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Background: Frozen shoulder (FS) is a pathological condition that involves a painful and stiff shoulder joint, most commonly in people aged 40-60 years. Most literature supports treatment with physical therapy (PT), although some studies have demonstrated years of continuing pain and functional deficits. Manipulation under anesthesia is effective at eliminating the contracture of intra-articular lesions for refractory FS. This study aimed to compare whether manipulation under anesthesia or PT is a more effective treatment in refractory FS., Methods: This study was a prospective observational study. A total of 102 patients with refractory FS were enrolled in this study in the medical records, all of whom had severe and multidirectional loss of motion and thickening of the joint capsule and coracohumeral ligament on magnetic resonance imaging. Fifty-one patients were in the manipulation under brachial plexus block (MUB) group (34 females, median age: 57 years), and 51 patients were in the PT group (34 females, median age: 59 years). The MUB procedure consisted of the conventional method with additional adduction manipulation, in which one examiner initially abducted the shoulder joint as much as possible. We recorded the visual analog scale, shoulder range of motion, and American Shoulder and Elbow Surgeons and Constant Scores at the initial baseline visit and at the 1-, 3-, 6-, and 12-month follow-ups. The total cost was calculated from the medical records, and cost-effectiveness was evaluated using quality-adjusted life year and incremental cost-effectiveness ratio., Results: Visual analog scale ( P  < .001), range of motion ( P  < .001), and American Shoulder and Elbow Surgeons and Constant Scores ( P  < .001) in the MUB group were significantly superior to those in the PT group at 1, 3, 6, and 12 months after treatment. The median cost and total quality-adjusted life year in the MUB and PT groups were $1375 versus $2751 and 2.95 versus 2.68, respectively, and the cost-effectiveness ratio between the MUB and PT groups was calculated as -$560., Conclusions: The new MUB procedure provides a shorter treatment period, better clinical outcomes, and higher cost-effectiveness in patients with refractory FS compared to PT., (© 2023 The Author(s).)

Background: A frozen shoulder (FS) is characterized by pain and limited range of motion (ROM). Although physical assessment of ROM is important for diagnosing and staging FS, ROM cannot be accurately assessed in clinical practice because of pain and muscle contraction. This study aimed to measure changes in shoulder joint ROM before and after anesthesia (ΔROM) in patients with FS and investigate the factors affecting these changes., Methods: This study included 54 patients (age, 55.6 ± 9.4 years; 17 males; disease duration, 6.6 ± 3.4 months) with FS before manipulation under transmission anesthesia. FS was defined as having a ROM in external rotation (ER) that was less than 50% of that in the unaffected shoulder. Pain at night and during motion was assessed using a numerical rating scale. Before anesthesia, the passive ROM of forward flexion (FF), abduction (AD), and ER were measured in the supine position. After confirming that the anesthesia was effective, passive ROM was measured again., Results: The ROM in the FF, AD, and ER after anesthesia was significantly higher than that before anesthesia ( P  < .001). ΔROM in the FF, AD, and ER was significantly correlated with pain at night (r = 0.51, P  < .001; r = 0.45, P  < .001; and r = 0.39, P  = .004, respectively). Furthermore, ΔROM in the ER was significantly correlated with pain during motion (r = 0.31, P  = .023) and disease duration (r = -0.31, P  = .021)., Conclusion: The ROM of the FS is susceptible to pain and muscle contraction. Interventions, such as physical therapy, may be recommended after pain relief., (© 2023 The Author(s).)

Adult T-cell leukemia (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). Microsatellite instability (MSI) has been observed in ATL cells. Although MSI results from impaired mismatch repair (MMR) pathway, no null mutations in the genes encoding MMR factors are detectable in ATL cells. Thus, it is unclear whether or not impairment of MMR causes the MSI in ATL cells. HTLV-1 bZIP factor (HBZ) protein interacts with numerous host transcription factors and significantly contributes to disease pathogenesis and progression. Here we investigated the effect of HBZ on MMR in normal cells. The ectopic expression of HBZ in MMR-proficient cells induced MSI, and also suppressed the expression of several MMR factors. We then hypothesized that the HBZ compromises MMR by interfering with a transcription factor, nuclear respiratory factor 1 (NRF-1), and identified the consensus NRF-1 binding site at the promoter of the gene encoding MutS homologue 2 (MSH2), an essential MMR factor. The luciferase reporter assay revealed that NRF-1 overexpression enhanced MSH2 promoter activity, while co-expression of HBZ reversed this enhancement. These results supported the idea that HBZ suppresses the transcription of MSH2 by inhibiting NRF-1. Our data demonstrate that HBZ causes impaired MMR, and may imply a novel oncogenesis driven by HTLV-1., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masao Matsuoka reports a relationship with Kyowa Kirin Co Ltd that includes: speaking and lecture fees. Masao Matsuoka reports a relationship with Meiji Seika Pharma Co Ltd that includes: speaking and lecture fees. Masao Matsuoka reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Masao Matsuoka reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Akifumi Takaori-Kondo reports a relationship with Ono Pharmaceutical Co Ltd that includes: funding grants., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The safety of acoustic radiation force impulse (ARFI) elastography, which applies higher acoustic power with a longer pulse duration (PD) than conventional diagnostic ultrasound, is yet to be verified. We assessed the ARFI-induced lung injury risk and its relationship with peak rarefactional pressure amplitude (PRPA) and mechanical index (MI)., Methods: Eighteen and two rabbits were included in the ARFI (0.3-ms push pulses) and sham groups, respectively. A 5.2-MHz linear probe was applied to the subcostal area and aimed at both lungs through the liver for 30 ARFI emissions. The derated PRPA varied among the six ARFI groups-0.80 MPa, 1.13 MPa, 1.33 MPa, 1.70 MPa, 1.91 MPa, and 2.00 MPa, respectively., Results: The occurrence of lung hemorrhage and the mean lesion area among all samples in the seven groups were 0/6, 0/6, 1/6 (1.7 mm 2 ), 4/6 (8.0 mm 2 ), 4/6 (11.2 mm 2 ), 5/6 (23.8 mm 2 ), and 0/4 (sham), respectively. Logistic regression analysis showed that derated PRPA was significantly associated with lung injury occurrence (odds ratio: 207, p < 0.01), with the threshold estimated to be 1.1 MPa (MI, 0.5). Spearman's rank correlation showed a positive correlation between derated PRPA and lesion area (r = 0.671, p < 0.01)., Conclusion: This study demonstrated that the occurrence and severity of ARFI-induced lung hemorrhage increased with a rise in PRPA under clinical conditions in rabbits. This indicates a potential risk of lung injury due to ARFI elastography, especially when ARFI is unintentionally directed to the lungs during liver, heart, or breast examinations., (© 2023. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Background: The prognostic importance of osteopenia in patients with intrahepatic cholangiocarcinoma (ICC) undergoing hepatectomy is unclear. The aim of this study was to evaluate the impact of osteopenia on survival in patients with ICC., Methods: A total of 71 patients who underwent hepatectomy at Jichi Medical University between July 2008 and June 2022 were included in this study. Non-contrast computed tomography scan images at the eleventh thoracic vertebra were used to assess bone mineral density. The cutoff value was calculated using a threshold value of 160 Hounsfield units. Overall survival curves were made using the Kaplan-Meier method and the log-rank test was used to evaluate survival. The hazard ratio (HR) and 95% confidence interval (CI) for overall survival were calculated using Cox's proportional hazard model., Results: In multivariable analysis, osteopenia (HR 3.66, 95%CI 1.16-14.1, p = 0.0258) and the platelet-lymphocyte ratio (HR 6.26, 95%CI 2.27-15.9, p = 0.0008) were significant independent factors associated with overall survival. There were no significant independent prognostic factors for recurrence-free survival., Conclusions: Preoperative osteopenia is significantly associated with postoperative survival in patients with ICC undergoing hepatectomy.

