Age-related remodelling of oesophageal epithelia by mutated cancer drivers.

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

Quasi-Periodic Growth of One-Dimensional Copper Boride on Cu(110).

An unexplored material of copper boride has been realized recently in two-dimensional form at a (111) surface of the fcc copper crystal. Here, one-dimensional (1-D) boron growth was observed on the Cu(110) surface, as probed by atomically resolved scanning probe microscopy. The 1-D copper boride was composed of quasi-periodic atomic chains periodically aligned parallel to each other, as confirmed by Fourier transform analysis. The 1-D growth unexpectedly proceeded across surface steps in a self-assembled manner and extended over several 100 nm. The long-range formation of a 1-D quasi-periodic structure on a surface has been theoretically modeled as a 1-D quasi-crystal and the predicted conditions matched the structural parameters obtained by the experimental work here. The quasi-periodic 1-D copper boride system enabled a way to examine 1-D quasi-crystallinity on an actual material.

Design of artificial molecular motor inheriting directionality and scalability.

Realizing artificial molecular motors with autonomous functionality and high performance is a major challenge in biophysics. Such motors not only provide new perspectives in biotechnology but also offer a novel approach for the bottom-up elucidation of biological molecular motors. Directionality and scalability are critical factors for practical applications. However, the simultaneous realization of both remains challenging. In this study, we propose a novel design for a rotary motor that can be fabricated using a currently available technology, DNA origami, and validate its functionality through simulations with practical parameters. We demonstrate that the motor rotates unidirectionally and processively in the direction defined by structural asymmetry, which induces kinetic asymmetry in motor motion. The motor also exhibits scalability, such that increasing the number of connections between the motor and stator allows for a larger speed, run length, and stall force.

A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus.

Protein prenylation is essential for many cellular processes including signal transduction, cytoskeletal reorganization, and membrane trafficking. Here, we identify a novel type of protein prenyltransferase, which we named geranylgeranyltransferase type-III (GGTase-III). GGTase-III consists of prenyltransferase alpha subunit repeat containing 1 (PTAR1) and the ß subunit of RabGGTase. Using a biotinylated geranylgeranyl analogue, we identified the Golgi SNARE protein Ykt6 as a substrate of GGTase-III. GGTase-III transfers a geranylgeranyl group to mono-farnesylated Ykt6, generating doubly prenylated Ykt6. The crystal structure of GGTase-III in complex with Ykt6 provides structural basis for Ykt6 double prenylation. In GGTase-III-deficient cells, Ykt6 remained in a singly prenylated form, and the Golgi SNARE complex assembly was severely impaired. Consequently, the Golgi apparatus was structurally disorganized, and intra-Golgi protein trafficking was delayed. Our findings reveal a fourth type of protein prenyltransferase that generates geranylgeranyl-farnesyl Ykt6. Double prenylation of Ykt6 is essential for the structural and functional organization of the Golgi apparatus.

Squamous cell carcinoma-derived G-CSF promotes tumor growth and metastasis in mice through neutrophil recruitment and tumor cell proliferation, associated with poor prognosis of the patients.

Tumor-derived G-CSF is a well-known factor to aggravate disease progression in various types of cancers. In this study, we investigated a role of G-CSF in squamous cell carcinoma (SCC). High expression of G-CSF in the tumor tissues of esophageal SCC (ESCC) patients correlated with poor prognosis. Murine SCC NR-S1M cells produce considerable amount of G-CSF, which expression is correlated with its metastatic potentials. Deletion of G-CSF in NR-S1M cells mitigated tumor growth and metastasis to lymph node and lung of subcutaneous NR-S1M tumors in the mice. Mechanistically, G-CSF enhanced cell proliferation in autocrine manner in vitro, whereas in NR-S1M tumor-bearing mice, accumulation of plasma G-CSF was associated with expansion of peripheral neutrophils, which led to a decreased proportion of CD8+ T cells. Antibody depletion of neutrophils restored the number of CD8+ T cells and modestly suppressed tumor outgrowth, albeit no changes in distant metastasis. We propose that G-CSF produced by NR-S1M cells facilitates tumor progression in mice through bi-functional effects to promote neutrophil recruitment and tumor cell proliferation, which may render poor prognosis to the ESCC patients with high G-CSF expression.

