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Background: Postoperative pneumonia is one of the major complications after esophagectomy. The aim of this study was to determine whether bacterial cultures before esophagectomy could predict occurrence of postoperative pneumonia and help treatment strategies for postoperative pneumonia. Methods: Sixty-nine patients who underwent subtotal esophagectomy at Fukushima Medical University Hospital between January 2017 and May 2021 were included in this study. We collected sputum, oral, and/or nasopharyngeal swabs for bacterial culture preoperatively from all patients and from those who were suspected of postoperative pulmonary infections. We compared cultured pathogenic bacteria obtained preoperatively and postoperatively from patients who developed postoperative pneumonia, and investigated their association with incidence of postoperative pneumonia. Results: Postoperative pneumonia occurred in 22 of 69 patients (31%), including 13 cases of severe pneumonia with a Clavien-Dindo classification of grade IIIa or higher. Multivariate analysis revealed that longer operative duration (for 30 minutes increase; odds ratio 1.27, 95% CI 1.01-1.51, p=0.039) and positivity for preoperative bacterial culture (odds ratio 5.03, 95% CI 1.31-19.2, p=0.018) were independent risk factors for severe postoperative pneumonia, but not for all incidences of postoperative pneumonia. Of note, in only 5 of the 22 patients with pneumonia, the same pathogenic species were detected preoperatively and after the onset of pneumonia. Conclusions: Our results imply that preoperative bacterial culture may be useful to predict severe postoperative pneumonia. However, it may not be useful in determining pathogenic bacteria responsible for postoperative pneumonia. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic and endoscopic cooperative surgery (LECS) is a well-recognized surgical procedure for gastric gastrointestinal stromal tumor (GIST). In this report, we describe the clinical outcomes of LECS procedures for gastric GIST in our institution. Methods: We performed LECS procedures, including classical LECS, inverted LECS, closed LECS, and combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET), in 40 gastric intraluminal and intramural type GIST patients, whose tumors were = 50 mm in diameter, between September 2012 and December 2020. The patient background, surgical outcomes, postoperative morbidity and mortality, as well as the tumors' clinicopathological characteristics were analyzed retrospectively. Results: Pathological findings showed that most patients had a low or very low risk of tumor recurrence, while one patient had a high risk according to the modified-Fletcher's classification. The median length of postoperative hospital stay was 7 days. Only one patient had severe postoperative grade III complications according to the Clavien-Dindo (C-D) classification, after closed LECS, but was treated successfully with endoscopic hemostasis for postoperative hemorrhage. The remaining patients treated with LECS did not have severe complications. During the follow-up period (median, 31 months), all patients were disease-free, with no tumor recurrence or metastases. Conclusion: LECS is a safe surgical procedure for gastric intraluminal and intramural type GIST = 50 mm in diameter, with good clinical outcomes. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) is an important biomarker of infection and inflammation, as CRP is one of the most prominent acute-phase proteins. CRP is usually detected using anti-CRP antibodies (Abs), where the intermolecular interactions between CRP and the anti-CRP Ab are largely affected by the pH and ionic strength of environmental solutions. Therefore, it is important to understand the environmental effects of CRP-anti-CRP Ab interactions when designing highly sensitive biosensors. Here, we investigated the efficiency of fluorescently labeled CRP-anti-CRP monoclonal antibody (mAb) interactions at different pHs and ionic strengths. Our results indicate that the affinity was insensitive to pH changes in the range of 5.9 to 8.1, while it was significantly sensitive to ionic strength changes. The binding affinity decreased by 55% at an ionic strength of 1.6 mM, when compared to that under a physiological condition (~150 mM). Based on the isoelectric focusing results, both the labeled CRP and anti-CRP mAb were negatively charged in the studied pH range, which rendered the system insensitive to pH changes, but sensitive to ionic strength changes. The decreased ionic strength led to a significant enhancement of the repulsive force between CRP and the anti-CRP mAb. Although the versality of the findings is not fully studied yet, the results provide insights into designing highly sensitive CRP sensors, especially field-effect transistor -based sensors. [ABSTRACT FROM AUTHOR]

Objectives: To determine the clinical characteristics of methotrexate-associated lymphoproliferative disorder (MTX-LPD). Methods: In this study, 12 RA patients who developed MTX-LPD were assessed. The peripheral blood lymphocyte (PBL) count at the onset of MTX-LPD was compared to that 6 months before the onset, in Epstein-Barr virus-encoded RNA (EBER)-positive and -negative subgroups. We examined the change in the PBL count after MTX withdrawal. In patients with relapsed LPD, changes in the PBL count before relapse were also examined. Results: Regression of LPD after MTX withdrawal was noted in eight patients. In these patients, the PBL count was decreased at the onset of MTX-LPD compared to 6 months before the onset; the decrease was significantly more prominent in EBER-positive patients. In cases of spontaneous regression of LPD, the PBL count recovered quickly after MTX withdrawal. Four of eight patients showed a recurrence of LPD after they improved following MTX withdrawal. These patients also exhibited a decreased PBL count at recurrence compared to 6 months before recurrence. Conclusion: A decrease in the PBL count might be involved in the pathogenesis of MTX-LPD, especially in EBER-positive cases and in patients with LPD relapse after MTX withdrawal following initial improvement. [ABSTRACT FROM AUTHOR]