Background: The role of various serum tumor markers (TMs) has been reported in non-small cell lung cancer (NSCLC). However, the prognosis of patients with multiple TM-negative NSCLC remain unclear., Aims: This study aimed to describe the characteristics and outcomes of patients with NSCLC undergoing surgery and to investigate their prognostic association with preoperative serum TM-negative cases., Methods and Results: We retrospectively evaluated 442 patients who underwent complete resection of stage I NSCLC between January 2004 and December 2019. These 442 patients were classified into a group whose preoperative serum levels of carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), carbohydrate antigen 19-9 (CA19-9), and squamous cell carcinoma antigen (SCC Ag) were all negative (TM-negative group; n = 249, 56%) and a group with at least one positive marker (TM-positive group; n = 193, 44%). Among all patients, the TM-negative group showed higher 5-year recurrence-free survival (RFS) (92.6% vs. 79.1%; p < .01), and overall survival (OS) rates (86.3% vs. 68.6%; p < .01). After propensity score matching, patients in the TM-negative group still exhibited good 5-year RFS (92.1% vs. 81.4%; p = .01) and OS rates (87.6% vs. 72.6%; p < .01)., Conclusion: Our study suggests that NSCLC patients who are preoperatively negative for all serum TMs, such as CEA, CYFRA21-1, CA19-9, and SCC Ag, represent a subgroup with a particularly good prognosis., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis., Competing Interests: Declaration of interests The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/purpose: Metal stents (MS) are recommended for preoperative biliary drainage (PBD) in patients with periampullary cancer, but whether MS are superior in terms of re-intervention and direct cost is debatable. This study aimed to compare the effects of MS and PS on the outcomes of patients with periampullary cancer., Methods: For this random-effects meta-analysis, electronic databases were screened for randomized controlled trials (RCTs) published until January 2022. Subgroup analyses were performed basis on the center type and presence of NAC., Results: In this meta-analysis, seven RCTs (440 participants) were included. MS reduced re-interventions (risk ratio [RR] = 0.42, 95% confidence interval [CI] = 0.25-0.72) and direct costs (mean difference = -474 USD, 95% CI = -656 to -292). PBD-related complications (RR = 0.74, 95% CI = 0.32-1.71) and postoperative complications (RR = 0.73, 95% CI = 0.45-1.17) did not differ between MS and PS. Compared PS, MS reduced postoperative complications in high-volume centers (RR = 0.64, 95% CI = 0.49-0.84) and PBD-related complications in patients receiving NAC (RR = 0.29, 95% CI = 0.08-1.08)., Conclusions: Metal stents likely reduces re-interventions and direct costs. Further studies are needed to confirm the effects of MS on the outcomes., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves the active catalysis of topoisomerase II (TOP2) at transcription regulatory sequences. TOP2 untangles DNAs by transiently generating double-strand breaks (DSBs), where TOP2 covalently binds to DSB ends. When TOP2 fails to rejoin, called "abortive" catalysis, the resulting DSBs are repaired by tyrosyl-DNA phosphodiesterase 2 (TDP2) and non-homologous end-joining (NHEJ). A steroid, cortisol, is the most important glucocorticoid, and dexamethasone (Dex), a synthetic glucocorticoid, is widely used for suppressing inflammation in clinics. We here revealed that clinically relevant concentrations of Dex and physiological concentrations of cortisol efficiently induce DSBs in G 1 phase cells deficient in TDP2 and NHEJ. The DSB induction depends on glucocorticoid receptor (GR) and TOP2. Considering the specific role of TDP2 in removing TOP2 adducts from DSB ends, induced DSBs most likely represent stalled TOP2-DSB complexes. Inhibition of RNA polymerase II suppressed the DSBs formation only modestly in the G 1 phase. We propose that cortisol and Dex frequently generate DSBs through the abortive catalysis of TOP2 at transcriptional regulatory sequences, including promoters or enhancers, where active TOP2 catalysis occurs during early transcriptional response., (© 2022 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background: Many non-small cell lung cancer (NSCLC) tumors present complex histology with various components. The effects of the lepidic growth component (LGC) on the prognosis of NSCLC have not been investigated. Here, we investigated whether an LGC is a relevant prognostic factor for NSCLC., Methods: This study retrospectively investigated the clinicopathologic characteristics of 379 patients with NSCLC ≤3 cm who underwent complete surgical resection between 2004 and 2016 at the University of Yamanashi Hospital. The histologic subtypes were classified into NSCLC with or without an LGC. We evaluated the effect of an LGC on the clinicopathologic features and 5-year overall survival of patients with NSCLC., Results: On final pathology, 214 (56%) of 379 patients had an LGC, and 165 (44%) did not. Sex, smoking history, ground-glass opacity component, pathologic invasive size, lymph node metastasis, pleural invasion, vessel invasion, pathologic stage, and histologic type were significantly different between the groups. Multivariate analysis of 5-year overall survival, identified age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.035-1.105; p < 0.001), pathologic invasive size (HR, 1.548; 95% CI, 1.088-2.202; p = 0.015) and LGC (HR, 2.11; 95% CI, 1.099-4.051; p = 0.025) as independent prognostic factors. When the pathologic invasive size was matched, the 5-year overall survival of the LGC and non-LGC groups was 93% and 77%, respectively (p = 0.006)., Conclusions: LGC is a significantly favorable prognostic factor for NSCLC with a pathologic invasive size of ≤3 cm., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