Therapeutic Potential of Antibody Targeting Neuronal Pentraxin Receptor in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite advances in multidisciplinary treatments and immune checkpoint inhibitors. We previously reported that neural pentraxin receptor (NPTXR), a transmembrane protein mainly expressed in the brain and involved in synaptic transmission, is implicated in gastric cancer malignancy. This study evaluated the expression and function of NPTXR in ESCC, the therapeutic potential of monoclonal antibody (mAb) against NPTXR, and its prognostic value in ESCC patients. METHODS: The study involved analyzing the NPTXR expression in 21 ESCC cell lines and total 371 primary ESCC tissue samples using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. The impact of NPTXR on the malignant behavior of ESCC was examined using small interfering RNA-mediated knockdown and a subsequent assessment of cell proliferation, apoptosis, and adhesion. This study further investigated the efficacy of anti-NPTXR mAb in vitro and associations between the expression of NPTXR messenger RNA (mRNA) and protein with clinicopathological factors and the prognosis. RESULTS: NPTXR was overexpressed in several ESCC cell lines and primary ESCC tissues. Knockdown of NPTXR in ESCC cells resulted in reduced proliferation, increased apoptosis, and decreased cell adhesion. The mAb against NPTXR significantly inhibited ESCC cell proliferation in vitro. A high NPTXR expression in patient tissues was correlated with a worse overall survival, suggesting its potential as a prognostic biomarker. CONCLUSIONS: NPTXR influences the malignant behavior of ESCC cells. Anti-NPTXR mAb may be a promising therapeutic agent, and its expression in ESCC tissues may serve as a prognostic biomarker.

Six-year outcomes of robot-assisted radical prostatectomy versus volumetric modulated arc therapy for localized prostate cancer: A propensity score-matched analysis.

BACKGROUND: Although robot-assisted radical prostatectomy (RARP) and intensity-modulated radiotherapy are the leading respective techniques of prostatectomy and radiotherapy for localized prostate cancer, almost no study has directly compared their outcomes; none have compared mortality outcomes. METHODS: We compared 6­year outcomes of RARP (n = 500) and volumetric modulated arc therapy (VMAT, a rotational intensity-modulated radiotherapy, n = 360) in patients with cT1-4N0M0 prostate cancer. We assessed oncological outcomes, namely overall survival (OS), cancer-specific survival (CSS), radiological recurrence-free survival (rRFS), and biochemical recurrence-free survival (bRFS), using propensity score matching (PSM). We also assessed treatment-related complication outcomes of prostatectomy and radiotherapy. RESULTS: The median follow-up duration was 79 months (> 6 years). PSM generated a matched cohort of 260 patients (130 per treatment group). In the matched cohort, RARP and VMAT showed equivalent results for OS, CSS, and rRFS: both achieved excellent 6­year outcomes for OS (> 96%), CSS (> 98%), and rRFS (> 91%). VMAT had significantly longer bRFS than RARP, albeit based on different definitions of biochemical recurrence. Regarding complication outcomes, patients who underwent RARP had minimal (2.6%) severe perioperative complications and achieved excellent continence recovery (91.6 and 68.8% of the patients achieved ≤ 1 pad/day and pad-free, respectively). Patients who underwent VMAT had an acceptable rate (20.0%) of grade ≥ 2 genitourinary complications and a very low rate (4.4%) of grade ≥ 2 gastrointestinal complications. CONCLUSION: On the basis of PSM after a 6-year follow-up, RARP and VMAT showed equivalent and excellent oncological outcomes, as well as acceptable complication profiles.

The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus.

Host innate recognition triggers key immune responses for viral elimination. The sensing mechanism of hepatitis B virus (HBV), a DNA virus, and the subsequent downstream signaling events remain to be fully clarified. Here we found that type III but not type I interferons are predominantly induced in human primary hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated sensing of the 5'-ε region of HBV pregenomic RNA. In addition, RIG-I could also counteract the interaction of HBV polymerase (P protein) with the 5'-ε region in an RNA-binding dependent manner, which consistently suppressed viral replication. Liposome-mediated delivery and vector-based expression of this ε region-derived RNA in liver abolished the HBV replication in human hepatocyte-chimeric mice. These findings identify an innate-recognition mechanism by which RIG-I dually functions as an HBV sensor activating innate signaling and to counteract viral polymerase in human hepatocytes.