Although viral RNA or infectious virions have been detected in the feces of individuals infected with human influenza A and B viruses (IAV/IBV), the mechanism of viral survival in the gastrointestinal tract remains unclear. We developed a model that attempts to recapitulate the conditions encountered by a swallowed virus. While IAV/IBV are vulnerable to simulated digestive juices (gastric acid and bile/pancreatic juice), highly viscous mucus protects viral RNA and virions, allowing the virus to retain its infectivity. Our results suggest that virions and RNA present in swallowed mucus are not inactivated or degraded by the gastrointestinal environment, allowing their detection in feces. [ABSTRACT FROM AUTHOR]

Lactic acid bacteria (LAB) form a major component of gut microbiota and are often used as probiotics for fermented foods, such as yoghurt. In this study, we aimed to evaluate immunomodulatory activity of LAB, especially that of Lactobacillus bulgaricus ME-552 (ME552) and Streptococcus thermophilus ME-553 (ME553). In vivo/in vitro assay was performed in order to investigate their effects on T cell function. After oral administration of ME553 to C57BL/6 mice, the amount of both γ (IFN-γ) and interleukin 17 (IL-17) produced by cluster of differentiation (CD) 4+ T cells from Peyer's patches (PPs) were significantly enhanced. On the other hand, ME552 only up-regulated the production of IL-17 from PP cells. The extent of induction for IFN-γ production differed between ME552 and ME553. These results suggest that LAB modulate T cell effector functions and mucosal immunity. [ABSTRACT FROM AUTHOR]

Probiotics, such as lactic acid bacteria (LAB) and Bacillus subtilis var. natto, have been shown to modulate immune responses. It is important to understand how probiotic bacteria impact intestinal epithelial cells (IECs), because IECs are the first line of defense at the mucosal surface barrier and their activities substantially affect the gut microenvironment and immunity. However, to date, their precise mechanism remains unknown due to a lack of analytical systems available for live animal models. Recently, we generated a conditional Ca2+ biosensor Yellow Cameleon (YC3.60) transgenic mouse line and established 5D (x, y, z, time, and Ca2+) intravital imaging systems of lymphoid tissues including those in Peyer's patches and bone marrow. In the present study, we further advance our intravital imaging system for intestinal tracts to visualize IEC responses against orally administrated food compounds in real time. Using this system, heat-killed B. subtilis natto, a probiotic TTCC012 strain, is shown to directly induce Ca2+ signaling in IECs in mice housed under specific pathogen-free conditions. In contrast, this activation is not observed in the Lactococcus lactis strain C60; however, when we generate germ-free YC3.60 mice and observe the LAB stimulation of IECs in the absence of gut microbiota, C60 is capable of inducing Ca2+ signaling. This is the first study to successfully visualize the direct effect of probiotics on IECs in live animals. These data strongly suggest that probiotic strains stimulate IECs under physiological conditions and that their activity is affected by the microenvironment of the small intestine, such as commensal bacteria. [ABSTRACT FROM AUTHOR]

The incidence of human infection by zoonotic avian influenza viruses, especially H5N1 and H7N9 viruses, has increased. Current zoonotic H7N9 avian influenza viruses (identified since 2013) emerged during reassortment of viruses belonging to different subtypes. Despite analyses of their genetic background, we do not know why current H7N9 viruses are zoonotic. Therefore, there is a need to identify the factor(s) responsible for the extended host tropism that enables these viruses to infect humans as well as birds. To identify H7N9-specific amino acids that confer zoonotic properties on H7N9 viruses, we performed multiple alignment of the hemagglutinin (HA) amino acid sequences of A/Shanghai/1/2013 (H7N9) and A/duck/Zhejiang/12/2011(H7N3) (a putative, non- or less zoonotic HA donor to the zoonotic H7N9 virus). We also analyze the function of an H7N9 HA-specific amino acid with respect to HA acid stability, and evaluated the effect of acid stability on viral infectivity and virulence in a mouse model. HA2-116D, preserved in current zoonotic H7N9 viruses, was crucial for loss of HA acid stability. The acid-labile HA protein in H7 viruses played an important role in infection of human airway epithelial cells; HA2-116D contributed to infection and replication of H7 viruses. Finally, HA2-116D served as a H7 virulence factor in mice. These results suggest that acid-labile HA harboring HA2-116D confers zoonotic characteristics on H7N9 virus and that future novel zoonotic avian viruses could emerge from non-zoonotic H7 viruses via acquisition of mutations that remove HA acid stability. Author summary: Despite detailed analyses of the genetic background, we do not know why H7N9 avian influenza viruses circulating since 2013 behave as zoonotic viruses. Here, we (i) identified a specific amino acid, HA2-116D, in the HA protein that confers zoonotic properties on the H7N9 virus; (ii) show that HA2-116D plays an important role in viral infectivity and replication in human airway epithelial cells through its ability to increase pH sensitivity, which readily induces viral-cell membrane fusion in host cells and subsequent infection; (iii) show that HA2-116D is not usually present in the HA protein of H7 viruses with low zoonotic potential; and (iv) show that HA2-116D increases the virulence of the H7 virus in mice. These results suggest that acid-labile HA is an important factor underlying efficient infection of human airway epithelial cells, as well as a virulence factor for mammalian hosts, and that novel zoonotic avian viruses could emerge from non-zoonotic H7 viruses that acquire mutations resulting in loss of HA acid stability. [ABSTRACT FROM AUTHOR]