DNA-protein cross-links (DPCs) are generated by internal factors such as cellular aldehydes that are generated during normal metabolism and external factors such as environmental mutagens. A nucleoside analog, 5-aza-2'-deoxycytidine (5-azadC), is randomly incorporated into the genome during DNA replication and binds DNA methyltransferase 1 (DNMT1) covalently to form DNMT1-DPCs without inducing DNA strand breaks. Despite the recent progress in understanding the mechanisms of DPCs repair, how DNMT1-DPCs are repaired is unclear. The metalloprotease SPRTN has been considered as the primary enzyme to degrade protein components of DPCs to initiate the repair of DPCs. In this study, we showed that SPRTN-deficient ( SPRTN -/- ) human TK6 cells displayed high sensitivity to 5-azadC, and the removal of 5-azadC-induced DNMT1-DPCs was significantly slower in SPRTN -/- cells than that in wild-type cells. We also showed that the ubiquitination-dependent proteasomal degradation, which was independent of the SPRTN-mediated processing, was also involved in the repair of DNMT1-DPCs. Unexpectedly, we found that cells that are double deficient in tyrosyl DNA phosphodiesterase 1 and 2 ( TDP1 -/- TDP2 -/- ) were also sensitive to 5-azadC, although the removal of 5-azadC-induced DNMT1-DPCs was not compromised significantly. Furthermore, the 5-azadC treatment induced a marked accumulation of chromosomal breaks in SPRTN -/- as well as TDP1 -/- TDP2 -/- cells compared to wild-type cells, strongly suggesting that the 5-azadC-induced cell death was attributed to chromosomal DNMT1-DPCs. We conclude that SPRTN protects cells from 5-azadC-induced DNMT1-DPCs, and SPRTN may play a direct proteolytic role against DNMT1-DPCs and TDP1/TDP2 also contributes to suppress genome instability caused by 5-azadC in TK6 cells.

Background/purpose: Previous systematic reviews have shown that radical antegrade modular pancreatosplenectomy (RAMPS) had favorable outcomes including prognosis. However, recent large studies have shown opposite results, thus necessitating clarification of RAMPS efficacy. We aimed to update existing evidence on the clinical outcomes of RAMPS for left-sided pancreatic cancer by comparing them to those of the conventional approach., Methods: Electronic databases and registries were searched until August 2021 to perform random-effect meta-analysis. Methodological quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The protocol was registered at protocols.io (https://doi.org/10.17504/protocols.io.bxhfpj3n)., Results: Thirteen cohort studies (1641 patients) and four ongoing randomized controlled trials (RCTs) were identified. RAMPS increased disease-free survival (hazard ratio [HR] 0.62, 95% confidence interval [CI] = 0.42-0.91), but it had little effect on overall survival (HR 0.92, 95% CI = 0.79-1.09) and recurrence-free survival (HR 0.72, 95% CI = 0.37-1.38) with low certainty of evidence., Conclusion: The meta-analysis of recent studies suggests that RAMPS may have little effect on clinical outcomes. These findings highlight the necessity of further studies, including RCTs to determine the efficacy and subsequent indication of RAMPS in clinical cases., (© 2022 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Estimation of the functional reserve of the remnant liver is important to reduce morbidity and mortality., Aim: To estimate the functional reserve of the remnant liver in patients with hepatocellular carcinoma (HCC)., Methods: We reviewed the medical records of 199 patients who underwent resection of HCC. Hepatic clearance of the remnant liver was calculated using fusion images of 99m Tc-labelled galactosyl-human serum albumin liver scintigraphy and computed tomography. Posthepatectomy liver failure (PHLF) was classified according to the International Study Group of Liver Surgery. Complications was classified according to Clavien-Dindo classification. We analyzed by the risk factors for PHLF, morbidity and mortality with multivariate analysis., Results: Twenty-seven (30%) patients had major complications and 23 (12%) developed PHLF. The incidence of major complications increased with increasing albumin-bilirubin (ALBI) grade. The area under the curve values for hepatic clearance of the remnant liver, liver to heart-plus-liver radioactivity at 15 min (LHL15), and ALBI score predicting PHLF were 0.868, 0.629, and 0.655, respectively. The area under the curve for hepatic clearance of the remnant liver, LHL15, and ALBI score predicting major complications were 0.758, 0.594, and 0.647, respectively. The risk factors for PHLF and major complications were hepatic clearance of the remnant liver and intraoperative bleeding., Conclusion: The measurement of hepatic clearance may predict PHLF and major complications for patients undergoing resection of HCC., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest for this study., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Adhesive capsulitis (AC) is characterized by pain and limited range of motion, caused by stiffness of the joint capsule and coracohumeral ligament. On the other hand, there have been few reports on muscle stiffness in AC. The purpose of this study was to assess muscle stiffness in patients of AC with a portable and noninvasive device, Myoton PRO. We hypothesized that muscle stiffness around shoulder joint increases in AC., Methods: At first, we surveyed correlation between Myoton PRO and shear wave elastography with phantoms. Second, reproducibility and repeatability of healthy volunteers with Myoton PRO were evaluated. Finally, muscle stiffness was measured in 40 patients who were diagnosed with AC. Muscle stiffness was quantitatively measured with Myoton PRO. We compared the stiffness of the anterior deltoid (AD), pectoralis major, and latissimus dorsi (LD) in AC patients on both the affected and nonaffected sides., Results: Correlation coefficient in shear wave elastography and Myoton PRO was 0.99( P  = .001). Reliability of intraoperator and interoperator with Myoton PRO was 0.9 or higher. Muscle stiffness values (N/m) of the AD, pectoralis major, and LD were 355 ± 61, 252 ± 54, 207 ± 51 in the affected sides and 328 ± 50, 252 ± 41, 186 ± 37 in the nonaffected sides, and the differences were significant in the AD and LD ( P  = .005, P  = .002, respectively)., Conclusions: We used Myoton PRO to evaluate muscle stiffness in AC. The AD and LD muscles of AC patients were significantly stiffer on the affected side compared to the nonaffected side., (© 2022 The Authors.)

