Lactate promotes bone healing by regulating the osteogenesis of bone marrow mesenchymal stem cells through activating Olfr1440.

Bone malunion or nonunion leads to functional and esthetic problems and is a major healthcare burden. Activation of bone marrow mesenchymal stem cells (BMSCs) and subsequent induction of osteogenic differentiation by local metabolites are crucial steps for bone healing, which has not yet been completely investigated. Here, we found that lactate levels are rapidly increased at the local injury site during the early phase of bone defect healing, which facilitates the healing process by enhancing BMSCs regenerative capacity. Mechanistically, lactate serves as a ligand for the Olfr1440 olfactory receptor, to trigger an intracellular calcium influx that in turn activates osteogenic phenotype transition of BMSCs. Conversely, ablation of Olfr1440 delays skeletal repair and remodelling, as evidenced by thinner cortical bone and less woven bone formation in vivo. Administration of lactate in the defect area enhanced bone regeneration. These findings thus revealed the key roles of lactate in the osteogenic differentiation of BMSCs, which deepened our understanding of the bone healing process, as well as provided cues for a potential therapeutic option that might greatly improve bone defect treatment.

Construct Amorphous Polymer Interface to Enhance the Thermoelectric Performance of Commercial Bi0.5Sb1.5Te3 Materials.

Interfaces, such as grain boundaries and phase boundaries in thermoelectric (TE) materials, play a crucial role in the carrier/phonon transport. Accurate control of the features of interfaces, including composition, crystalline nature, and thickness may give rise to a promising pathway to break the trade-off between phonon and carrier transport properties, which is essential to design high-performance TE materials. In this work, the amorphous polymer interface (API) layer is introduced to the p-type commercial Bi0.5Sb1.5Te3 (BST) TE material by the liquid-phase sintering process. Due to the larger mismatch in the acoustic impedance or phonon spectra between the amorphous polymer layer and the BST phase, the additional interfacial thermal resistance is introduced, which results in a large decrease in lattice thermal conductivity. It is found that the interfacial thermal resistance at the API is much higher than that of normal grain boundary and hetero interface reported in the literature. Conversely, taking advantage of the strong electron and phonon scattering, a large net get of ZT was achieved. A maximum ZT of ∼1.22 at 350 K was obtained in the BST/polyimide-0.5% sample, which is considerably greater than that of the commercial BST matrix (∼0.99 at 350 K). Furthermore, the optimized BST/polymer sample also exhibited almost 20% enhancement in hardness compared with the pure BST sample. This work has opened a new window for designing high-performance TE composites, which may extend to other material systems.

Safety and Tolerability of Accelerated Infliximab Infusions in Patients With Inflammatory Bowel Disease.

INTRODUCTION: Infliximab for inflammatory bowel disease (IBD) is FDA-approved to be administered 2 h or more. We adopted a new protocol to infuse infliximab over 1 h and in this study, we aimed to determine the safety of a 1-h infusion. METHODS: This retrospective cohort included adult IBD patients who received infliximab between June and December 2017 and compared reaction rates of 1-h maintenance infusions to that of 2-h maintenance infusions. RESULTS: A total of 551 infusions were administered to 179 patients. The infusion groups demonstrated no significant differences in reaction rates. CONCLUSIONS: Infliximab infusion over 1 h is well-tolerated.

Incidence of first and second primary cancers diagnosed among people with HIV, 1985-2013: a population-based, registry linkage study.