This document is a corrigendum for an article titled "Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient." The corrigendum addresses two sentences in the abstract section of the published paper that needed revision. The corrections involve clarifying the mutations and drug resistance observed in the study. The authors confirm that these changes are typographical errors and do not affect the interpretation of the results. [Extracted from the article]

Although the coronavirus disease 2019 (COVID-19) pandemic is coming to an end, it still poses a threat to the immunocompromised and others with underlying diseases. Especially in cases of persistent COVID-19, new mutations conferring resistance to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapies have considerable clinical implications. We present a patient who independently acquired a T21I mutation in the 3CL protease after nirmatrelvir exposure. The T21I mutation in the 3CL protease is one of the most frequent mutations responsible for nirmatrelvir resistance. However, limited reports exist on actual cases of SARS-CoV-2 with T21I and other mutations in the 3CL protease. The patient, a 55 year-old male, had COVID-19 during chemotherapy for multiple myeloma. He was treated with nirmatrelvir early in the course of the disease but relapsed, and SARS-CoV-2 with a T21I mutation in the 3CL protease was detected in nasopharyngeal swab fluid. The patient had temporary respiratory failure but later recovered well. During treatment with remdesivir and dexamethasone, viruses with the T21I mutation in the 3CL protease showed a decreasing trend during disease progression while increasing during improvement. The impact of drug-resistant SARS-CoV-2 on the clinical course, including its severity, remains unknown. Our study is important for examining the clinical impact of nirmatrelvir resistance in COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Various therapeutic agents are being developed for the treatment of coronavirus disease 2019 (COVID-19). Therefore, it is crucial to accumulate information regarding the features of drug-resistant viruses to these antiviral drugs. Methods: We investigated the emergence of dual-drug resistance in a kidney transplant recipient who received sotrovimab (from day 0) and remdesivir (RDV) (from day 8 to day 17). We sequenced the whole viral genomes from nasopharyngeal swabs taken on day 0 and seven points after starting treatment (on days 12, 19, 23, 37, 43, 48, and 58). The genetic traits of the wild-type (day 0) and descendant viruses (after day 12) were determined by comparing the genomes with those of a Wuhan strain and the day 0 wild-type strain, respectively. Three viral isolates (from samples collected on days 0, 23, and 37) were investigated for their escape ability and growth kinetics in vitro. Results: The sotrovimab resistant mutation (S:E340K) and the RDV resistant mutation RdRp:V792I (nt: G15814A) emerged within 12 days (day 12) and 11 days (day 19) after the treatment, respectively. The day 23 isolate harboring S:E340K/RdRp:V791I was resistant to both sotrovimab and RDV, showing 364- and 2.73-fold higher resistance respectively, compared with the wild-type. Moreover, compared with the day 23 isolate, the day 37 isolate accumulated multiple additional mutations and had a higher level of resistance to both drugs. Conclusion: Drug-resistant variants with double mutations (S:E340K/RdRp:V791I) became dominant within 23 days after starting treatment, suggesting that even a combination therapy involving sotrovimab and RDV, dual-drug resistant viruses may emerge rapidly in immunocompromised patients. The dual-resistant variants had lower virus yields than those of the wild-type virus in vitro, suggesting that they paid a fitness cost. [ABSTRACT FROM AUTHOR]

There are global concerns about threat of pandemic caused by the human-infectious avian influenza virus. To prevent the oncoming pandemic, it is crucial to analyze the viral affinity to human-type or avian-type sialoglycans with high sensitivity at high speed. Graphene-FET (G-FET) realizes such high-sensitive electrical detection of the targets, owing to graphene’s high carrier mobility. In the present study, G-FET was functionalized using sialoglycans and employed for the selective detection of lectins from Sambucus sieboldiana and Maackia amurensis as alternatives of the human and avian influenza viruses. Glycan-functionalized G-FET selectively monitored the sialoglycan-specific binding reactions at subnanomolar sensitivity. [ABSTRACT FROM AUTHOR]

Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rc2/2 (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American- British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia. [ABSTRACT FROM AUTHOR]