Acoustic radiation force impulse (ARFI) imaging and shear wave elastography use a "push pulse." The push pulse, which is referenced as an ARFI in this study, has a longer duration than that of conventional diagnostic pulses (several microseconds). Therefore, there are concerns regarding thermal safety in vivo. However, few in vivo studies have been conducted using living animals. In this study, to suggest a concept for deciding an ARFI output and cooling time while considering thermal safety, the liver (with and without an ultrasound contrast agent) and femur bone surface of living rabbits were exposed to an ARFI, and the maximum temperature rise, temperature rise for 5-min duration, and cooling time were measured via a thermocouple. While testing within the regulation limits of diagnostic ultrasound outputs, a maximum temperature rise on the femur bone surface exceeded the allowable temperature rise (1.5°C) in the British Medical Ultrasound Society (BMUS) statement. However, using the linear relationships between the pulse intensity integral (PII) of a single pulse and the above three temperature parameters, PII may be determined so that the maximum temperature rise is within the allowable temperature rise in the BMUS statement. The cooling time can be estimated from the PII., Competing Interests: Conflict of interest disclosure— The authors have no potential conflicts of interest to disclose., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Partial-thickness rotator cuff tears are commonly found in the articular-side tendon of the supraspinatus; however, isolated lesions, except those occurring in the supraspinatus tendons, are rare. We report three cases of isolated bursal-side infraspinatus tears that were difficult to detect by magnetic resonance imaging but could be visualized by computed tomography bursography., Case Presentation: Three Asian patients (59-71 years old) with shoulder pain ranging from 1 month to 3 years in duration were each diagnosed with shoulder impingement syndrome. Magnetic resonance imaging studies failed to show a tear of the rotator cuff tendon complex. However, computed tomography bursography showed a longitudinal infraspinatus partial-thickness tear on the bursal side in each case. Arthroscopic decompression of the subacromial space and debridement of the infraspinatus tendon tear successfully alleviated the shoulder pain in two of the three patients; the third patient did not undergo surgery and remained symptomatic at follow-up., Conclusions: In patients with chronic shoulder pain but normal magnetic resonance imaging findings, computed tomography bursography should be considered, as bursal-side infraspinatus tears may be found in these patients. Furthermore, our findings provide a basis for larger studies to further establish the accuracy of computed tomography bursography for these lesions., (© 2022. The Author(s).)

Base excision repair (BER) removes damaged bases by generating single-strand breaks (SSBs), gap-filling by DNA polymerase β (POLβ), and resealing SSBs. A base-damaging agent, methyl methanesulfonate (MMS) is widely used to study BER. BER increases cellular tolerance to MMS, anti-cancer base-damaging drugs, temozolomide, carmustine, and lomustine, and to clinical poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib. The poisons stabilize PARP1/SSB complexes, inhibiting access of BER factors to SSBs. PARP1 and XRCC1 collaboratively promote SSB resealing by recruiting POLβ to SSBs, but XRCC1 -/- cells are much more sensitive to MMS than PARP1 -/- cells. We recently report that the PARP1 loss in XRCC1 -/- cells restores their MMS tolerance and conclude that XPCC1 facilitates the release of PARP1 from SSBs by maintaining its autoPARylation. We here show that the PARP1 loss in XRCC1 -/- cells also restores their tolerance to the three anti-cancer base-damaging drugs, although they and MMS induce different sets of base damage. We reveal the synthetic lethality of the XRCC1 -/- mutation, but not POLβ -/- , with olaparib and talazoparib, indicating that XRCC1 is a unique BER factor in suppressing toxic PARP1/SSB complex and can suppress even when PARP1 catalysis is inhibited. In conclusion, XRCC1 suppresses the PARP1/SSB complex via PARP1 catalysis-dependent and independent mechanisms., (© 2022 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Introduction and Importance: Intussusception is invagination of the bowel and is rare in adults, representing only 5% of all cases of intussusception. Duodenal intussusception is also very rare. To the best of our knowledge, there is only one previous report of a malignant tumor in the fourth portion of the duodenum as the lead point of intussusception (Vaibhav et al., 2021 [1]). This reports a duodenal-duodenal intussusception caused by a malignant tumor in the third portion of the duodenum., Case Presentation: A 36-year-old woman with abdominal pain was diagnosed with duodenal intussusception by abdominal ultrasonography and computed tomography scan. Double balloon endoscopy showed that the intussusception had spontaneously reduced, and a tumor was found in the third portion of the duodenum. Open resection was performed because of the tumor location. Pathologic examination revealed adenocarcinoma with an adenoma of the duodenum. The patient had no evidence of recurrence for 4 years after resection., Clinical Discussion: This patient had a primary duodenal malignancy and presented with intussusception, Duodenal intussusception is a rare condition requiring prompt intervention, usually requiring surgery. In this patient, since endoscopic resection was difficult, partial resection of duodenum was performed by open surgery assisted by double balloon enteroscopy. The pathological diagnosis of the resected specimen was primary duodenal malignancy., Conclusion: This is a report of adult duodenal intussusception caused by a primary duodenal malignancy. This rare condition posed an intriguing challenge for the optimal operative approach., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Osteopenia is defined as low bone mineral density (BMD) and has been shown to be associated with outcomes of patients with various cancers. The association between osteopenia and perihilar cholangiocarcinoma is unknown. The aim of this study was to evaluate osteopenia as a prognostic factor in patients with perihilar cholangiocarcinoma. Methods: A total of 58 patients who underwent surgery for perihilar cholangiocarcinoma were retrospectively analyzed. The BMD at the 11th thoracic vertebra was measured using computed tomography scan within one month of surgery. Patients with a BMD < 160 HU were considered to have osteopenia and b BMD ≥ 160 did not have osteopenia. The log-rank test was performed for survival using the Kaplan−Meier method. After adjusting for confounding factors, overall survival was assessed by Cox′s proportional-hazards model. Results: The osteopenia group had 27 (47%) more females than the non-osteopenia group (p = 0.036). Median survival in the osteopenia group was 37 months and in the non-osteopenia group was 61 months (p = 0.034). In multivariable analysis, osteopenia was a significant independent risk factor associated with overall survival in patients with perihilar cholangiocarcinoma (hazard ratio 3.54, 95% confidence interval 1.09−11.54, p = 0.036), along with primary tumor stage. Conclusions: Osteopenia is associated with significantly shorter survival in patients with perihilar cholangiocarcinoma.

