Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-α) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-α. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-α stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1α and/or HIF-2α, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-α activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA.

Background: ZyCoV-D is a DNA vaccine candidate, which comprises a plasmid DNA carrying spike-S gene of SARS-CoV-2 virus along with gene coding for signal peptide. The spike(S) region includes the receptor-binding domain (RBD), which binds to the human angiotensin converting Enzyme (ACE)-2 receptor and mediates the entry of virus inside the cell. Methods: We conducted a single-center, open-label, non-randomized, Phase 1 trial in India between July 2020 and October 2020. Healthy adults aged between 18 and 55 years were sequentially enrolled and allocated to one of four treatment arms in a dose escalation manner. Three doses of vaccine were administered 28 days apart and each subject was followed up for 28 days post third dose to evaluate safety and immunogenicity. Findings: Out of 126 individuals screened for eligibility. Forty-eight subjects (mean age 34¢9 years) were enrolled and vaccinated in the Phase 1 study Overall, 12/48 (25%) subjects reported at least one AE (i.e. combined solicited and unsolicited) during the study. There were no deaths or serious adverse events reported in Phase 1 of the study. The proportion of subjects who seroconverted based on IgG titers on day 84 was 4/11 (36¢36%), 4/12 (33¢33%), 10/10 (100¢00%) and 8/10 (80¢00%) in the treatment Arm 1 (1 mg: Needle), Arm 2 (1 mg: NFIS), Arm 3 (2 mg: Needle) and Arm 4 (2 mg: NFIS), respectively. Interpretation: ZyCoV-D vaccine is found to be safe, well-tolerated and immunogenic in the Phase 1 trial. Our findings suggest that the DNA vaccine warrants further investigation.

We provide evidence that arsenic trioxide (As 2 O 3 ) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/ SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or ca- IntroductionElements of the autophagic machinery have attracted recently considerable attention as a potential target for the development of novel approaches for the treatment of malignancies. 1,2 Similar to apoptosis, autophagy is a programmed cell death mechanism, but it is distinguished by a self-catabolic process involving lysosomal proteolytic degradation of cellular components. 3 This is initiated by the formation of a double-membrane enclosed structure, known as the autophagosome. 4 On fusion with a lysosome, a cellular organelle characterized by low pH and hydrolytic enzymes, 5,6 such structure eventually develops into the autophagolysosome where degradation of organelles occurs.Under different circumstances, autophagy can either inhibit or promote malignant cell survival, but its precise role in tumorigenesis remains to be established. 7,8 The role of inducible autophagy in BCR-ABL expressing leukemia cells is poorly understood. For example, there is previous evidence suggesting that autophagy may play regulatory roles in BCR-ABL leukemogenesis, 9 whereas other studies have shown that pharmacologic inhibition of autophagy enhances the effects of imatinib mesylate and other targeted therapies in CML. [10][11][12] There are also opposing lines of evidence, pointing toward tumor inhibitory effects of autophagy, 13,14 although a recent study demonstrated that BCR-ABL exerts suppressive effects on autophagy via engagement of the PI3K/FoxO4/ATF5/ mTOR pathway. 15 Arsenic trioxide (AS 2 O 3 ) exhibits potent antileukemic effects in vitro and in vivo and has major clinical activity in the treatment of patients with acute promyelocytic leukemia (APL). [16][17][18] This agent was previously shown to target and eliminate leukemia initiating stem cells (LICs) in mouse models in vivo via PML targeting. 19 Notably, there is evidence that AS 2 O 3 degrades BCR-ABL, 20 raising the possibility that this agent may provide an approach to target CML LICs. However, a major limiting factor for the incorporation of arsenic in non-APL malignancies has been the requirement of high concentrations for induction of cell death in non-APL cells and the incomplete understanding of the mechanisms by which it promotes antileukemic responses.A major mechanism contributing to the antineoplastic effects of arsenic is induction of apoptosis, 16-18 with upstream JNK activation being a prominent regulatory mechanism. 21 In a recent study, we provided evidence that arsenic trioxide induces autophagy in AML leukemic progenitors and demonstrated that such autophagy is essential for generation of the inhibitory effects of arsenic on primitive leukemic precursors. 22 However, the key downstream cellular events by which such arsenic-de...

Background:The potential involvement of Spry proteins in IFN signaling is unknown. Results: Type I IFN treatment results in up-regulation of Spry proteins, which negatively control generation of IFN responses. Conclusion: Spry proteins play important regulatory roles in IFN signaling and the generation of the biological effects of IFNs. Significance: This study provides evidence for the existence of a key signaling pathway that controls IFN responses.

Background: The precise roles for Rictor/Sin1 complexes in IFN signaling remain to be defined. Results: Targeted disruption Rictor/Sin1 results in defects in activation of elements of Stat pathways. These proteins are required for IFN antineoplastic effects on malignant erythroid precursors. Conclusion: Rictor/Sin1 play critical roles in IFN signaling. Significance: This study provides evidence for a key mechanism for gene regulation associated with generation of IFN antineoplastic responses.

IFN␥ exhibits potent antitumor effects and plays important roles in the innate immunity against cancer. However, the mechanisms accounting for the antiproliferative effects of IFN␥ still remain to be elucidated. We examined the role of

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