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Thiamin pyrophosphate (ThDP), the active form of thiamin (vitamin B1), is believed to be an essential cofactor for all living organisms1,2. Here, we report the unprecedented result that thiamin is dispensable for the growth of the Lyme disease pathogen Borrelia burgdorferi (Bb)3. Bb lacks genes for thiamin biosynthesis and transport as well as known ThDP-dependent enzymes4, and we were unable to detect thiamin or its derivatives in Bb cells. We showed that eliminating thiamin in vitro and in vivo using BcmE, an enzyme that degrades thiamin, has no impact on Bb growth and survival during its enzootic infectious cycle. Finally, high-performance liquid chromatography analysis reveals that the level of thiamin and its derivatives in Ixodes scapularis ticks, the enzootic vector of Bb, is extremely low. These results suggest that by dispensing with use of thiamin, Borrelia, and perhaps other tick-transmitted bacterial pathogens, are uniquely adapted to survive in tick vectors before transmitting to mammalian hosts. To our knowledge, such a mechanism has not been reported previously in any living organisms.

Thiamin pyrophosphate (ThDP), the active form of thiamin (vitamin B1), is believed to be an essential cofactor for all living organisms1,2. Here, we report the unprecedented result that thiamin is dispensable for the growth of the Lyme disease pathogen Borrelia burgdorferi (Bb)3. Bb lacks genes for thiamin biosynthesis and transport as well as known ThDP-dependent enzymes4, and we were unable to detect thiamin or its derivatives in Bb cells. We showed that eliminating thiamin in vitro and in vivo using BcmE, an enzyme that degrades thiamin, has no impact on Bb growth and survival during its enzootic infectious cycle. Finally, high-performance liquid chromatography analysis reveals that the level of thiamin and its derivatives in Ixodes scapularis ticks, the enzootic vector of Bb, is extremely low. These results suggest that by dispensing with use of thiamin, Borrelia, and perhaps other tick-transmitted bacterial pathogens, are uniquely adapted to survive in tick vectors before transmitting to mammalian hosts. To our knowledge, such a mechanism has not been reported previously in any living organisms.

Here, we report recurrent focal deletions of the chr14q32.31- 32 locus, including TRAF3, a negative regulator of NF- kB signaling, in de novo diffuse large B cell lymphoma (DLBCL) (24/324 cases). Integrative analysis revealed an association between TRAF3 copy number loss with accumulation of NIK, the central noncanonical (NC) NF- kB kinase, and increased NC NF- kB pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF- kB downstream signaling. Knockdown or pharmacological inhibition of NIK in TRAF3- deficient cells differentially impaired their proliferation and survival, suggesting an acquired onco- addiction to NC NF- kB. TRAF3 ablation also led to exacerbated secretion of the immunosuppressive cytokine IL- 10. Coculturing of TRAF3- deficient DLBCL cells with CD8+ T cells impaired the induction of Granzyme B and interferon (IFN) γ, which were restored following neutralization of IL- 10. Our findings corroborate a direct relationship between TRAF3 genetic alterations and NC NF- kB activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL. [ABSTRACT FROM AUTHOR]

In the era of free flap reconstruction, mandibular defects are routinely reconstructed with osseous free flaps, and non‐free flap bony reconstruction options are limited. A patient with T4N0 mandibular squamous cell carcinoma underwent resection with fibula free flap reconstruction of a parasymphyseal to angle defect. After free flap failure due to venous congestion, the flap was explanted. He declined additional free flap reconstruction and elected to proceed with pedicled osteomyocutaneous pectoralis major with rib. In this case presentation, we discuss the technical details of harvest of this flap using the 6th rib. The pedicled osteomyocutaneous pectoralis major flap with osseous rib harvest, which is infrequently described in the literature, remains a viable option for bony reconstruction, particularly in the salvage setting. [ABSTRACT FROM AUTHOR]

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies., Introduction The current treatment standard of combined immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has achieved significant improvement in patient outcomes in diffuse large B cell lymphoma (DLBCL) [...]