Acoustic radiation force impulse (ARFI) elastography has been used to diagnose acute pancreatitis (AP). The present study aimed to assess the effectiveness of ARFI elastography in the diagnosis of AP. Studies examining the efficacy of ARFI elastography in AP were selected by searching MEDLINE, EMBASE, CENTRAL, ICTRP, and ClinicalTrial.gov. until September 2021. Meta-analyses were performed using random effects models. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to assess the certainty of the evidence. Eight case-control studies (994 patients) were included in the meta-analysis. The ARFI-Virtual Touch Quantification value (or ARFI shear wave propagation velocity) of the AP patient group was 0.83 m/s higher (95% confidence interval [CI]: 0.36-1.3) than that in the control group (95% CI: 1.0-1.28). The sensitivity and specificity of ARFI elastography for diagnosing AP were 98.3% (95% CI: 92.6-96.6%) and 95.5% (95% CI: 87.5-98.5%), respectively. The results showed that physicians could use ARFI elastography to accurately diagnose patients with AP. Additional well-designed studies are necessary to validate the efficacy of ARFI elastography in patients with AP., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2021 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Sarcopenia, as assessed by body composition, can affect morbidity and survival in several gastrointestinal cancer. However, the impact of sarcopenia, referring to both quantity and quality of skeletal muscle, in biliary tract cancer (BTC) is debatable. We aimed to investigate the impact of sarcopenia on morbidity and mortality in patients with BTC., Methods: Electronic databases and trial registries were searched through July 2021 to perform random-effects meta-analyses. Study selection, data abstraction and quality assessment were independently performed using the Grading of Recommendations, Assessment, Development, and Evaluation approach., Results: Twenty-nine studies (4443 patients) were included; 28 used computed tomography and one used dual-energy X-ray absorptiometry to assess body composition. Eighteen studies reported the impact of pre-operative sarcopenia on postoperative outcomes; namely, sarcopenia increased postoperative complications (risk ratio = 1.23, 95% confidence interval [CI] = 1.07 to 1.41; I 2  = 2%), and decreased recurrence-free survival (hazard ratio [HR] = 2.20, 95% CI = 1.75 to 2.75; I 2  = 0%) in multivariable analyses. Low muscle quantity (HR = 2.26, 95% CI = 1.75 to 2.92; I 2  = 66%) and quality (HR = 1.75, 95% CI = 1.33 to 2.29; I 2  = 50%) decreased overall survival in multivariable analyses. The certainty of the evidence was low because of heterogeneity and imprecision., Conclusions: In sarcopenia, low muscle quantity and quality by body composition conferred an independent risk of morbidity and mortality in patients with BTC. Further studies are needed to confirm these findings and mitigate risk., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: We previously reported a characteristic dynamic magnetic resonance imaging (MRI) change in patients with frozen shoulder (FS) and named this abnormal blood flow pattern the "burning sign". In this study, a semiquantitative method was used to evaluate changes in this abnormal blood flow pattern on dynamic MRI after shoulder manipulation under ultrasound-guided cervical nerve root block (MUC) in patients with FS., Methods: Nineteen patients with FS underwent MUC, with dynamic MRI performed before and after. We used dynamic MRI to semiquantitatively assess changes in the burning sign at the axillary pouch (AP) and rotator interval (RI) by examining the enhancement rate in the signal intensity and the enhancement velocity. Functional assessments included a numeric rating scale score, the range of shoulder motion, the American Shoulder and Elbow Surgeons score, and the Constant score., Results: The burning sign in the AP and RI was observed with dynamic MRI in all patients before MUC. The average interval from MUC until dynamic MRI was 8.2 months (range, 6-12). Clinical results for all patients improved after MUC. The before and after MUC enhancement rates (%) were 217 ± 51 and 85 ± 36 in the AP and 233 ± 61 and 73 ± 40 in the RI, respectively (both P  < .001). The before and after MUC enhancement velocities (ms/s) were 902 ± 335 and 203 ± 125 in the AP and 1249 ± 634 and 213 ± 146 in the RI, respectively (both P  < .001)., Conclusion: Dynamic MRI semiquantitatively demonstrated a reduction in abnormal blood flow and improvement in clinical results after MUC in patients with FS., (© 2022 The Authors.)

Introduction: Shoulder manipulation under ultrasound-guided cervical nerve root block (MUC) gives good clinical results in patients with frozen shoulder 1 week after the procedure. However, some patients are refractory to MUC. The present study was performed to investigate the prognostic factors of MUC for frozen shoulder., Methods: We evaluated 73 frozen shoulders (70 patients) to investigate the prognostic factors of MUC. The patients' mean age was 56.6 years, and 60% were female. The mean duration of symptoms before MUC was 8.6 months. We assessed pain using a numeric rating scale (NRS), range of motion (ROM), and the American Shoulder and Elbow Surgeons (ASES) score before and 1 year after MUC. We compared patients with an ASES score of <80 (defined as a poor clinical result) with those with an ASES score of ≥80 (good clinical result). To identify the risk factors for a poor clinical result, multiple logistic regression analysis was performed using the following variables: age, sex, duration of symptoms before MUC, diabetes mellitus (DM), initial NRS score, and initial ROM., Results: The initial NRS score and the prevalence of DM were significantly greater in the poor clinical results group. Multiple logistic regression analysis revealed that DM was the only independent risk factor for a poor clinical result after MUC (odds ratio, 51; 95% confidence interval, 10.9-237; p = .01)., Conclusions: DM is a negative prognostic factor of MUC for frozen shoulder, and patients with DM should be informed of this before they undergo treatment for frozen shoulder., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction and Importance: Shoulder stiffness in postoperative breast cancer causes a decrease in their quality of life. However, the underlying pathology is not fully understood, and no study has investigated the dynamic magnetic resonance imaging (MRI) findings in these patients. Therefore, the current preliminary study aimed to investigate the dynamic MRI findings in patients with shoulder stiffness occurring after breast cancer surgery., Methods: We retrospectively analyzed the electronic medical records of postoperative breast cancer patients with shoulder stiffness, dated from January 2015 to December 2020. The baseline characteristics, breast cancer treatment methods, range of active shoulder motion, and location of the abnormal enhancement on dynamic MRI were assessed., Results: The mean age of the patients was 57.8 ± 6.1 years (range, 47-63 years) and the mean duration of shoulder symptoms was 5.6 ± 3.6 months (range, 2-12 months). An abnormal enhancement of the rotator interval and axillary pouch was observed on dynamic MRI of all the included patients., Conclusion: This study presents the first case reports of the dynamic MRI findings in postoperative breast cancer patients with shoulder stiffness. All patients had abnormal enhancement of the rotator interval and axillary pouch., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Germline mutations in the mismatch repair (MMR) genes MSH2 , MSH6 , MLH1 , and PMS2 are linked to cancer of the colon and other organs, characterized by microsatellite instability and a large increase in mutation frequency. Unexpectedly, mutations in EXO1 , encoding the only exonuclease genetically implicated in MMR, are not linked to familial cancer and cause a substantially weaker mutator phenotype. This difference could be explained if eukaryotic cells possessed additional exonucleases redundant with EXO1. Analysis of the MLH1 interactome identified FANCD2-associated nuclease 1 (FAN1), a novel enzyme with biochemical properties resembling EXO1. We now show that FAN1 efficiently substitutes for EXO1 in MMR assays and that this functional complementation is modulated by its interaction with MLH1. FAN1 also contributes to MMR in vivo ; cells lacking both EXO1 and FAN1 have an MMR defect and display resistance to N -methyl- N -nitrosourea (MNU) and 6-thioguanine (TG). Moreover, FAN1 loss amplifies the mutational profile of EXO1-deficient cells, suggesting that the two nucleases act redundantly in the same antimutagenic pathway. However, the increased drug resistance and mutator phenotype of FAN1/EXO1-deficient cells are less prominent than those seen in cells lacking MSH6 or MLH1. Eukaryotic cells thus apparently possess additional mechanisms that compensate for the loss of EXO1.