Broadcast Encryption (BE) is public-key encryption allowing a sender to encrypt a message by specifing recipients, and only the specified recipients can decrypt the message. In several BE applications, since the privacy of recipients allowed to access the message is often as important as the confidentiality of the message, anonymity is introduced as an additional but important security requirement for BE. Kiayias and Samari (IH 2013) presented an asymptotic lower bound on the ciphertext sizes in BE schemes satisfying anonymity (ANO-BE for short). More precisely, their lower bound is derived under the assumption that ANO-BE schemes have a special property. However, it is insufficient to show their lower bound is asymptotically tight since it is unclear whether existing ANO-BE schemes meet the special property. In this work, we derive asymptotically tight lower bounds on the ciphertext size in ANO-BE by assuming only properties that most existing ANO-BE schemes satisfy. With a similar technique, we first derive asymptoticallyqueryPlease provide MSC codes. For more details, please visit http://www.ams.org/msc/. tight lower bounds on the authenticator sizes in Anonymous Broadcast Authentication (ABA). Furthermore, we extend the above result and present (non-asymptotically) tight lower and upper bounds on thequeryPlease check and confirm the Running title. ciphertext sizes in ANO-BE. We show that a variant of ANO-BE scheme proposed by Li and Gong (ACNS 2018) is optimal. We also provide tight bounds on the authenticator sizes in ABA via the same approach as ANO-BE, and propose an optimal construction for ABA. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation has been reported to be associated with cancer progression and metastasis. Systemic inflammation score (SIS), calculated from preoperative serum albumin level and lymphocyte-to-monocyte ratio, has been shown to be a novel prognostic factor for several types of tumors. This study aimed to evaluate the prognostic value of the SIS in patients with pT2–4 resectable gastric cancer (GC). Methods: Total 97 patients with pT2–4 GC who underwent curative surgery from 322 cases between 2009 and 2015 in Fukushima Medical University Hospital were included. We performed univariate and multivariate analyses to evaluate the usefulness of preoperative SIS and other prognostic factors for relapse-free survival (RFS) and overall survival (OS). Results: The higher SIS score was associated with undifferentiated cancer and recurrence. Univariate analysis of RFS identified deeper tumor invasion and higher SIS were significant risk factors and multivariate analysis revealed that both of them were independent prognostic factors for RFS. As for OS, age, tumor invasion, SIS and LNR were significantly correlated with RFS. In multivariate analysis, tumor invasion, SIS and LNR were independent prognostic factors for OS. Conclusions: SIS was an independent prognostic factor for RFS and OS in pT2–4 resectable gastric cancer patients who underwent curative gastrectomy. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has evolved continuously and accumulated spike mutations with each variant having a different binding for the cellular ACE2 receptor. It is not known whether the interactions between such mutated spikes and ACE2 glycans are conserved among different variant lineages. Here, we focused on three ACE2 glycosylation sites (53, 90 and 322) that are geometrically close to spike binding sites and investigated the effect of their glycosylation pattern on spike affinity. These glycosylation deletions caused distinct site-specific changes in interactions with the spike and acted cooperatively. Of note, the particular interaction profiles were conserved between the SARS-CoV-2 parental virus and the variants of concern (VOCs) Delta and Omicron. Our study provides insights for a better understanding of the importance of ACE2 glycosylation on ACE2/SARS-CoV-2 spike interaction and guidance for further optimization of soluble ACE2 for therapeutic use. Three glycosylation sites on the cellular receptor for SARS-CoV-2, ACE2, are probed for interactions with the spike protein and cooperativity. [ABSTRACT FROM AUTHOR]

Surgery is one of the most common tumor intervention methods in the clinical field, which results in postsurgical tumor regrowth and destruction of the body's immune system. As a new method of tumor treatment, phototherapy has high selectivity and space–time accuracy and is minimally invasive. The therapeutic effects of traditional phototherapy are seriously damaged because of its limited permeability, and it can cause serious damage to surrounding healthy tissues. Benefiting from the development of nanotechnology, nanomaterial-based photosensitive materials can specialize in overcoming poor drug penetration depth, unfavorable biodistributions, prolonged blood circulation times, and also efficiently accumulate at tumor areas through enhanced permeability and retention (EPR) effects. Photothermal therapy triggered by near-infrared (NIR) irradiation based on nanomaterials can directly destroy cancer cells, promote the production of tumor-associated antigens (TAAs), and thus trigger anti-tumor immune responses. Therefore, TAAs can explosively release the natural ineffective antigens, and present immune vaccine-like functions in situ. Considering the immunosuppressive tumor microenvironment postsurgery, immunotherapy against cancer cells is a highly complex process. Moreover, phototherapy-induced "abscopal effects" are weak in inhibiting cancer growth, usually resulting in unsatisfactory tumor therapy outcomes. Therefore, phototherapy synergistic immune reagents can promote lymphocyte infiltration and induce the microenvironment of immunogenic tumor, so as to obtain the greatest benefits in anti-tumor treatment. In this article, we will summarize some strategies of nanomaterial-based phototherapy synergistic immunotherapy in inhibiting tumor growth and prevention of cancer cell metastasis and recurrence. [ABSTRACT FROM AUTHOR]

