Computed tomography is commonly used to evaluate patients with blunt facial trauma. With the high definition of the current scanners, even small fractures of the facial skeleton can be visualized. In complex midface injuries, it can be difficult for the radiologist to know which fractures are important to point out to the surgeon. An understanding of the anatomically relevant and surgically accessible craniofacial buttresses is critical for management of these injuries. Naso-orbitoethmoid fractures are classified according to the degree of injury to the medial canthal attachment. If the nasofrontal ducts are disrupted, surgical obliteration of the frontal sinus is needed to prevent formation of a mucocele. Displaced fractures of the zygomaticomaxillary complex often increase orbital volume due to angulation of the lateral orbital wall at the zygomaticosphenoid suture. If the zygomatic arch is severely comminuted or angulated, surgical exposure is indicated. In orbital fractures, the position and shape of the medial and inferior rectus muscles can indicate whether entrapment and diplopia are likely. Pediatric “trapdoor” orbital fractures and fractures of the orbital apex associated with decreasing vision represent surgical emergencies. Le Fort fractures involve disruption of the pterygoid plates from the posterior maxilla; any combination of Le Fort I, II, and III patterns can occur. © RSNA, 2006

https://pubs.rsna.org/doi/pdf/10.1148/rg.263045710

Diagnosis of Midface Fractures with CT: What the Surgeon

Hydrogen sulfide can signal through 3 distinct mechanisms: 1) reduction and/or direct binding of metalloprotein heme centers, 2) serving as a potent antioxidant through reactive oxygen species/reactive nitrogen species scavenging, or 3) post-translational modification of proteins by addition of a thiol (-SH) group onto reactive cysteine residues: a process known as persulfidation. Below toxic levels, hydrogen sulfide promotes mitochondrial biogenesis and function, thereby conferring protection against cellular stress. For these reasons, increases in hydrogen sulfide and hydrogen sulfide-producing enzymes have been implicated in several human disease states. This review will first summarize our current understanding of hydrogen sulfide production and metabolism, as well as its signaling mechanisms; second, this work will detail the known mechanisms of hydrogen sulfide in the mitochondria and the implications of its mitochondrial-specific impacts in several pathologic conditions.-Murphy, B., Bhattacharya, R., Mukherjee, P. Hydrogen sulfide signaling in mitochondria and disease.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201901304R

Hydrogen sulfide signaling in mitochondria and disease.

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used "CBS inhibitors" (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.

Cystathionine-β-Synthase: Molecular Regulation and Pharmacological Inhibition.

To enable survival in adverse conditions, cancer cells undergo global metabolic adaptations. The amino acid cysteine actively contributes to cancer metabolic remodelling on three different levels: first, in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, a reversible post-translational modification; second, as a substrate for the production of hydrogen sulphide (H2S), which feeds the mitochondrial electron transfer chain and mediates per-sulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, finally, as a carbon source for epigenetic regulation, biomass production and energy production. This review will provide a systematic portrayal of the role of cysteine in cancer biology as a source of carbon and sulphur atoms, the pivotal role of cysteine in different metabolic pathways and the importance of H2S as an energetic substrate and signalling molecule. The different pools of cysteine in the cell and within the body, and their putative use as prognostic cancer markers will be also addressed. Finally, we will discuss the pharmacological means and potential of targeting cysteine metabolism for the treatment of cancer.

/pdf/cysteine-metabolic-circuitries-druggable-targets-in-cancer-3nhh8402ns.pdf

Cysteine metabolic circuitries: druggable targets in cancer

Tumor cells have increased requirements for NAD+. Thus, many cancers exhibit an increased reliance on NAD+ production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD+-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

/pdf/beyond-energy-metabolism-exploiting-the-additional-roles-of-pntngy0zqp.pdf

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Background Cystathione β-synthase (CBS) catalyzes the conversion of homocysteine and cysteine to hydrogen sulfide (H2S) and cystathione, via the trans-sulfuration pathway. CBS protein expression levels are increased in several different human malignancies, with increased protein expression correlating with parameters such as tumor stage, anaplasia, metastases, and chemotherapy resistance. Materials and methods This study employed tissue microarrays to examine CBS expression in benign thyroid tissue, thyroid oncocytomas, thyroid follicular adenomas, and in follicular, papillary, anaplastic, and medullary thyroid carcinomas. Results CBS expression was increased in all thyroid carcinomas types compared to benign thyroid tissue, but not in thyroid follicular adenomas or oncocytomas. A similar pattern was observed for nicotinamide phosphoribosyltransferase (NAMPT) tissue microarray analysis comparing thyroid adenomas and follicular carcinomas. Conclusion For the first time, we showed that an H2S-syntheszing enzyme plays a role in thyroid malignancies. Additionally, our data suggest that CBS and NAMPT immunohistochemistry may be useful in differentiating follicular adenomas from follicular carcinomas.

Cystathione β-Synthase Is Increased in Thyroid Malignancies.

Background/aim Hydrogen sulfide (H2S) and the enzymes that synthesize it, cystathionine-b-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate, are increased in different human malignancies. Due to its short half-life, H2S concentrations have not been directly measured in a human malignancy. Here we directly measured in vivo H2S levels within oral squamous cell carcinoma (OSCC). Patients and methods Punch biopsies of OSCC and benign mucosae from 15 patients were analyzed by HPLC, western blotting, and tissue microarray analyses. Results H2S concentrations were significantly higher in OSCC compared to adjacent benign oral mucosae. Western blot and tissue microarray studies revealed significantly increased cystathionine-b-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate, phopho-Stat3, mitoNEET, hTERT, and MAPK protein levels in OSCC. Conclusion H2S concentrations and the enzymes that synthesize it are significantly increased in OSCC. Here, for the first time H2S concentrations within a living human malignancy were measured and compared to adjacent counterpart benign tissue.

Hydrogen Sulfide Is Increased in Oral Squamous Cell Carcinoma Compared to Adjacent Benign Oral Mucosae.

Recent evidence has revealed that exposing cells to exogenous H 2 S or inhibiting cellular H 2 S synthesis can modulate cell cycle checkpoints, DNA damage and repair, and the expression of proteins involved in the maintenance of genomic stability, all suggesting that H 2 S plays an important role in the DNA damage response (DDR). Here we review the role of H 2 S in the DRR and maintenance of genomic stability. Treatment of various cell types with pharmacologic H 2 S donors or cellular H 2 S synthesis inhibitors modulate the G 1 checkpoint, inhibition of DNA synthesis, and cause p21, and p53 induction. Moreover, in some cell models H 2 S exposure induces PARP-1 and g-H2AX foci formation, increases PCNA, CHK2, Ku70, Ku80, and DNA polymerase-d protein expression, and maintains mitochondrial genomic stability. Our group has also revealed that H 2 S bioavailability and the ATR kinase regulate each other with ATR inhibition lowering cellular H 2 S concentrations, whereas intracellular H 2 S concentrations regulate ATR kinase activity via ATR serine 435 phosphorylation. In summary, these findings have many implications for the DDR, for cancer chemotherapy, and fundamental biochemical metabolic pathways involving H 2 S.

Andrew T. Meram

Papers

Cystathione β-Synthase Is Increased in Thyroid Malignancies.

Hydrogen Sulfide Is Increased in Oral Squamous Cell Carcinoma Compared to Adjacent Benign Oral Mucosae.

Hydrogen sulfide and DNA repair

Molecular Functions of Hydrogen Sulfide in Cancer

The Ataxia telangiectasia-mutated and Rad3-related protein kinase regulates cellular hydrogen sulfide concentrations