Artificial Intelligence Imaging Diagnosis Using Super-Resolution and 3D Shape for Lymph Node Metastasis of Low Rectal Cancer: A Pilot Study From a Single Center.

BACKGROUND: Although accurate preoperative diagnosis of lymph node metastasis is essential for optimizing treatment strategies for low rectal cancer, the accuracy of present diagnostic modalities has room for improvement. OBJECTIVE: To establish a high-precision diagnostic method for lymph node metastasis of low rectal cancer using artificial intelligence. DESIGN: A retrospective observational study. SETTINGS: A single cancer center and a college of engineering in Japan. PATIENTS: Patients with low rectal adenocarcinoma who underwent proctectomy, bilateral lateral pelvic lymph node dissection, and contrast-enhanced multi-detector row computed tomography (slice ≤1 mm) between July 2015 and August 2021 were included in the present study. All pelvic lymph nodes from the aortic bifurcation to the upper edge of the anal canal were extracted, regardless of whether within or beyond the total mesenteric excision area, and pathological diagnoses were annotated for training and validation. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. RESULTS: A total of 596 pathologically negative and 43 positive nodes from 52 patients were extracted and annotated. Four diagnostic methods, with and without using super-resolution images and without using 3D shape data, were performed and compared. The super-resolution + 3D shape data method had the best diagnostic ability for the combination of sensitivity, negative predictive value, and accuracy (0.964, 0.966, and 0.968, respectively), while the super-resolution only method had the best diagnostic ability for the combination of specificity and positive predictive value (0.994 and 0.993, respectively). LIMITATIONS: Small number of patients at a single center and the lack of external validation. CONCLUSIONS: Our results enlightened the potential of artificial intelligence for the method to become another game changer in the diagnosis and treatment of low rectal cancer. See Video Abstract.

Forced intercalation-induced light-up peptides as fluorogenic indicators for the HIV-1 TAR RNA-ligand assay.

Fluorescence indicators capable of binding to human immunodeficiency virus-1 (HIV-1) trans-activation responsive (TAR) RNA are powerful tools for the exploratory studies of the identification of anti-HIV drug candidates. This work presents a new design strategy for fluorogenic indicators with a transactivator of transcription (Tat)-derived peptide based on the forced intercalation of thiazole orange (TO) dyes (FIT). The developed 9-mer FIT peptide (RKKRR-TO-RRR: named FiLuP) features the TO unit integrated onto a Dap (2,3-diaminopropionic acid) residue in the middle of the Tat peptide sequence; the Q (glutamic acid) residue in the Tat peptide (RKKRR-Q-RRR) is replaced with TO as if it were an amino acid surrogate. This facilitates a significant light-up response (450-fold at λem = 541 nm, Φfree = 0.0057, and Φbound = 0.61) upon binding to TAR RNA. The response of FiLuP is highly selective to TAR RNA over other non-cognate RNAs, and FiLuP maintains strong binding affinity (Kd = 1.0 ± 0.6 nM). Significantly, in contrast to previously developed Tat peptide-based FRET probes, FiLuP is able to discriminate between "competitive" and "noncompetitive" inhibitors when used in the fluorescence indicator displacement (FID) assay. The FID assay under stringent screening conditions is also possible, enabling super-strong competitive binders toward TAR RNA to be sieved out.

Multiplex intraoperative rapid immunohistochemistry with non-contact antibody mixing for distinguishing the histologic phenotype of lung cancer.

INTRODUCTION: Determining a surgical strategy for early-stage lung cancer requires an accurate histologic diagnosis. Immunohistochemistry (IHC) enables reliable diagnosis of histological types but requires more time and more tumor tissue slides than hematoxylin and eosin staining. We aimed to assess the clinical validity of a new rapid multiplex IHC technique utilizing alternating current (AC) mixing for intraoperative lung cancer diagnosis. METHODS: Forty-three patients who underwent radical resection of lung cancers were enrolled in a retrospective observational study. Frozen sections were prepared from lung tumor samples, and rapid IHC employing AC mixing was implemented alongside a multiplex IHC protocol targeting thyroid transcription factor-1 + Cytokeratin 5, Desmoglein 3 + Napsin A, and p63 + tripartite motif containing 29. We then evaluated the concordance between intraoperative diagnoses derived from rapid multiplex IHC and final pathology. RESULTS: The concordance rate between the pathological diagnosis made with added rapid multiplex IHC and the final pathology was 93.0% (Cohen's 𝜅 coefficient = 0.860 and 95% CI 0.727-0.993). When considering only adenocarcinoma and squamous cell carcinoma, the diagnoses were in agreement for all cases. CONCLUSIONS: We suggest rapid multiplex IHC as a promising tool for determining surgical strategies for lung tumors.