Card-based cryptography is a variety of secure multiparty computation (MPC). Recently, a new technique called private operations was introduced because the protocol can be implemented with fewer cards than that by using the conventional technique called the shuffle. For example, Nakai et al. showed that if the private operations are available, secure computations of AND and OR operations for two inputs can be realized simultaneously by using four cards, and the protocol is applied to a four-card majority voting protocol with three inputs. This paper shows that only three cards are sufficient to construct a majority voting protocol with three inputs. Specifically, we propose two constructions of three-input majority voting protocols. One is a protocol assuming that players can announce their output, and the other is not allowed. Compared to Nakai et al.'s protocol, the protocol with the announcement is realized without any additional private operations and communications. On the other hand, the second construction requires two more private operations and communications because it removes the assumption on the announcement from the first construction. More importantly, the idea of the second protocol can be extended to an n-input majority voting protocol with n cards, which is the main result of this paper. [ABSTRACT FROM AUTHOR]

Background: Upper extremity deep vein thrombosis (UEDVT) is relatively rare but cannot be negligible because it can cause fatal complications. Although it is reported that the occurrence rate of UEDVT has increased due to central venous catheter (CVC), cancer, and surgical invasion, there is still limited information for esophagectomy. The aim of this study was to evaluate the clinical factors, including CVC placement and thromboprophylaxis approach, as well as retrosternal space's width as a predictive factor for UEDVT in patients receiving esophagectomy.Methods: This study included 66 patients who underwent esophagectomy with retrosternal reconstruction using a gastric tube. All patients routinely underwent contrast-enhanced computed tomography (CT) on the 4th postoperative day. Low-molecular-weight-heparin (LMWH) was routinely administered by the 2nd postoperative day. To evaluate retrosternal space's width, (a) The distance from sternum to brachiocephalic artery and (b) the distance from sternum to vertebra were measured by preoperative CT, and the ratio of (a) to (b) was defined as the width of retrosternal space.Results: Among all patients, 11 (16.7%) suffered from UEDVT, and none was preoperatively received CVC placement, while 7 were inserted in non-UEDVT cases. Retrosternal space's width in patients with UEDVT was significantly smaller than that in patients without UEDVT (0.17 vs. 0.26; P < 0.0001). A cutoff value of the width was 0.21, which has high sensitivity (87%) and specificity (82%) for UEDVT prediction, respectively.Conclusion: The existence of CVC may not affect the development of UEDVT, but preoperative evaluation of retrosternal ratio may predict the occurrence of UEDVT. [ABSTRACT FROM AUTHOR]

Background: Proximal gastrectomy is a widely performed procedure that has become more common with an increasing number of proximal gastric cancer cases. Several types of reconstructive procedures after proximal gastrectomy have been developed, and it remains controversial which procedure is the most advantageous with regard to the preservation of postoperative gastric stump function and nutritional status. In the present study, we retrospectively analyzed reconstructive procedures in a consecutive case series for proximal gastrectomy, primarily focusing on postoperative body weight maintenance, nutritional status, and gastric remnant functional preservation.Methods: We enrolled 69 patients who had undergone proximal gastrectomy for gastric cancer in our institute between 2005 and 2020. Short-term complications, preservation of gastric remnant functions, nutritional status, and post-operative weight changes were compared.Results: After proximal gastrectomy, the numbers of patients who underwent direct esophago-gastrostomy, jejunal interposition, double tract reconstruction, and the double flap technique were 9, 10, 14, and 36, respectively. The patients in whom the double flap technique was performed suffered no reflux esophagitis after surgery. Prevalence of gastric residual at 12 months after surgery was lowest in the double flap technique group. Moreover, the double flap technique group had a better tendency regarding post-operative changes of serum albumin ratios. Furthermore, the post-operative body weight change ratio of the double flap technique group was smallest among all groups and was significantly better than that of the double tract group.Conclusions: The double flap technique after proximal gastrectomy was considered the most effective technique for reconstruction which leads to better bodyweight maintenance, and results in less reflux esophagitis. [ABSTRACT FROM AUTHOR]