Background: Peroxiredoxin 1 (PRDX1) is a member of a ubiquitous family of thiol peroxidases that catalyze the reduction of peroxides, including hydrogen peroxide. It functions as an antioxidant enzyme, similar to catalase and glutathione peroxidase. PRDX1 was recently shown act as a sensor of reactive oxygen species (ROS) and play a role in ROS-dependent intracellular signaling pathways. To investigate its physiological functions, PRDX1 was conditionally disrupted in chicken DT40 cells in the present study., Results: The depletion of PRDX1 resulted in cell death with increased levels of intracellular ROS. PRDX1-depleted cells did not show the accumulation of chromosomal breaks or sister chromatid exchange (SCE). These results suggest that cell death in PRDX1-depleted cells was not due to DNA damage. 2-Mercaptoethanol protected against cell death in PRDX1-depleted cells and also suppressed elevations in ROS., Conclusions: PRDX1 is essential in chicken DT40 cells and plays an important role in maintaining intracellular ROS homeostasis (or in the fine-tuning of cellular ROS levels). Cells deficient in PRDX1 may be used as an endogenously deregulated ROS model to elucidate the physiological roles of ROS in maintaining proper cell growth., (© 2021. The Author(s).)

Mammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase β and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes "trapped" on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase β and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1 -/- cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an "anti-trapper" that prevents toxic PARP1 activity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

DNA double-strand breaks (DSBs) are repaired mainly by non-homologous end joining (NHEJ) or homologous recombination (HR). RIF1 negatively regulates resection through the effector Shieldin, which associates with a short 3' single-stranded DNA (ssDNA) overhang by the MRN (MRE11-RAD50-NBS1) complex, to prevent further resection and HR repair. In this study, we show that RIF1, but not Shieldin, inhibits the accumulation of CtIP at DSB sites immediately after damage, suggesting that RIF1 has another effector besides Shieldin. We find that protein phosphatase 1 (PP1), a known RIF1 effector in replication, localizes at damage sites dependent on RIF1, where it suppresses downstream CtIP accumulation and limits the resection by the MRN complex. PP1 therefore acts as a RIF1 effector distinct from Shieldin. Furthermore, PP1 deficiency in the context of Shieldin depletion elevates HR immediately after irradiation. We conclude that PP1 inhibits resection before the action of Shieldin to prevent precocious HR in the early phase of the damage response., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fanconi anemia (FA) is a devastating hereditary disease characterized by bone marrow failure (BMF) and acute myeloid leukemia (AML). As FA-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), ICLs are widely assumed to be the lesions responsible for FA symptoms. Here, we show that FA-mutated cells are hypersensitive to persistent replication stress and that FA proteins play a role in the break-induced-replication (BIR)-like pathway for fork restart. Both the BIR-like pathway and ICL repair share almost identical molecular mechanisms of 53BP1-BRCA1-controlled signaling response, SLX4- and FAN1-mediated fork cleavage and POLD3-dependent DNA synthesis, suggesting that the FA pathway is intrinsically one of the BIR-like pathways. Replication stress not only triggers BMF in FA-deficient mice, but also specifically induces monosomy 7, which is associated with progression to AML in patients with FA, in FA-deficient cells.

Purpose: We previously reported that acoustic radiation force impulse (ARFI) with concomitant administration of perfluorobutane as an ultrasound contrast agent (UCA)-induced arrhythmias at a mechanical index (MI) of 1.8 or 4.0 in a rabbit model. The present study identified the location of arrhythmias with a MI < 1.8 using a new system that can transmit ARFI with B-mode imaging., Methods: Under general anesthesia, six male Japanese white rabbits were placed in a supine position. Using this system, we targeted ARFI to the exact site of the heart. ARFI exposure with MI 0.9-1.2 was performed to the right or left ventricle of the heart 2 min after UCA injection., Results: ARFI with a MI lower than previously reported to rabbit heart evoked extrasystolic waves with single UCA infusion. Arrhythmias were not observed using ARFI without UCA. Extrasystolic waves were observed significantly more frequently in the right ventricle group than in the left ventricle group, with arrhythmias showing reversed shapes. No fatal arrhythmias were observed., Conclusion: ARFI applied to simulate clinical conditions in rabbit heart evoked extrasystolic waves with single UCA infusion. The right ventricle group was significantly more sensitive to ARFI exposure, resulting in arrhythmias, than the left ventricle group. The shapes of PVCs that occurred in the right ventricle group and the left ventricle group were reversed. Ultrasound practitioners who use ARFI should be aware of this adverse reaction, even if the MI is below the previously determined value of 1.9.

Background: Pancreatojejunostomy (PJ) is one of the most difficult and challenging abdominal surgical procedures. There are no appropriate training systems available outside the operating room (OR). We developed a structured program for teaching PJ outside the OR. We describe its development and results of a pilot study., Methods: We have created this structured program to help surgical residents and fellows acquire both didactic knowledge and technical skills to perform PJ. A manual was created to provide general knowledge about PJ and the specific PJ procedure used in our institution. Based on questionnaires completed by trainers and trainees, the procedure for PJ was divided into twelve steps and described in detail. After creating the manual, we developed organ models, needles and a frame box for simulation training. Three residents (PGY3-5) and three fellows (PGY6 or above) participated in a pilot study. Objective and subjective evaluations were performed., Results: Trainees learn about PJ by reading the procedure manual, acquiring both general and specific knowledge. We conducted simulation training outside the OR using the training materials created for this system. They simulate the procedure with surgical instruments as both primary and assistant surgeon. In this pilot study, as objective assessments, the fellow-group took less time to complete one anastomosis (36 min vs 48 min) and had higher scores in the objective structured assessment of technical skill (average score: 4.1 vs 2.0) compared to the resident-group. As a subjective assessment, the confidence to perform a PJ anastomosis increased after simulation training (from 1.6 to 2.6). Participants considered that this structured teaching program is useful., Conclusion: We developed a structured program for teaching PJ. By implementing this program, learning opportunities for surgical residents and fellows can be increased as a complement to training in the OR.