The hypothetical molecular mechanism of the ethnic variations in the manifestation of age-related macular degeneration; focuses on the functions of the most significant susceptibility genes.

Age-related macular degeneration (AMD) is the leading sight-threatening disease in developed countries. On the other hand, recent studies indicated an ethnic variation in the phenotype of AMD. For example, several reports demonstrated that the incidence of drusen in AMD patients is less in Asians compared to Caucasians though the reason has not been clarified yet. In the last decades, several genome association studies have disclosed many susceptible genes of AMD and revealed that the association strength of some genes was different among races and AMD phenotypes. In this review article, the essential findings of the clinical studies and genome association studies for the most significant genes CFH and ARMS2/HTRA1 in AMD of different races are summarized, and theoretical hypotheses about the molecular mechanisms underlying the ethnic variation in the AMD manifestation mainly focused on those genes between Caucasians and Asians are discussed.

Risk factors affecting delay of initiating adjuvant chemotherapy for stage III colorectal cancer.

PURPOSE: Delay in initiating adjuvant chemotherapy (AC) after curative resection of colorectal cancer (CRC) has been reported to lead to poor prognosis, but few studies have looked at associated factors. This study aimed to identify risk factors for delay in initiating AC. METHODS: Data from 200 consecutive patients who underwent curative resection and AC for stage III CRC between 2013 and 2018 were retrospectively collected and analyzed. RESULTS: AC was initiated more than 8 weeks after surgery in 12.5% of patients (the delay group). Compared to those with no delay (the non-delay group), patients in the delay group had significantly higher rates of synchronous double cancers (2.3% vs. 16.0%, p = 0.001), preoperative bowel obstruction (10.3% vs. 32.0%, p = 0.003), laparotomy (56.0% vs. 80.0%, p = 0.02), concomitant resection (2.9% vs. 24.0%, p < 0.001), and postoperative complications (32.0% vs. 56.0%, p = 0.02), and a significantly longer length of hospital stay (median 12 vs. 30 days, p < 0.001). In multivariate analysis, synchronous double cancers (odds ratio 10.2, p = 0.008), preoperative bowel obstruction (odds ratio 4.6, p = 0.01), concomitant resection (odds ratio 5.2, p = 0.03), and postoperative complications of Clavien-Dindo grade ≥ IIIa (odds ratio 4.0, p = 0.03) were identified as independent risk factors for delay in initiating AC. CONCLUSION: Careful preoperative treatment planning for CRC patients with synchronous double cancers, preoperative bowel obstruction, and concomitant resection, and management for postoperative complication are necessary to avoid delay in initiating AC.

Efficacy and safety of intravesical dimethyl sulfoxide treatment for patients with refractory Hunner-type interstitial cystitis: Real-world data postofficial approval in Japan.

OBJECTIVES: To examine real-world data regarding intravesical dimethyl sulfoxide (DMSO) therapy after official approval as a treatment for Hunner-type interstitial cystitis (HIC) in Japan. METHODS: This single institution, retrospective observational study was conducted between 2021 and 2022 to evaluate the outcomes of 30 patients with refractory HIC who received intravesical DMSO therapy according to the approved standardized regimen: administration of DMSO every 2 weeks for a total of 12 weeks. Treatment outcomes were evaluated using a 7-graded global response assessment scale, O'Leary and Sant's symptom and problem indices (OSSI/OSPI), the overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, quality of life (QOL) score, and frequency volume chart variables. Related complications were also documented. RESULTS: The response rates at 2, 4, 6, 8, 10, and 12 weeks were 36.7%, 43.3%, 53.3%, 60.0%, 70.0%, and 70.0%, respectively. Compared with baseline, OSSI/OSPI, pain intensity, urinary frequency, and the QOL score improved significantly from 4 weeks of treatment. The OABSS score and functional bladder capacity also showed a tendency toward moderate improvement, but the difference was not significant. The mean duration of symptom relapse after termination of treatment was 6.4 ± 3.9 months. No patients discontinued treatment due to adverse events, although acute bladder irritation during infusion was noted in 21 patients (70%), which disappeared within 3 days. CONCLUSIONS: This study verifies the safety, moderately durable efficacy, and tolerability of the standard intravesical treatment with DMSO for HIC in Japan.