Hierarchical key-insulated identity-based encryption (HKIBE) is identity-based encryption (IBE) that allows users to update their secret keys to achieve (hierarchical) key-exposure resilience, which is an important notion in practice. However, existing HKIBE constructions have limitations in efficiency: sizes of ciphertexts and secret keys depend on the hierarchical depth. In this paper, we first triumph over the barrier by proposing simple but effective design methodologies to construct efficient HKIBE schemes. First, we show a generic construction from any hierarchical IBE (HIBE) scheme that satisfies a special requirement, called MSK evaluatability introduced by Emura et al. (Des. Codes Cryptography 89(7):1535–1574, 2021). It provides several new and efficient instantiations since most pairing-based HIBE schemes satisfy the requirement. It is worth noting that it preserves all parameters' sizes of the underlying HIBE scheme, and hence we obtain several efficient HKIBE schemes under the k-linear assumption in the standard model. Since MSK evaluatability is dedicated to pairing-based HIBE schemes, the first construction restricts pairing-based instantiations. To realize efficient instantiation from various assumptions, we next propose a generic construction of an HKIBE scheme from any plain HIBE scheme. It is based on Hanaoka et al.'s HKIBE scheme (Asiacrypt 2005), and does not need any special properties. Therefore, we obtain new efficient instantiations from various assumptions other than pairing-oriented ones. Though the sizes of secret keys and ciphertexts are larger than those of the first construction, it is more efficient than Hanaoka et al.'s scheme in the sense of the sizes of master public/secret keys. [ABSTRACT FROM AUTHOR]

Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8+ T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of CXCL9/10/11 in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC. [ABSTRACT FROM AUTHOR]

Alternative splicing of pre‐mRNAs can regulate gene expression levels by coupling with nonsense‐mediated mRNA decay (NMD). In order to elucidate a repertoire of mRNAs regulated by alternative splicing coupled with NMD (AS‐NMD) in an organism, we performed long‐read RNA sequencing of poly(A)+ RNAs from an NMD‐deficient mutant strain of Caenorhabditis elegans, and obtained full‐length sequences for mRNA isoforms from 259 high‐confidence AS‐NMD genes. Among them are the S‐adenosyl‐L‐methionine (SAM) synthetase (sams) genes sams‐3 and sams‐4. SAM synthetase activity autoregulates sams gene expression through AS‐NMD in a negative feedback loop. We furthermore find that METT‐10, the orthologue of human U6 snRNA methyltransferase METTL16, is required for the splicing regulation in␣vivo, and specifically methylates the invariant AG dinucleotide at the distal 3′ splice site (3′SS) in␣vitro. Direct RNA sequencing coupled with machine learning confirms m6A modification of endogenous sams mRNAs. Overall, these results indicate that homeostasis of SAM synthetase in C. elegans is maintained by alternative splicing regulation through m6A modification at the 3′SS of the sams genes. SYNOPSIS: Alternative splicing (AS) of pre‐mRNAs can regulate gene expression levels by coupling with nonsense‐mediated mRNA decay (NMD). Here, assessment of the organismal substrate repertoire of this process reveals SAM synthetase (sams) gene expression regulation via m6A modification in C. elegans. Long‐read sequencing of poly(A)+ RNAs from an NMD‐deficient mutant strain reveals 259 high‐confidence AS‐NMD genes, including the SAM synthetase (sams) genes.SAMS activity negatively autoregulates AS‐NMD of the sams genes in␣vivo.Direct RNA sequencing coupled with machine learning reveals m6A modification of endogenous sams mRNAs at the distal 3′ splice sites.Methyltransferase METT‐10 catalyzes m6A modification specifically at the distal 3′ splice site of sams pre‐mRNA in␣vitro.METT‐10 regulates alternative splicing of the sams genes in␣vivo. [ABSTRACT FROM AUTHOR]

Revocable identity-based encryption (RIBE) is an extension of IBE with an efficient key revocation mechanism. Revocable hierarchical IBE (RHIBE) is its further extension with key delegation functionality. Although there are various adaptively secure pairing-based RIBE schemes, all known hierarchical analogues only satisfy selective security. In addition, the currently known most efficient adaptively secure RIBE and selectively secure RHIBE schemes rely on non-standard assumptions, which are referred to as the augmented DDH assumption and q-type assumptions, respectively. In this paper, we propose a simple but effective design methodology for RHIBE schemes. We provide a generic design framework for RHIBE based on an HIBE scheme with a few properties. Fortunately, several state-of-the-art pairing-based HIBE schemes have the properties. In addition, our construction preserves the sizes of master public keys, ciphertexts, and decryption keys, as well as the complexity assumptions of the underlying HIBE scheme. Thus, we obtain the first RHIBE schemes with adaptive security under the standard k-linear assumption. We prove adaptive security by developing a new proof technique for RHIBE. Due to the compactness-preserving construction, the proposed R(H)IBE schemes have similar efficiencies to the most efficient existing schemes. [ABSTRACT FROM AUTHOR]

Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) encodes an enzyme that catalyzes de novo purine biosynthesis. Although PAICS has been implicated as a potential therapeutic target in several cancers, its clinical and prognostic significance in colorectal cancer (CRC) is not fully understood. To elucidate the roles of PAICS in CRC, we investigated PAICS expression in four cohorts consisting of a total of 1659 samples based on quantitative RT-PCR, microarray and RNA-seq analysis. Despite upregulated PAICS levels in tumor compared to those of normal mucosa, we found a decreasing trend of PAICS expression during tumor progression and metastasis. We conducted immunohistochemistry on 252 specimens, showing that PAICS protein was strongly expressed in the majority of CRCs, but not in adjacent mucosa. Notably, 29.0% of tumors lacked PAICS staining, and PAICS-negative expression in tumor had significant prognostic impact on poor cancer-specific survival in stage III CRC. Correspondingly, decreased levels of PAICS transcript were also correlated with poor relapse-free survival particularly in stage III patients, and this finding was robustly confirmed in three microarray datasets of a total of 802 stage II-III patients. Bioinformatics analysis of CRC tissues and cell lines consistently indicated a correlation between decreased PAICS expression and copy number loss of chromosome arm 4q. In conclusion, our results suggest that PAICS expression is downregulated during tumor progression due to genetic deletion of chromosome 4q in microsatellite stable but chromosomally unstable tumors. Furthermore, decreased expression of PAICS transcript or loss of PAICS protein may provide prognostic stratification for postoperative patients with stage III CRC. [ABSTRACT FROM AUTHOR]

Sporadic cases of rheumatoid nodules (RNs) in the lung during treatment with tumour necrosis factor (TNF) inhibitors have been reported, but no treatment has been established. Here, we report a case of symptomatic lung RNs refractory to abatacept (ABT) and intravenous cyclophosphamide (IVCY) that improved with tofacitinib (TOF) treatment. A 75-year-old Japanese woman with a 10-year history of rheumatoid arthritis (RA) presented with a cough and haemoptysis during treatment with etanercept (ETN). Radiographic examinations revealed multiple nodules that were diagnosed as lung RNs via biopsy. The ETN was discontinued and ABT followed by IVCY was introduced; however, neither was sufficiently effective against the lung RNs. Thereafter, TOF was started and the lung RNs improved rapidly. The precise mechanisms that induce RNs during treatment with TNF inhibitors are unknown. Cytokines (IL-23 and IL-6) are suspected to be involved. TOF may be a reasonable strategy for treating symptomatic lung RNs. [ABSTRACT FROM AUTHOR]

A 70-year-old man underwent endoscopy, which revealed a slightly depressed and elevated gastric cancer with suspected submucosal invasion of the mid gastric body. Biopsy specimens revealed differentiated tubular adenocarcinoma. We also detected lung and esophageal cancer and prioritized treatment of these lesions, and the patient underwent three endoscopies to monitor changes in gastric cancer. The tumor size and color remained unchanged; however, the marginal ridge was prominent, and the depressed area was deeper on subsequent evaluation. Total gastrectomy was performed 9 months after the first endoscopy. Histopathological examination of the resected specimens showed muscularis propria invasion, well-differentiated tubular adenocarcinoma involving the superficial mucosa, and tumor cells showing clear cytoplasm and a columnar or three-dimensional structure, between the deep mucosa and submucosa. The cells were immunopositive for Sal-like protein 4 and glypican 3; therefore, the patient was diagnosed with gastric adenocarcinoma with enteroblastic differentiation (GAED). This rare gastric cancer variant constituted approximately 70% of the entire lesion, and we observed significant lymphovascular invasion and lymph node metastasis. GAED is a rare histopathological subtype of gastric cancer described in recent years. Few cases of this tumor are reported to date; therefore, our study significantly contributes to the literature. [ABSTRACT FROM AUTHOR]

Checkpoint blockade therapy has provided noteworthy benefits in multiple cancers in recent years; however, its clinical benefits remain confined to 10–40% of patients with extremely high costs. Here, we design an ultrafast, low-temperature, and universal self-assembly route to integrate immunology-associated large molecules into metal-organic-framework (MOF)-gated mesoporous silica (MS) as cancer vaccines. Core MS nanoparticles, acting as an intrinsic immunopotentiator, provide the niche, void, and space to accommodate antigens, soluble immunopotentiators, and so on, whereas the MOF gatekeeper protects the interiors from robust and off-target release. A combination of MOF-gated MS cancer vaccines with systemic programmed cell death 1 (PD-1) blockade therapy generates synergistic effects that potentiate antitumour immunity and reduce the effective dose of an anti-PD-1 antibody to as low as 1/10 of that for PD-1 blockade monotherapy in E.G7-OVA tumour-bearing mice, with eliciting the robust adaptive OVA-specific CD8+ T-cell responses, reversing the immunosuppressive pathway and inducing durable tumour suppression. Nanoparticle-based strategies have been proposed to enhance the benefit of cancer immunotherapy. Here the authors show that a cancer vaccine based on metal organic frameworks-gated mesoporous silica nanoparticles for antigen and immune potentiators delivery boosts the therapeutic efficacy of low-dose anti-PD1. [ABSTRACT FROM AUTHOR]

