TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.DOI: http://dx.doi.org/10.7554/eLife.17929.001

The opioid epidemic has had a significant, negative impact in the United States, and people living with HIV/AIDS (PLWHA) represent a vulnerable sub-population that is at risk for negative sequela from prolonged opioid use or opioid use disorder (OUD). PLWHA are known to suffer from HIV-related pain and are commonly treated with opioids, leading to subsequent addictive disorders. PLWHA and OUD are at an increased risk for attrition in the HIV care continuum, including suboptimal HIV laboratory testing, delayed entry into HIV care, and initiation or adherence to antiretroviral therapy. Barriers to OUD treatment, such as medication-assisted therapy, are also apparent for PLWHA with OUD, particularly those living in rural areas. Additionally, PLWHA and OUD are at a high risk for serious drug–drug interactions through antiretroviral-opioid metabolic pathway-related inhibition/induction, or via the human ether-a-go-go-related gene potassium ion channel pathways. HIV-associated neurocognitive disorders can also be potentiated by the off-target inflammatory effects of opioid use. PLWHA and OUD might require more intensive, individualized protocols to sustain treatment for the underlying opioid addiction, as well as to provide proactive social support to aid in improving patient outcomes. Advancements in the understanding and management of PLWHA and OUD are needed to improve patient care. This review describes the effects of prescription and non-prescription opioid use in PLWHA.

Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. This is mainly due to the resistance that patients develop against chemotherapeutic agents over the course of treatment. In the context of non-small cell lung cancers (NSCLC) harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a sub-population of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines, and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR-oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.

Polymer-based thermoelectric generators hold great appeal in the realm of wearable electronics as they enable the utilization of body heat for power generation. Fibers produced from conducting polymers for use in thermoelectric generators have high porosity and good flexibility, providing comfort-based performance advantages over thin films for wearable electronics. Some fiber processing techniques have been explored to produce textile-based thermoelectric generators; however, they fail to approach the conductivities of polymeric thin films. Ultrafine fibers solution processed through electrospinning yield fiber diameters on the nanoscale, allowing for high surface area to volume ratios and thus low thermal conductivity; however, a number of processing challenges in electrospinning conducting polymers limit the success of preparing high performing thermoelectric textiles. In this work, the specific processing challenges inherent to electrospinning conducting polymers are addressed for both n- and p-type materials. For the p-type polymer, 63 wt % PEDOT:PSS fibers are fabricated through solution formulation improvements yielding a conductivity of 3 S/cm and a power factor of 0.1 μW/mK2. The first of their kind n-type poly­(NiETT)/PVA electrospun fibers were created yielding a conductivity of 0.11 S/cm and a power factor of 0.0036 μW/mK2. These nonwoven ultrafine fiber mats show progress toward achieving textile-based thermoelectric materials with equivalent performance of comparable polymeric thin films. This work shows the feasibility of creating ultrafine fibers for use in thermoelectric generators through electrospinning including the first demonstration of poly­(NiETT)/PVA fibers.

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