Engineering a BCR-ABL–Activated Caspase for the Selective Elimination of Leukemic Cells

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations

Predicting clinical outcomes of cancer patients with a p53 deficiency gene signature

The tumor suppressor p53, encoded by the TP53 gene, is mutated or nullified in nearly 50% of human cancers. It has long been debated whether TP53 mutations can be utilized as a biomarker to predict clinical outcomes of cancer patients. In this study, we applied computational methods to calculate p53 deficiency scores (PDSs) that reflect the inactivation of the p53 pathway, instead of TP53 mutation status. Compared to TP53 mutation status, the p53 deficiency gene signature is a powerful predictor of overall survival and drug sensitivity in a variety of cancer types and treatments. Interestingly, the PDSs predicted clinical outcomes more accurately than drug sensitivity in cell lines, suggesting that tumor heterogeneity and/or tumor microenvironment may play an important role in predicting clinical outcomes using p53 deficiency gene signatures

Phospholipase Cδ4 is required for Ca2+ mobilization essential for acrosome reaction in sperm

Zona pellucida (ZP)–induced acrosome reaction in sperm is a required step for mammalian fertilization. However, the precise mechanism of the acrosome reaction remains unclear. We previously reported that PLCδ4 is involved in the ZP-induced acrosome reaction in mouse sperm. Here we have monitored Ca2+ responses in single sperm, and we report that the [Ca2+]i increase in response to ZP, which is essential for driving the acrosome reaction in vivo, is absent in PLCδ4−/− sperm. Progesterone, another physiological inducer of the acrosome reaction, failed to induce sustained [Ca2+]i increases in PLCδ4−/− sperm, and consequently the acrosome reaction was partially inhibited. In addition, we observed oscillatory [Ca2+]i increases in wild-type sperm in response to these acrosome inducers. Calcium imaging studies revealed that the [Ca2+]i increases induced by exposure to ZP and progesterone started at different sites within the sperm head, indicating that these agonists induce the acrosome reaction via different Ca2+ mechanisms. Furthermore, store-operated channel (SOC) activity was severely impaired in PLCδ4−/− sperm. These results indicate that PLCδ4 is an important enzyme for intracellular [Ca2+]i mobilization in the ZP-induced acrosome reaction and for sustained [Ca2+]i increases through SOC induced by ZP and progesterone in sperm

A Comprehensive Study of Repetitive Transcranial Magnetic Stimulation in Parkinson's Disease

The clinical benefits of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's disease (PD) remain controversial. We performed a comprehensive study to examine whether rTMS is a safe and effective treatment for PD. Twelve PD patients received rTMS once a week. The crossover study design consisted of 4-week sham rTMS followed by 4-week real rTMS. The Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoehn and Yahr Stage, Schwab and England ADL Scale, Actigraph, Mini-Mental State Examination, Hamilton Depression Scale, Wechsler Adult Intelligence Scale-revised, and cerebral blood flow (CBF) and cerebrospinal fluid (CSF) examinations were used to evaluate the rTMS effects. Under both drug-on and drug-off conditions, the real rTMS improved the UPDRS scores significantly, while the sham rTMS did not. There were no significant changes in the results of the neuropsychological tests, CBF and CSF. rTMS seems to be a safe and effective therapeutic option for PD patients, especially in a wearing-off state

Human Blood Feeding Activity of Female Hybrids between Culex pipiens pipiens and Culex pipiens quinquefasciatus（Diptera: Culicidae）

Human blood feeding activity was examined in females of hybrids between Culex pipiens pipiens and Culex pipiens quinquefasciatus during long photoperiod at 25℃. Blood feeding rates of hybrids were lower than in Culex pipiens quinquefasciatus and Culex pipiens pallens, and higher than in Culex pipiens pipiens, because no females fed on human blood in Culex pipiens pipiens

Real-world clinical outcomes of nivolumab and taxane as a second- or later-line therapy for recurrent or unresectable advanced esophageal squamous cell carcinoma

BackgroundNivolumab is approved in Japan as a second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC) resistant to fluoropyrimidine and platinum-based drugs. It is also used in adjuvant and primary postoperative therapies. This study aimed to report real-world data on nivolumab use for esophageal cancer treatment.MethodsIn total, 171 patients with recurrent or unresectable advanced ESCC who received nivolumab (n = 61) or taxane (n = 110) were included. We collected real-world data of patients treated with nivolumab as a second- or later-line therapy and evaluated treatment outcomes and safety.ResultsMedian overall survival was longer and progression-free survival (PFS) was significantly longer (p = 0.0172) in patients who received nivolumab than in patients who received taxane as a second- or later-line therapy. Furthermore, subgroup analysis for second-line treatment only showed the superiority of nivolumab in increasing the PFS rate (p = 0.0056). No serious adverse events were observed.ConclusionsIn real-world practice, nivolumab was safer and more effective than taxane in patients with ESCC with diverse clinical profiles who did not meet trial eligibility criteria, including those with poor Eastern Cooperative Oncology Group performance status, comorbidities, and receiving multiple treatments

Minimally Invasive Surgery for Giant Oesophageal and Gastric Leiomyomas

Herein, we describe a case of a 41-year-old woman with two giant leiomyomas located in the lower thoracic oesophagus and gastric cardia that were treated by minimally invasive thoracoscopic and laparoscopic surgery. We first resected the gastric cardia and laparoscopically prepared a gastric tube, and then we resected the lower thoracic oesophagus and intrathoracically anastomosed the oesophagus and gastric tube using thoracoscopic surgery with the patient in the prone position. Two concurrent giant leiomyomas of the oesophagus and stomach are rare, and the choice of surgical procedure to address the tumour from the mediastinum into the abdominal cavity was particularly challenging. We selected a minimally invasive thoracoscopic approach with the patient in the prone position. This strategy seems effective for resecting these giant tumours in the lower thoracic oesophagus and gastric cardia

Metabolic activation of CaMKII by coenzyme A

Active metabolism regulates oocyte cell death via calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation of caspase-2, but the link between metabolic activity and CaMKII is poorly understood. Here we identify coenzyme A (CoA) as the key metabolic signal that inhibits Xenopus laevis oocyte apoptosis by directly activating CaMKII. We found that CoA directly binds to the CaMKII regulatory domain in the absence of Ca(2+) to activate CaMKII in a calmodulin-dependent manner. Furthermore, we show that CoA inhibits apoptosis not only in X. laevis oocytes but also in Murine oocytes. These findings uncover a direct mechanism of CaMKII regulation by metabolism and further highlight the importance of metabolism in preserving oocyte viability

Cryptosporidium oocyst検出法

The protozoa Cryptosporidium parvum has been identified as one of the agents responsible for numerous outbreaks of diarrheal diseases. Detection of C.parvum oocysts in clinical and environmental samples is the key in the diagnosis of cryptosporidiosis in human and in identifying a water-borne and/or food-borne outbreaks. Therfore, it is very important and necessary to have simples, sensitive and specific methods. However, no such perfect methods are available as yet. In this context, we studies the various methods available by modifying at different aspects and steps using samples collected in Nepal. This study revealed that morphological test using microscopy in combination with specific immunological is valuable for quick screening and the genetic method is effective method for identifying Cryptosporidium species