Background: SLFN11 has recently been reported to execute cancer cells harboring replicative stress induced by DNA damaging agents. However, the roles of SLFN11 under physiological conditions remain poorly understood. Germinal center B-cells (GCBs) undergo somatic hypermutations and class-switch recombination, which can cause physiological genotoxic stress. Hence, we tested whether SLFN11 expression needs to be suppressed in GCBs during B-cell development., Objective: To clarify the expression profile of SLFN11 in different developmental stages of B-cells and B-cell-derived cancers., Methods: We analyzed the expression of SLFN11 by mining cell line databases for different stages of normal B-cells and various types of B-cell-derived cancer cell lines. We performed dual immunohistochemical staining for SLFN11 and B-cell specific markers in normal human lymphatic tissues. We tested the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in GCB-derived lymphoma cell lines. We also examined the therapeutic efficacy of these drugs in combination with cytosine arabinoside and the effects of SLFN11 on the efficacy of cytosine arabinoside in SLFN11-overexpressing cells., Results: SLFN11 mRNA level was found low in both normal GCBs and GCB-DLBCL (GCB like-diffuse large B-cell lymphoma). Immunohistochemical staining showed low SLFN11 expression in GCBs and high SLFN11 expression in plasmablasts and plasmacytes. The EZH2 and HDAC epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphoma cells and made them more susceptible to cytosine arabinoside. SLFN11 overexpression further sensitized GCB-derived lymphoma cells to cytosine arabinoside., Conclusions: The expression of SLFN11 is epigenetically suppressed in normal GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: M.N. and A.T-K received honorarium and research funding from Eisai Co., Ltd. Other authors declare no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of colonic polyps, and extracolonic manifestations are likely to occur. Pancreatic tumors are rare extracolonic manifestations in patients with FAP, among which solid-pseudopapillary neoplasm (SPN) are extremely rare. We report here a patient with an SPN of the pancreas found during the follow-up of FAP., Case Presentation: A 20-year-old woman was diagnosed with FAP 3 years previously by colonoscopy which revealed less than 100 colonic polyps within the entire colon. She complained of left upper abdominal pain and a 10-cm solid and cystic pancreatic tumor was found by computed tomography scan. Solid and cystic components within the tumor were seen on abdominal magnetic resonance imaging. Simultaneous laparoscopic resection of the distal pancreas and subtotal colectomy was performed. Histopathological findings confirmed the pancreatic tumor as an SPN without malignancy. Abnormal staining of beta-catenin was observed by immunohistochemical study. Multiple polyps in the colorectum were not malignant. Molecular biological analysis from peripheral blood samples revealed a decrease in the copy number of the promoter 1A and 1B region of the APC gene, which resulted in decreased expression of the APC gene., Conclusions: A rare association of SPN with FAP is reported. The genetic background with relation to beta-catenin abnormalities is interesting to consider tumor development. So far, there are few reports of SPN in a patient with FAP. Both lesions were treated simultaneously by laparoscopic resection.

Ribonucleoside triphosphates are often incorporated into genomic DNA during DNA replication. The accumulation of unrepaired ribonucleotides is associated with genomic instability, which is mediated by DNA topoisomerase 1 (Top1) processing of embedded ribonucleotides. The cleavage initiated by Top1 at the site of a ribonucleotide leads to the formation of a Top1-DNA cleavage complex (Top1cc), occasionally resulting in a DNA double-strand break (DSB). In humans, tyrosyl-DNA phosphodiesterases (TDPs) are essential repair enzymes that resolve the trapped Top1cc followed by downstream repair factors. However, there is limited cellular evidence of the involvement of TDPs in the processing of incorporated ribonucleotides in mammals. We assessed the role of TDPs in mutagenesis induced by a single ribonucleotide embedded into DNA. A supF shuttle vector site-specifically containing a single riboguanosine (rG) was introduced into the human lymphoblastoid TK6 cell line and its TDP1-, TDP2-, and TDP1/TDP2-deficient derivatives. TDP1 and TDP2 insufficiency remarkably decreased the mutant frequency caused by an embedded rG. The ratio of large deletion mutations induced by rG was also substantially lower in TDP1/TDP2-deficient cells than wild-type cells. Furthermore, the disruption of TDPs reduced the length of rG-mediated large deletion mutations. The recovery ratio of the propagated plasmid was also increased in TDP1/TDP2-deficient cells after the transfection of the shuttle vector containing rG. The results suggest that TDPs-mediated ribonucleotide processing cascade leads to unfavorable consequences, whereas in the absence of these repair factors, a more error-free processing pathway might function to suppress the ribonucleotide-induced mutagenesis. Furthermore, base substitution mutations at sites outside the position of rG were detected in the supF gene via a TDPs-independent mechanism. Overall, we provide new insights into the mechanism of mutagenesis induced by an embedded ribonucleotide in mammalian cells, which may lead to the fatal phenotype in the ribonucleotide excision repair deficiency., Competing Interests: The authors have declared that no competing interests exist.

Homologous recombination (HR) repairs DNA double-strand breaks using intact homologous sequences as template DNA. Broken DNA and intact homologous sequences form joint molecules (JMs), including Holliday junctions (HJs), as HR intermediates. HJs are resolved to form crossover and noncrossover products. A mismatch repair factor, MLH3 endonuclease, produces the majority of crossovers during meiotic HR, but it remains elusive whether mismatch repair factors promote HR in nonmeiotic cells. We disrupted genes encoding the MLH3 and PMS2 endonucleases in the human B cell line, TK6, generating null MLH3 -/- and PMS2 -/- mutant cells. We also inserted point mutations into the endonuclease motif of MLH3 and PMS2 genes, generating endonuclease death MLH3 DN/DN and PMS2 EK/EK cells. MLH3 -/- and MLH3 DN/DN cells showed a very similar phenotype, a 2.5-fold decrease in the frequency of heteroallelic HR-dependent repair of restriction enzyme-induced double-strand breaks. PMS2 -/- and PMS2 EK/EK cells showed a phenotype very similar to that of the MLH3 mutants. These data indicate that MLH3 and PMS2 promote HR as an endonuclease. The MLH3 DN/DN and PMS2 EK/EK mutations had an additive effect on the heteroallelic HR. MLH3 DN/DN /PMS2 EK/EK cells showed normal kinetics of γ-irradiation-induced Rad51 foci but a significant delay in the resolution of Rad51 foci and a 3-fold decrease in the number of cisplatin-induced sister chromatid exchanges. The ectopic expression of the Gen1 HJ re-solvase partially reversed the defective heteroallelic HR of MLH3 DN/DN /PMS2 EK/EK cells. Taken together, we propose that MLH3 and PMS2 promote HR as endonucleases, most likely by processing JMs in mammalian somatic cells., (Copyright © 2020 © 2020 Rahman et al. Published by Elsevier Inc. All rights reserved.)