BACKGROUND: Cancer survivors are at increased risk for subsequent primary cancers. People living with HIV are at increased risk for AIDS-defining and non-AIDS-defining cancers, but little is known about their risk of first versus second primary cancers. We identified first and second primary cancers that occurred in above population expected numbers among people diagnosed with HIV in San Francisco, and compared first and second cancer incidence across five time periods that corresponded to important advances in antiretroviral therapy. METHODS: In this population-based study, we used the San Francisco HIV/AIDS case registry to identify people aged 16 years and older who were diagnosed with HIV/AIDS in San Francisco (CA, USA) between Jan 1, 1990, and Dec 31, 2010. We computer-matched records from the registry with the California Cancer Registry to identify primary cancers diagnosed between Jan 1, 1985, and Dec 31, 2013. We calculated year, age, sex, and race adjusted standardised incidence ratios with exact 95% CIs and trends in incidence of first and second AIDS-defining and non-AIDS-defining cancers from 1985 to 2013. FINDINGS: Of the 22 623 people diagnosed with HIV between Jan 1, 1990, and Dec 31, 2010, we identified 5655 incident primary cancers. We excluded 48 cancers with invalid cancer sequence numbers and 1062 in-situ anal cancers, leaving 4545 incident primary cancers, comprising 4144 first primary cancers, 372 second primary cancers, 26 third primary cancers, and three fourth or later primary cancers. First primary cancer standardised incidence ratios were elevated for Kaposi sarcoma (127, 95% CI 121-132), non-Hodgkin lymphoma (17·2, 16·1-18·4), invasive cervical cancer (8·0, 4·1-11·9), anal cancer (46·7, 39·7-53·6), vulvar cancer (13·3, 6·1-20·6), Hodgkin's lymphoma (10·4, 8·4-12·5), eye and orbit cancer (4·2, 1·4-6·9), lip cancer (3·8, 1·3-6·2), penile cancer (3·8, 1·4-6·1), liver cancer (3·0, 2·3-3·7), miscellaneous cancer (2·3, 1·7-3·0), testicular cancer (2·0, 1·4-2·6), tongue cancer (1·9, 1·1-2·7), and lung cancer (1·3, 95% CI 1·1-1·6). Second primary cancer risks were increased for Kaposi sarcoma (28·0, 95% CI 20·2-35·9), anal cancer (17·0, 10·2-23·8), non-Hodgkin lymphoma (11·1, 9·3-12·8), Hodgkin's lymphoma (5·4, 1·1-9·7), and liver cancer (3·6, 1·4-5·8). We observed lower first primary cancer standardised incidence ratios for prostate cancer (0·6, 95% CI 0·5-0·7), colon cancer (0·6, 0·4-0·8), and pancreatic cancer (0·6, 0·3-1·0), and lower second primary cancer standardised incidence ratios for testicular cancer (0·3, 0·0-0·9), kidney cancer (0·4, 0·0-0·9), and prostate cancer (0·6, 0·2-0·9). First and second primary AIDS-defining cancer incidence declined, and second primary non-AIDS-defining cancer incidence increased over time. INTERPRETATION: Because of an increased risk for both first and second primary cancers, enhanced cancer prevention, screening, and treatment efforts are needed for people living with HIV both before and after initial cancer diagnosis. FUNDING: University of California San Francisco and US Centers for Disease Control and Prevention.

Changing temporal trends in non-AIDS cancer mortality among people diagnosed with AIDS: San Francisco, California, 1996-2013.

BACKGROUND: Antiretroviral therapy (ART) has reduced AIDS-defining cancer (ADC) mortality, but its effect on non-AIDS-defining cancer (NADC) mortality is unclear. To help inform cancer prevention and screening, we evaluated trends in NADC mortality among people with AIDS (PWA) in the ART era. METHODS: This retrospective cohort study analyzed AIDS surveillance data, including causes of death from death certificates, for PWA in San Francisco who died in 1996-2013. Proportional mortality ratios (PMRs), and year, age, race, sex-adjusted standardized mortality ratios (SMRs) were calculated for 1996-1999, 2000-2005, and 2006-2013, corresponding to advances in ART. RESULTS: The study included 5822 deceased PWA of whom 90% were male and 68% were aged 35-54 at time of death. Over time, the PMRs significantly decreased for ADCs (2.6%, 1.4%, 1.2%) and increased for NADCs (4.3%, 7.0%, 12.3%). For all years combined (1996-2013) and compared to the California population, significantly elevated SMRs were observed for these cancers: all NADCs combined (2.1), anal (58.4), Hodgkin lymphoma (10.5), liver (5.2), lung/larynx (3.0), rectal (5.2), and tongue (4.7). Over time, the SMRs for liver cancer (SMR 19.8, 11.2, 5.0) significantly decreased while the SMRs remained significantly elevated over population levels for anal (SMR 123, 48.2, 45.5), liver (SMR 19.8, 11.2, 5.0), and lung/larynx cancer (SMR 5.3, 4.7, 3.6). CONCLUSION: A decline in ADC PMRs and increase in NADC PMRs represent a shift in the cancer burden, likely due to ART use. Moreover, given their elevated SMRs, anal, liver, and lung/larynx cancer remain targets for improved cancer prevention, screening, and treatment.