Does vacuum phenomenon at non-fused discs affect the postoperative course after transforaminal lumbar interbody fusion in patients showing a positive value of difference in lumbar lordosis?

INTRODUCTION: Preoperative difference in lumbar lordosis (DiLL) was associated with surgical outcomes after single-level transforaminal lumbar interbody fusion (TLIF). Patients with DiLL>0 (DiLL (+)) tended to show worse clinical outcomes and postoperative greater restoration of lumbar lordosis (LL). However, some patients with DiLL (+) showed relatively good outcomes and no postoperative LL restration. This study aimed to elucidate whether the lumbar intervertebral disc vacuum phenomenon (VP) influences clinical course after single-level TLIF in patients with DiLL (+) and DiLL (-). METHODS: Patients with lumbar spinal stenosis and degenerative spondylolisthesis treated with single-level TLIF were included. Pre- and postoperative LL were measured, and postoperative LL improvement was calculated. Preoperative DiLL was calculated as preoperative supine LL minus standing LL. Severity of VP at the non-fused discs (SVP (non-FS)) was evaluated using preoperative reconstructed computed tomography imaging. Clinical outcomes were assessed using the Oswestry disability index, visual analogue scale (VAS; low back pain (LBP), lower-extremity pain, numbness, and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Patients were stratified by the median preoperative SVP (non-FS) score into severe and mild VP groups in patients with DiLL (+) or DiLL (-), and their surgical outcomes were compared. RESULTS: Overall, 89 patients were included. In patients with DiLL (+) (n = 37), patients with severe VP showed worse clinical outcomes, particulary for LBP and DiLL (+) patients with mild VP showed greater LL improvement (6.5° ± 10.0°). In patients with DiLL(-) (n = 52), patients with severe VP showed worse clinical outcomes, particularly for LBP and no differences in preoperative, postoperative, and improvement of LL were observed between two groups. CONCLUSION: Patients with DiLL (+) and DiLL (-) showed different clinical courses depending on VP severity at the non-fused discs after single-level TLIF.

[Tips and Outcomes of Safe Laparoscopic Rectal Resection with Adequate Lymph Node Dissection in Patients with Obesity].

BACKGROUND: This study aimed to describe the surgical procedures involved in laparoscopic rectal resection in patients with obesity and report the short-term outcomes. MATERIALS AND METHODS: A total of 194 consecutive patients who underwent laparoscopic rectal resection in our department from 2013 to 2018 were divided into non-obese(body mass index[BMI] <25 kg/m2; n=161)and obese groups(BMI≥25 kg/m2; n=33)and subsequently analyzed. RESULTS: The operative time was significantly longer in the obese group(225 vs 266 min; p=0.003)than in the non-obese group. No conversions to laparotomy occurred in either group, and no discernible differences in blood loss(1 vs 5 mL; p=0.582), number of harvested lymph nodes(20 vs 17; p=0.356), and postoperative complication rates(9.3 vs 6.1%; p=0.547)were observed. CONCLUSION: Establishing an appropriate operative field, clarifying landmarks, and standardizing the procedure are important to assure safe laparoscopic rectal resection with adequate lymph node dissection in patients with obesity.

Pretreatment periodontitis is predictive of a poorer prognosis after esophagectomy for esophageal cancer.