Background: This study compared the clinical results for nonporous stems vs. trabecular metal (TM) stems used in reverse shoulder arthroplasty (RSA) for comminuted proximal humeral fractures (CPHFs) in elderly patients., Methods: In this retrospective study, a total of 41 shoulders (39 women) of patients with CPHF aged >70 years who underwent RSA were investigated. The minimum follow-up period was 2 years. A total of 15 shoulders were treated with Grammont-style RSA using nonporous stems (the G-RSA group), and 26 shoulders were treated with RSA combining TM stems (the FR-RSA group). The American Shoulder and Elbow Surgeons (ASES) shoulder score, Constant score, shoulder joint range of motion (ROM), and radiographic findings were compared between the 2 groups., Results: ASES scores and Constant scores were significantly higher in the FR-RSA group than in the G-RSA group. External rotation at the side in the FR-RSA group was significantly higher than that in the G-RSA group. In the FR-RSA and G-RSA groups, the union rates at the greater tuberosity (GT) were 88.5% and 46.7%, respectively, and scapular notching rates were 20% and 7.7%, respectively. Based on a subanalysis, the age was lower, body mass index was higher, and ASES scores, Constant scores, and external rotation ROM were higher in the GT union group than in the GT nonunion group., Conclusion: GT bone union rates were high, and external rotation ROM of the shoulder joint were more improved for RSA using TM stems than those for RSA using nonporous stems in elderly patients with CPHF., (© 2020 The Author(s).)

Traumatic injury to the main pancreatic duct requires surgical treatment, but optimal management strategies have not been established. In patients with isolated pancreatic injury, the pancreatic parenchyma must be preserved to maintain long-term quality of life. We herein report a case of traumatic pancreatic injury with main pancreatic duct injury in the head of the pancreas. Two years later, the patient underwent a side-to-side anastomosis between the distal pancreatic duct and the jejunum. Eleven years later, he presented with abdominal pain and severe gastrointestinal bleeding from the Roux limb. Emergency surgery was performed with resection of the Roux limb along with central pancreatectomy. We attempted to preserve both portions of the remaining pancreas, including the injured pancreas head. We considered the pancreatic fluid outflow tract from the distal pancreatic head and performed primary reconstruction with a double pancreaticogastrostomy to avoid recurrent gastrointestinal bleeding. The double pancreaticogastrostomy allowed preservation of the injured pancreatic head considering the distal pancreatic fluid outflow from the pancreatic head and required no anastomoses to the small intestine.

Background: Osteochondral autograft transplant (OAT), a surgical treatment for capitellar osteochondritis dissecans (OCD), has favorable rates of elbow recovery and return to sports in adolescents. However, few reports have investigated how long patients continue to play baseball after OAT and their satisfaction with their treatment outcome., Purpose: To evaluate the rate of boys who played baseball and received OAT for OCD in junior high school or earlier (age <15 years) and continued to play baseball in high school and the players' satisfaction with their elbow function during play., Study Design: Cohort study; Level of evidence, 3., Methods: A total of 32 elbows of boys who played baseball and received OAT at age ≤15 years (mean, 14.1 years) were examined and divided into pitcher (n = 11) and nonpitcher (n = 21) groups according to their player position before surgery. The clinical Timmerman-Andrews score at the end of their high school baseball, participation percentage of players who continued to play baseball, and satisfaction level during play (on a scale of 0-10 during pitching and batting and in a 4-choice format) were compared between the 2 groups., Results: The Timmerman-Andrews scores significantly improved after surgery in both groups, with no significant difference between the groups. Of the 32 players, 30 (93.8%) continued to play baseball throughout high school, including all players in the pitcher group and 19 (90.5%) of those in the nonpitcher group. The percentage of players who continued to pitch was 55.6% (6/11) in the pitcher group. Satisfaction with elbow joint function at the time of pitching was significantly lower in the pitcher group. Further, 5 players reported being "a little unsatisfied" because of elbow pain during pitching. All of the players indicated satisfaction with elbow function during batting., Conclusion: The percentage of players who received OAT for OCD in junior high school and continued to play baseball in high school was favorable. However, satisfaction with elbow function during throwing was lower in pitchers than in nonpitchers., Clinical Relevance: Before surgery, consent should be obtained from patients who are pitchers after it is explained that satisfaction with elbow joint function during pitching could be decreased after OAT.

Radiotherapy kills malignant cells by generating double-strand breaks (DSBs). Ionizing- radiation (IR) generates "dirty" DSBs, which associates with blocking chemical adducts at DSB ends. Homologous-directed repair (HDR) efficiently removes IR-induced blocking adducts from both 3' and 5' ends of DSBs. Nonhomologous end-joining (NHEJ) rejoins virtually all DSBs in G 1 phase and ∼80 % of DSBs in G 2 phase. However, DNA Ligase IV, an essential NHEJ factor, rejoins only "clean" ligatable DSBs carrying 3'-OH and 5'-phosphate DSB ends but not dirty DSBs. Recent studies have identified a number of nucleases, especially the MRE11 nuclease, as key factors performing the removal of blocking chemical adducts to restore clean ligatable DSBs for subsequent NHEJ. This restoration, but not subsequent NHEJ, is the rate-limiting step in the rejoining of IR- induced DSBs. This review describes repair factors that contribute to the restoration of clean DSBs before NHEJ., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The OECD guidelines define the bioassays of identifying mutagenic chemicals, including the thymidine kinase (TK) assay, which specifically detects the mutations that inactivate the TK gene in the human TK6 lymphoid line. However, the sensitivity of this assay is limited because it detects mutations occurring only in the TK gene but not any other genes. Moreover, the limited sensitivity of the conventional TK assay is caused by the usage of DNA repair-proficient wild-type cells, which are capable of accurately repairing DNA damage induced by chemicals. Mutagenic chemicals produce a variety of DNA lesions, including base lesions, sugar damage, crosslinks, and strand breaks. Base damage causes point mutations and is repaired by the base excision repair (BER) and nucleotide excision repair (NER) pathways. To increase the sensitivity of TK assay, we simultaneously disrupted two genes encoding XRCC1, an important BER factor, and XPA, which is essential for NER, generating XRCC1 -/- /XPA -/- cells from TK6 cells. We measured the mutation frequency induced by four typical mutagenic agents, methyl methane sulfonate (MMS), cis-diamminedichloro-platinum(II) (cisplatin, CDDP), mitomycin-C (MMC), and cyclophosphamide (CP) by the conventional TK assay using wild-type TK6 cells and also by the TK assay using XRCC1 -/- /XPA -/- cells. The usage of XRCC1 -/- /XPA -/- cells increased the sensitivity of detecting the mutagenicity by 8.6 times for MMC, 8.5 times for CDDP, and 2.6 times for MMS in comparison with the conventional TK assay. In conclusion, the usage of XRCC1 -/- /XPA -/- cells will significantly improve TK assay., (© 2020 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.)

Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double-strand breaks (DSBs), where TOP2 homodimers covalently bind to 5' DSB ends, called TOP2-DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase-2 (TDP2) removes 5' TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G 0 /G 1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G 0 /G 1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G 1 phase, and loss of TDP2 causes a five times higher number of androgen-induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2-deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs., (© 2020 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)