Taiwan cobra (Naja atra) bites account for approximately 20% of all venomous snakebites in Taiwan. In Taiwan, the rates of wound necrosis and secondary infection from Taiwan cobra bites are higher than those associated with other venomous snakebites. Clinical tools to evaluate the infection risk after Taiwan cobra bites are lacking. Therefore, in this study, we developed a useful clinical tool to evaluate the infection risk after Taiwan cobra bites. Moreover, we investigated wound infection bacteriology. We analyzed the data of patients bitten by N. atra who had undergone freeze-dried neurotoxic antivenin treatment in emergency rooms of the Chang Gung Memorial Hospital network, which comprises seven hospitals and the largest medical system in Taiwan, from January 2001 to May 2017. Because patients with wound necrosis required antibiotics for infection treatment, we included only patients with wound infection but without tissue necrosis in the development of our Cobra Bacteriology of Infections in Taiwanese snake Envenomation (Cobra BITE) score by using univariate and multiple logistic regression. In total, 8,295,497 emergency department visits occurred from January 2001 to May 2017, and 195 patients were diagnosed has having cobra bites. Among them, 23 and 30 patients had wound necrosis and wound infection, respectively. The wound infection rate was 27.2% (53/195). Regardless of whether the patients had necrosis, Enterococcus faecalis and Morganella morganii were the main bacteria identified in the culture report. Gentamicin, ceftriaxone, ciprofloxacin, and levofloxacin are the ideal first-line antibiotics for treating N. atra bite wounds in Taiwan. As per our Cobra BITE score, the three factors predicting secondary wound infection after cobra bites are hospital admission, a white blood cell count (in 103/µL) × by neutrophil–lymphocyte ratio value of ≥114.23, and the use of antivenin medication. The area under the receiver operating characteristic curve for the Cobra BITE score system was 0.88. The ideal sensitivity and specificity were 0.89 and 0.76, respectively, and the optimal cutoff point for Cobra BITE score was 7. The Hosmer–Lemeshow p value was 0.4. In conclusion, our Cobra BITE study established a new practical clinical tool for clinicians to evaluate infection risk after N. atra bites. This score system enables the assessment of wound infections after N. atra bites, and it could be modified and improved in future for other Naja spp. bites.

In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

Relapses and resistance to therapeutic agents are major barriers for treatment of acute myeloid leukemia (AML) patients. This unfavorable circumstance emphasizes the need for new strategies targeting drug-resistant cells. As IDH mutation is present in the preleukemic stem cells and systematically conserved at relapse, targeting mutant IDH cells would be essential to achieve a long-term remission in the AML subgroup with IDH mutation. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutation, we showed that the presence of IDH mutation through the production of an oncometabolite (R)-2-HG induces vitamin D receptor related transcriptional programs, priming these AML cells to differentiate with pharmacological doses of ATRA or/and VD. This activation occurs in a CEBP-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutation and vitamin D pathway to differentiate in AML, revealing a novel therapeutic approach easily transferable/immediately applicable in clinics for this subgroup of AML patients.

Deuterostomes make a sudden appearance in the fossil record during the Early Cambrian. Two deuterostome groups, the chordates and the vetulicolians, are of particular interest for understanding the evolutionary dynamics of the Cambrian evolutionary event. Lagerstätten in China and elsewhere have dramatically improved our understanding of the range of variation in these ancient animals. Cephalochordate and vertebrate body plans are well established at least by Cambrian Series 2. Taken together, roughly a dozen chordate genera and fifteen vetulicolian genera document an explosive radiation of deuterostomes at the base of the Cambrian. A new vetulicolian (••• nov. gen. nov. sp.) with a polygonal anterior section and a narrow, unsegmented posterior region (‘tail’) bearing possible myotomes provides new insight into the affinities of the various body plans that emerged during the Early Cambrian. It seems clear that the advent of deuterostomes near the Cambrian boundary involved both a reversal of gut polarity and a two-sided retinoic acid gradient, with a gradient discontinuity at the midpoint of the organism that is reflected in the sharp division of vetulicolians into anterior and posterior sections.