those with multiple lesion progression (58% vs. 24%; P < .0001). The overall response rate and progression-free survival on initial EGFR-TKIs were significantly better in patients who acquired T790M after failure of EGFR-TKIs than those without T790M (overall response rate, 80% vs. 60%; P = .0033 and progression-free survival, 11.4 vs. 9.3 months; P = .0050). The multivariate analysis showed that gender, initial EGFR-TKI response, and progression patterns were significantly associated with T790M mutation status., Discussion: The progression patterns during initial EGFR-TKIs and initial EGFR-TKI response are associated with the T790M mutation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Approximately 60 cases of schwannoma unrelated to the cranial nerve have been reported, and only 12 arose from the tentorium. We present a case of tentorial schwannoma extending into the pons and midbrain without cranial nerve involvement, which was almost totally resected with an occipital transtentorial approach., Case Description: A 37-year-old man was admitted to our institution with memory disturbance beginning 2 years ago and gait disturbance from 1 year ago. Magnetic resonance imaging on admission revealed a heterogeneously enhanced 33 × 33 × 35 mm tumor in the pons and midbrain, and a dural tail sign connecting the lesion to the tentorial edge. Gross total resection of the tumor was performed with an occipital transtentorial approach. The trochlear nerve was identified and preserved, and the tumor did not involve this cranial nerve. The tumor was firmly attached to the edge of tentorium, and extended into the pons with sharp tumor border. Postoperative recovery was good, and brain magnetic resonance imaging performed 2 months after the surgical procedure revealed gross total removal of the lesion without signs of recurrence, but a slightly enhanced lesion in the right edge of the tentorium., Conclusions: The occipital transtentorial approach provides a direct approach to tentorial schwannoma, resulting in total resection even if the tumor extends into the pons and midbrain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C-C chemokine receptor 4, recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan., Materials and Methods: A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study., Results: Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35-86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3-4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non-HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21-53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III-IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively., Conclusion: Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre-HSCT mogamulizumab treatment regimen is thus a priority., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Proton magnetic resonance spectroscopy ((1)H-MRS) was recently used to examine altered metabolism in the white matter (WM) of patients experiencing carbon monoxide (CO) poisoning; however, only a small number of patients with delayed neurologic sequelae (DNS) were analyzed. We aimed to detect altered metabolism in the WM of patients with DNS using (1)H-MRS; to explore its clinical relevance in the management of patients experiencing CO poisoning. Patients experiencing acute CO poisoning underwent (1)H-MRS and cerebrospinal fluid (CSF) examination within 1week and at 1month after acute poisoning. Metabolites including choline-containing compounds (Cho), creatine (Cr), N-acetylaspartate (NAA), and lactate were measured from the periventricular WM. Myelin basic protein (MBP) concentrations were measured in CSF. Fifty-two patients experiencing acute CO poisoning (15 with DNS, 37 without DNS; median age, 49years; 65% males) underwent (1)H-MRS. Within 1week, NAA/Cr ratios, reflecting neuroaxonal viability, were lower in patients with DNS than in those without DNS (P<0.05). At 1month, when 9 of 15 patients (60%) developed DNS, Cho/Cr ratios were higher, and NAA/Cr and NAA/Cho ratios lower in patients with DNS (P=0.0001, <0.0001, and <0.0001, respectively), indicating increased membrane metabolism and decreased neuroaxonal viability. (1)H-MRS parameter abnormalities correlated with the elevation of MBP in CSF. The presence of a lactate peak was a predictor for a poor long-term outcome. (1)H-MRS within 1week may be useful for predicting DNS development; (1)H-MRS at 1month may be useful for discriminating patients with DNS and predicting long-term outcomes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Crystalline state of pharmaceutical materials is of great importance in preparation of pharmaceutics, because their physicochemical properties affect bioavailability, quality of products, therapeutic level and manufacturing process. In this study, we have estimated time-dependent changes of nifedipine in nifedipine-polyvinylpyrrolidone (PVP) solid dispersion by measuring terahertz time-domain spectroscopy (THz-TDS) and by X-ray powder diffractometry (XRPD), and compared their correlativity. Crystallinity of nifedipine-PVP solid dispersion was changed by storing the amorphous sample at 25°C-75°C and relative humidity of over 80% for 0.25-24.00 h. To compare the results of two types of measurements, we have used a general method of linear regression analysis. Crystallinities estimated using THz-TDS were plotted on the x-axis and that of XRPD were on the y-axis. From the result of the calculation, the correlativity of them was confirmed. THz-TDS has the capability of becoming the replacement of XRPD., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)