ImportanceBlepharoplasty is one of the most commonly performed facial aesthetic surgeries. While myriad techniques exist to improve the appearance of the lower eyelids, there is no clear consensus on the optimal management of the orbital septum.ObjectivesTo evaluate the safety and feasibility of the use of the holmium:yttrium aluminum garnet (Ho:YAG) laser for orbital septal tightening, and to determine whether modest use of this laser would provide some degree of clinical efficacy.Design, setting, and participantsDirect laser irradiation of ex vivo bovine tissue was used to determine appropriate laser dosimetry using infrared thermal imaging and optical coherence tomography before conducting a pilot clinical study in 5 patients. Laser irradiation of the lower eyelid orbital septum was performed through a transconjunctival approach. Standardized preoperative and postoperative photographs were taken for each patient and evaluated by 6 unbiased aesthetic surgeons.ExposureUse of the Ho:YAG laser for orbital septal tightening.Main outcome and measureTo determine appropriate laser dosimetry, infrared thermal imaging and optical coherence tomography were used to monitor temperature and tissue shape changes of ex vivo bovine tissue that was subjected to direct laser irradiation. For the clinical study, preoperative and postoperative photographs were evaluated by 6 surgeons on a 10-point Likert scale.ResultsOptical coherence tomography demonstrated that laser irradiation of bovine tissue to a temperature range of 60°C to 80°C resulted in an increase in thickness of up to 2-fold. There were no complications or adverse cosmetic outcomes in the patient study. Patient satisfaction with the results of surgery averaged 7 on a 10-point Likert scale. For 3 patients, 3 (50%) of the evaluators believed there was a mild improvement in appearance of the lower eyelids after surgery. The remaining patients were thought to have no significant changes.Conclusions and relevanceTransconjunctival Ho:YAG laser blepharoplasty is a safe procedure that may ameliorate mild pseudoherniation of lower eyelid orbital fat and is a first step toward the development of percutaneous techniques.

ImportanceBlepharoplasty is one of the most commonly performed facial aesthetic surgeries. While myriad techniques exist to improve the appearance of the lower eyelids, there is no clear consensus on the optimal management of the orbital septum.ObjectivesTo evaluate the safety and feasibility of the use of the holmium:yttrium aluminum garnet (Ho:YAG) laser for orbital septal tightening, and to determine whether modest use of this laser would provide some degree of clinical efficacy.Design, setting, and participantsDirect laser irradiation of ex vivo bovine tissue was used to determine appropriate laser dosimetry using infrared thermal imaging and optical coherence tomography before conducting a pilot clinical study in 5 patients. Laser irradiation of the lower eyelid orbital septum was performed through a transconjunctival approach. Standardized preoperative and postoperative photographs were taken for each patient and evaluated by 6 unbiased aesthetic surgeons.ExposureUse of the Ho:YAG laser for orbital septal tightening.Main outcome and measureTo determine appropriate laser dosimetry, infrared thermal imaging and optical coherence tomography were used to monitor temperature and tissue shape changes of ex vivo bovine tissue that was subjected to direct laser irradiation. For the clinical study, preoperative and postoperative photographs were evaluated by 6 surgeons on a 10-point Likert scale.ResultsOptical coherence tomography demonstrated that laser irradiation of bovine tissue to a temperature range of 60°C to 80°C resulted in an increase in thickness of up to 2-fold. There were no complications or adverse cosmetic outcomes in the patient study. Patient satisfaction with the results of surgery averaged 7 on a 10-point Likert scale. For 3 patients, 3 (50%) of the evaluators believed there was a mild improvement in appearance of the lower eyelids after surgery. The remaining patients were thought to have no significant changes.Conclusions and relevanceTransconjunctival Ho:YAG laser blepharoplasty is a safe procedure that may ameliorate mild pseudoherniation of lower eyelid orbital fat and is a first step toward the development of percutaneous techniques.