Efficient key revocation in Identity-based Encryption (IBE) has been a both fundamental and critical problem when deploying an IBE system in practice. Boneh and Franklin proposed the first revocable IBE (RIBE) scheme where the size of key updates is linear in the number of users. Then, Boldyreva, Goyal and Kumar proposed the first scalable RIBE by using the tree-based approach where the size of key updates is |$O(r\log (N/r))$| and the size of every user's long-term secret key is |$O(\log N)$| with |$N$| being the number of users and |$r$| the number of revoked users. Recently, Qin et al. presented the notion of server-aided RIBE where the size of every user's long-term secret key is |$O(1),$| and users do not need to communicate with Key Generator Center (KGC) during every key updates. However, users must change their identities once their secret keys are revoked as they cannot decrypt ciphertexts by using their revoked secret keys. To address the above problem, we formalize the notion of RIBE with identity reuse. In our system model, users can obtain a new secret key called the reuse secret key from KGC when their secret keys are revoked. The decryption key can be derived from the reuse secret key and new key updates while it cannot be derived from the revoked secret key and the new key updates. We present a concrete construction that is secure against adaptive-ID chosen plaintext attacks and decryption key exposure attacks under the |$\mathsf{ADDH}1$| and |$\mathsf{DDH}2$| assumptions in the standard model. Furthermore, we extend it to server-aided RIBE scheme with identity reuse property that is more suitable for lightweight devices. [ABSTRACT FROM AUTHOR]

Security and privacy are the key issues for the Internet of Things (IoT) systems. Especially, secure search is an important functionality for cooperation among users' devices and non-trusted servers. Public-key encryption with keyword search (PEKS) enables us to search encrypted data and is expected to be used between a cloud server and users' mobile devices or IoT devices. However, those mobile devices might be lost or stolen. For IoT devices, it might be difficult to store keys in a tamper-proof manner due to prohibitive costs. In this paper, we deal with such a key-exposure problem on PEKS and introduce the concept of PEKS with key-updating functionality, which we call key-updatable PEKS (KU-PEKS). Specifically, we propose two models of KU-PEKS: the key-evolution model and the key-insulation model. In the key-evolution model, a pair of public and secret keys can be updated if needed (e.g., the secret key is exposed). In the key-insulation model, the public key remains fixed while the secret key can be updated if needed. The former model makes a construction simple and more efficient than the latter. On the other hand, the latter model is preferable for practical use since a user never updates their public key. We show constructions in each model in a black-box manner. We also give implementation results on Raspberry Pi 3, which can be regarded as a reasonable platform of IoT devices. [ABSTRACT FROM AUTHOR]

Avian influenza virus H9N2 has been endemic in birds in the Middle East, in particular in Egypt with multiple cases of human infections since 1998. Despite concerns about the pandemic threat posed by H9N2, little is known about the biological properties of H9N2 in this epicentre of infection. Here, we investigated the evolutionary dynamics of H9N2 in the Middle East and identified phylogeny-associated PB2 mutations that acted cooperatively to increase H9N2 replication/transcription in human cells. The accumulation of PB2 mutations also correlated with an increase in H9N2 virus growth in the upper and lower airways of mice and in virulence. These mutations clustered on a solvent-exposed region in the PB2-627 domain in proximity to potential interfaces with host factors. These PB2 mutations have been found at high prevalence during evolution of H9N2 in the field, indicating that they have provided a selective advantage for viral adaptation to infect poultry. Therefore, continuous prevalence of H9N2 virus in the Middle East has generated a far more fit or optimized replication phenotype, leading to an expanded viral host range, including to mammals, which may pose public health risks beyond the current outbreaks. [ABSTRACT FROM AUTHOR]

A key exposure problem is unavoidable since it seems human error can never be eliminated completely, and key-insulated encryption is one of the cryptographic solutions to the problem. At Asiacrypt'05, Hanaoka et al. introduced hierarchical key-insulation functionality, which is attractive functionality that enhances key exposure resistance, and proposed an identity-based hierarchical key-insulated encryption (hierarchical IKE) scheme in the random oracle model. In this paper, we first propose the hierarchical IKE scheme in the standard model (i.e., without random oracles). Our hierarchical IKE scheme is secure under the symmetric external Diffie–Hellman (SXDH ) assumption, which is a static assumption. Particularly, in the non-hierarchical case, our construction is the first IKE scheme that achieves constant-size parameters including public parameters, secret keys, and ciphertexts. Furthermore, we also propose the first public-key-based key-insulated encryption (PK-KIE) in the hierarchical setting by using our technique. [ABSTRACT FROM AUTHOR]

Influenza viruses exist in each host as a collection of genetically diverse variants, which might enhance their adaptive potential. To assess the genetic and functional diversity of highly pathogenic avian influenza A(H5N1) viruses within infected humans, we used deep-sequencing methods to characterize samples obtained from infected patients in northern Vietnam during 2004-2010 on different days after infection, from different anatomic sites, or both. We detected changes in virus genes that affected receptor binding, polymerase activity, or interferon antagonism, suggesting that these factors could play roles in influenza virus adaptation to humans. However, the frequency of most of these mutations remained low in the samples tested, implying that they were not efficiently selected within these hosts. Our data suggest that adaptation of influenza A(H5N1) viruses is probably stepwise and depends on accumulating combinations of mutations that alter function while maintaining fitness. [ABSTRACT FROM AUTHOR]