BACKGROUND: Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal cancer. Several studies have investigated short-term outcomes after esophagectomy and the impact of periodontal disease, but few have examined the impact of periodontal disease on long-term outcomes. The purpose of this study was to investigate the rate of periodontitis among esophagectomy patients and the prognostic value of periodontitis and its effect on prognosis after esophagectomy. METHODS: A total of 508 patients who underwent esophagectomy received oral health care from a dentist before cancer treatment at Akita University Hospital between January 2009 and December 2021. We assessed the presence and severity of the patients' periodontitis and divided them into no-periodontitis, mild periodontitis, severe periodontitis and edentulous jaw groups. We then assessed 10-year overall survival (OS) and disease-specific survival (DSS) and determined whether periodontitis was an independent prognostic factor affecting OS and DSS. RESULTS: We found that 101 (19.9%) patients had no periodontitis, 207 (40.8%) had mild periodontitis, 176 (34.6%) had severe periodontitis requiring tooth extraction, and 24 (4.7%) had edentulous jaw. Both OS and DSS were significantly poorer in the periodontitis than no-periodontitis group (p < 0.001). In detail, the edentulous jaw group had the poorest prognosis (p < 0.001). Multivariate analysis showed that periodontitis was an independent risk factor affecting OS and DSS. CONCLUSION: Esophageal cancer patients had a high prevalence of periodontitis. Moreover, the presence of periodontitis and severity of periodontitis are independent risk factors contributing to a poorer prognosis after esophagectomy.

Oxidized alkyl phospholipids stimulate sodium transport in proximal tubules via a nongenomic PPARγ-dependent pathway.

Oxidized phospholipids have been shown to exhibit pleiotropic effects in numerous biological contexts. For example, 1-O-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocholine (azPC), an oxidized phospholipid formed from alkyl phosphatidylcholines, is a peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor agonist. Although it has been reported that PPARγ agonists including thiazolidinediones can induce plasma volume expansion by enhancing renal sodium and water retention, the role of azPC in renal transport functions is unknown. In the present study, we investigated the effect of azPC on renal proximal tubule (PT) transport using isolated PTs and kidney cortex tissues and also investigated the effect of azPC on renal sodium handling in vivo. We showed using a microperfusion technique that azPC rapidly stimulated Na+/HCO3- cotransporter 1 (NBCe1) and luminal Na+/H+ exchanger (NHE) activities in a dose-dependent manner at submicromolar concentrations in isolated PTs from rats and humans. The rapid effects (within a few minutes) suggest that azPC activates NBCe1 and NHE via nongenomic signaling. The stimulatory effects were completely blocked by specific PPARγ antagonist GW9662, ERK kinase inhibitor PD98059, and CD36 inhibitor sulfosuccinimidyl oleate. Treatment with an siRNA against PPAR gamma completely blocked the stimulation of both NBCe1 and NHE by azPC. Moreover, azPC induced ERK phosphorylation in rat and human kidney cortex tissues, which were completely suppressed by GW9662 and PD98059 treatments. These results suggest that azPC stimulates renal PT sodium-coupled bicarbonate transport via a CD36/PPARγ/mitogen-activated protein/ERK kinase/ERK pathway. We conclude that the stimulatory effects of azPC on PT transport may be partially involved in volume expansion.

Geography-Dependent Horizontal Gene Transfer from Vertebrate Predators to Their Prey.

Horizontal transfer (HT) of genes between multicellular animals, once thought to be extremely rare, is being more commonly detected, but its global geographic trend and transfer mechanism have not been investigated. We discovered a unique HT pattern of Bovine-B (BovB) LINE retrotransposons in vertebrates, with a bizarre transfer direction from predators (snakes) to their prey (frogs). At least 54 instances of BovB HT were detected, which we estimate to have occurred across time between 85 and 1.3 Ma. Using comprehensive transcontinental sampling, our study demonstrates that BovB HT is highly prevalent in one geographical region, Madagascar, suggesting important regional differences in the occurrence of HTs. We discovered parasite vectors that may plausibly transmit BovB and found that the proportion of BovB-positive parasites is also high in Madagascar where BovB thus might be physically transported by parasites to diverse vertebrates, potentially including humans. Remarkably, in two frog lineages, BovB HT occurred after migration from a non-HT area (Africa) to the HT hotspot (Madagascar). These results provide a novel perspective on how the prevalence of parasites influences the occurrence of HT in a region, similar to pathogens and their vectors in some endemic diseases.

Clinical utility of Todai OncoPanel in the setting of approved comprehensive cancer genomic profiling tests in Japan.

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).