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Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)—a master transcriptional regulator of lysosomal biogenesis and autophagy—is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti‐human podoplanin mAb, NZ‐1, and a rat–human chimeric anti‐human podoplanin antibody, NZ‐8, derived from NZ‐1, which induced antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity against podoplanin‐positive MPM cell lines. In this study, we showed the antitumor effect of NZ‐1, NZ‐8, and NZ‐12, a novel rat–human chimeric anti‐human podoplanin antibody derived from NZ‐1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ‐1 and rat NK (CD161a+) cells inhibited the growth of tumors and the production of pleural effusion in NCI‐H290/PDPN or NCI‐H226 orthotopic xenograft mouse models. NZ‐8 and human natural killer (NK) (CD56+) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ‐12 induced potent ADCC mediated by human MNC, compared with either NZ‐1 or NZ‐8. Antitumor effects were observed following treatment with NZ‐12 and human NK (CD56+) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ‐12 mediated by human NK (CD56+) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin‐targeting immunotherapy using both NZ‐12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM. Treatment of NZ‐1, NZ‐8, and NZ‐12 with NK cells induce therapeutic antitumor effect due to ADCC activity in MPM orthotopic xenograft mice models.In addition, treatment of both NZ‐12‐mediated immunotherapy and pemetrexed led to enhanced antitumor effects in MPM orthotopic xenograft mice. These data strongly suggested that NZ‐12 is an effective antibody against MPM.

Weather conditions affect the incidence of acute myocardial infarction (AMI). However, little is known on the association of weather temperature and humidity with AMI hospitalizations in a super-aging society. This study sought to examine this association. We included 87,911 consecutive patients with AMI admitted to Japanese acute-care hospitals between April 1, 2012 and March 31, 2015. The primary outcome was the number of AMI hospitalizations per day. Multilevel mixed-effects linear regression models were used to estimate the association of the average temperature and humidity, 1 day before hospital admission, with AMI hospitalizations, after adjusting for weather, hospital, and patient demographics.Lower temperature and humidity were associated with an increased number of AMI hospitalizations (coefficient − 0.500 [− 0.524 to − 0.474] per °C change, p  < 0.001 and coefficient − 0.012 [− 0.023 to − 0.001] per % change, p  = 0.039, respectively). The effects of temperature and humidity on AMI hospitalization did not differ by age and sex (all interaction p > 0.05), but differed by season. However, higher temperatures in spring (coefficient 0.089 [0.025 to 0.152] per °C change, p  = 0.010) and higher humidity in autumn (coefficient 0.144 [0.121 to 0.166] per % change, p  < 0.001) were risk factors for AMI hospitalization. Increased average temperatures and humidity, 1 day before hospitalization, are associated with a decreased number of AMI hospitalizations.

Background Hypermagnesemia is a rare electrolyte abnormality that is difficult to diagnose because its symptoms are nonspecific. In addition to magnesium administration, renal dysfunction is often a major risk factor associated with the condition; severe intestinal dysfunction is also a known risk factor. However, no cases of hypermagnesemia were observed in the absence of magnesium administration. Case presentation A 75-year-old woman with cognitive impairment presented to the emergency department with impaired consciousness. The patient was comatose and hypotensive and had a markedly distended abdomen. Her blood pressure was stabilized with infusion; however, the improvement in consciousness was insufficient and somnolence continued. Abdominal computed tomography revealed marked colonic distension due to fecal impaction in the rectum, with wall thickening and pericolonic fat stranding. Blood tests revealed elevated levels of C-reactive protein (10.2 mg/dL), lactate (6.04 mmol/L), and magnesium (5.9 mg/dL). There was no history of ingestion of magnesium-containing preparations; thus, the patient was diagnosed with hypermagnesemia associated with stercoral colitis. Magnesium levels and consciousness improved with the administration of calcium preparations, diuretics, antibiotics, and defecation control. Conclusions Severe bowel dysfunction can cause hypermagnesemia, even in the absence of magnesium administration.

Weather temperatures affect the incidence of cardiovascular diseases (CVD), but there is limited information on whether CVD hospitalizations are affected by changes in weather temperatures in a super-aging society. We aimed to examine the association of diurnal weather temperature changes with CVD hospitalizations. We included 1,067,171 consecutive patients who were admitted to acute-care hospitals in Japan between April 1, 2012 and March 31, 2015. The primary outcome was the number of CVD hospitalizations per day. The diurnal weather temperature range (DTR) was defined as the minimum weather temperature subtracted from the maximum weather temperature on the day before hospitalization. Multilevel mixed-effects linear regression models were used to estimate the association of DTR with cardiovascular hospitalizations after adjusting for weather, hospital, and patient demographics. An increased DTR was associated with a higher number of CVD hospitalizations (coefficient, 4.540 [4.310–4.765]/°C change, p  < 0.001), with greater effects in those aged 75–89 ( p  < 0.001) and ≥ 90 years ( p  = 0.006) than among those aged ≤ 64 years; however, there were no sex-related differences ( p  = 0.166). Greater intraday weather temperature changes are associated with an increased number of CVD hospitalizations in the super-aging society of Japan, with a greater effect in older individuals.

Although exposure to particulate matter with aerodynamic diameters ≤ 2.5 µm (PM 2.5 ) influences cardiovascular disease (CVD), its association with CVD-related hospitalizations of super-aged patients in Japan remains uncertain. We investigated the relationship between short-term PM 2.5 exposure and CVD-related hospitalizations, lengths of hospital stays, and medical expenses. We analyzed the Japanese national database of patients with CVD (835,405) admitted to acute-care hospitals between 2012 and 2014. Patients with planned hospitalizations and those with missing PM 2.5 exposure data were excluded. We classified the included patients into five quintiles based on their PM 2.5 exposure: PM-5, -4, -3, -2, and -1 groups, in descending order of concentration. Compared with the PM-1 group, the other groups had higher hospitalization rates. The PM-3, -4, and -5 groups exhibited increased hospitalization durations and medical expenses, compared with the PM-1 group. Interestingly, the hospitalization period was longer for the ≥ 90-year-old group than for the ≤ 64-year-old group, yet the medical expenses were lower for the former group. Short-term PM 2.5 exposure is associated with increased CVD-related hospitalizations, hospitalization durations, and medical expenses. The effects of incident CVDs were more marked in elderly than in younger patients. National PM 2.5 concentrations should be reduced and the public should be aware of the risks.

The modulation of pre‐mRNA splicing is proposed as an attractive anti‐neoplastic strategy, especially for the cancers that exhibit aberrant pre‐mRNA splicing. Here, we discovered that T‐025 functions as an orally available and potent inhibitor of Cdc2‐like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T‐025 reduced CLK‐dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo . Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive‐associated biomarker of T‐025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T‐025 treatment. MYC activation, which altered pre‐mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti‐tumor efficacy of T‐025 in an allograft model of spontaneous, MYC‐driven breast cancer, at well‐tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC‐driven cancer patients. Synopsis MYC oncogene is a highly valuable target for cancer therapy. A newly discovered CLK inhibitor, T‐025, exhibited anti‐tumor efficacies against cancers with a high CLK2 expression, as well as against MYC‐driven cancers, as a result of attacking a MYC‐dependent vulnerability. A novel and potent CLK inhibitor, T‐025, was discovered and characterized as a new pre‐mRNA splicing modulating anti‐cancer agent. T‐025 exhibited in vivo anti‐tumor efficacy in both cell line xenograft tumors and mice spontaneous allograft tumors. The expression level of CLK2 in each cell line was associated with the growth‐inhibitory sensitivity and magnitude of alternative skipped exons in response to T‐025 treatment. T‐025 showed a higher growth inhibition effect on MYC‐amplified solid cancer cell lines than on non‐MYC‐amplified solid cancer cell lines and induced synergistic cell death with ectopic MYC activation. Graphical Abstract MYC oncogene is a highly valuable target for cancer therapy. A newly discovered CLK inhibitor, T‐025, exhibited anti‐tumor efficacies against cancers with a high CLK2 expression, as well as against MYC‐driven cancers, as a result of attacking a MYC‐dependent vulnerability.

Disruption in the flow of blood vessels is of great concern during thoracic surgery. Preoperative 3-dimensional computed tomography facilitates visualization of the exact location and course of blood vessels. The right posterior upper lobe segmental vein, known as the right top pulmonary vein (RTPV), is an anomalous vein beginning at the right upper lobe and running through the posterior surface of the intermediate bronchus. We clinically investigated 31 patients with RTPV who underwent lobectomy or total resection of the right lung in our hospital or related institutions. We classified the final destination of RTPV into four types. The RTPV flowed into the left atrium in 35.5% of cases, superior pulmonary vein in 9.7%, inferior pulmonary vein in 41.9%, and independently into V6 in 12.9%. An RTPV with a diameter ≥ 5 mm was considered a main drainage vein in S2. We should pay attention to the RTPV during right lung lobectomy.

Brugada syndrome (BrS) can be diagnosed by a type 1 BrS tracing in a 12-lead electrocardiogram (ECG). However, there are daily variations in the ECGs of BrS patients, which presents a challenge when diagnosing BrS. Although many susceptibility genes have been identified, the SCN5A gene is reportedly the main causative gene of BrS. However, most patients do not have an evidence of genetic predisposition to develop BrS. In addition, the diagnosis and risk stratification for ventricular fibrillation (VF) in patients with BrS presents some problems. Meanwhile, circulating micro RNAs (miRNAs) have drawn increased attention as potential biomarkers of various diseases. We hypothesize that circulating miRNAs may be potential diagnostic biomarkers for BrS. We enrolled 70 Japanese BrS patients and 34 controls for the screening cohort. A total of 2,555 miRNA sequences were detected using the 3D-Gene miRNAs labeling kit and 3D-Gene Human miRNAs Oligo Chip. We compared the expression of the miRNAs between the BrS patients and the controls. We validated whether the miRNA were significantly up- or downregulated in the screening cohort using RT-PCR. We also enrolled 72 Japanese BrS patients and 56 controls to replicate these miRNAs. Eight miRNAs (hsa-miR-223-3p, hsa-miR-22-3p, hsa-miR-221-3p, hsa-miR-4485-5p, hsa-miR-550a-5p, hsa-miR-423-3p, hsa-miR-23a-3p, and hsa-miR-30d-5p) were downregulated, and one miRNA (hsa-miR-873-3p) was upregulated by more than 3-fold in BrS patients. The multivariate logistic regression analysis determined that hsa-miR-423-3p, hsa-miR-223-3p, and hsa-miR-23a-3p were independently associated with BrS (P < 0.0001). The AUC based on cross validation was 0.871 with a sensitivity and specificity of 83.5% and 81.1%, respectively. The plasma miRNAs are potential noninvasive biomarkers of BrS, and the constructed logistic model was useful for discriminating BrS.