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Hydrogen sulfide (H2S) is a gasotransmitter that exerts a multitude of functions in both physiologic and pathophysiologic processes. H2S-synthesizing enzymes are increased in a variety of human malignancies, including colon, prostate, breast, renal, urothelial, ovarian, oral squamous cell, and thyroid cancers. In cancer, H2S promotes tumor growth, cellular and mitochondrial bioenergetics, migration, invasion, angiogenesis, tumor blood flow, metastasis, epithelia–mesenchymal transition, DNA repair, protein sulfhydration, and chemotherapy resistance Additionally, in some malignancies, increased H2S-synthesizing enzyme expression correlates with a worse prognosis and a higher tumor stage. Here we review the role of H2S in cancer, with an emphasis on the molecular mechanisms by which H2S promotes cancer development, progression, dedifferentiation, and metastasis.

Soft tissue reconstruction of head and neck ablative defects is a broad, challenging, and subjective topic. The authors outline goals to keep in mind when deciding on a primary reconstructive option for defects created by oncologic resection. Factors considered in local, regional, and distant flap selection are discussed. Based on the goals of reconstruction and factors involved in flap selection, a defect-based reconstructive algorithm is developed to help choose the ideal reconstructive option. The authors also discuss indications, pearls, pitfalls, and challenges in the harvest and inset of commonly used soft tissue flaps for head and neck reconstructive surgery.

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., Highlights • Inhibition of the ATR kinase lowers intracellular H2S concentrations. • Inhibition of H2S synthesis activates the ATR kinase and increases its kinase activity. • Inhibition of H2S synthesis combined with low-level oxidative stress increases genomic instability. • These findings may have applications the cancer chemotherapeutics.

BACKGROUND: Cystathione β-synthase (CBS) catalyzes the conversion of homocysteine and cysteine to hydrogen sulfide (H(2)S) 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 H(2)S-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.

Mucoepidermoid carcinoma (MEC) is the most common malignant epithelial neoplasm of the salivary glands. MECs of the mouth floor are rare, with only a few cases reported. Here we report a MEC of the mouth floor in a 55-year-old woman. Since several studies have shown that hydrogen sulfide (H2S)-synthesizing enzymes are often increased in malignant tumors compared to benign counterpart tissues, we used western blotting to compare the protein levels of cystathionine-β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in a mouth floor MEC to adjacent benign oral mucosae. We also used high-performance liquid chromatography to quantify possible differences in tissue sulfur fraction concentrations between the two biopsy types. Last, we used western blotting to examine nicotinamide phosphoribosyl transferase (Nampt), mitoNEET, and phospho-ser727-Stat3 levels in the biopsies. We found that all the proteins and phospho-ser727-Stat3 are increased in the MEC compared to benign mucosae. Interestingly, free H2S levels, acid-labile, and the sulfane sulfur factions were essentially the same between the MEC and benign tissue. Although limited to a single and unusual tumor type, to our knowledge this is only the third time H2S concentrations were directly quantified inside a human tumor. Last, our results replicate those of two previous studies where the H2S-synthesizing enzymes are increased in a malignant tumor, while free H2S is either not increased or only slightly increased, suggesting that malignant tumors rapidly metabolize H2S as part of tumor maintenance and growth.

Adenoid cystic carcinomas (ACC) constitute 1% of all head and neck malignancies and are very rare in the oral cavity. With < 60 oral ACCs described, their pathobiology is incompletely understood. Here, we report a case of oral cavity ACC in a 54-year-old woman. Since recent studies have demonstrated that several human tumors overexpress the hydrogen sulfide (H2S)-synthesizing enzymes cystathionine-β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), and also show dysregulated H2S levels, we examined these biomarkers in the oral ACC and compared the results to those of adjacent benign oral epithelium. Western blotting was used to compare the protein expression of CBS, CSE, 3-MST, nicotinamide phosphoribosyl transferase, and mitoNEET in ACC and adjacent benign oral mucosae. High-performance liquid chromatography was used to quantify the differences in tissue H2S concentrations between the two biopsy types. We found that all the proteins examined here were increased in the ACC compared to adjacent benign oral mucosae. Interestingly, H2S concentrations were decreased approximately 30% in ACC compared to benign mucosae. Thus, in one example of this rare tumor type, the enzymes that synthesize H2S are increased, while tissue H2S levels are lower than those found in adjacent benign oral mucosae. Although limited to a single rare tumor type, to our knowledge this is the second time H2S concentrations have been directly quantified inside a human tumor. Last, our results may indicate that alterations in H2S synthesis and metabolism may be important in the pathobiology of ACC.

Background/aim Primary bone neoplasms include osteosarcomas (OS), chondrosarcomas (CS), and giant cell tumors (GCT). Nicotinamide phosphoribosyl transferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide synthesis and is increased in multiple tumor types. In malignancies, NAMPT expression often correlates positively with tumor grade, chemotherapy resistance, and metastatic potential. Materials and methods Tissue microarray was used to examine NAMPT expression in benign bone and cartilage, GCTs, OS, and different CS grades. Results For the first time, we showed that NAMPT expression was increased in GCTs and OS compared to benign bone, and in CS compared to benign cartilage. Its expression also increased with higher CS grade. Conclusion Our data indicate that NAMPT plays a role in bone sarcomas and GCTs, and its higher expression may contribute to increased tumor aggressiveness.

Surgical cases where the anesthesiologist has to maintain a patient’s airway and ventilation in the same anatomical space in which the surgeon operates are referred to as shared airway anesthesia. Shared airways are commonly encountered with several surgical and dental specialties that operate within the head and neck. These cases require open communication and careful planning between anesthesiologist and surgeon in order to prevent catastrophic complications. The first step in minimizing complications in shared airway anesthesia is a preoperative assessment with particular emphasis on the airway exam. The airway examination should include, at a minimum, an evaluation of the maximum incisal opening, Mallampati-Samsoon classification, condition of dentition, range of motion of the neck, thyromental distance, tracheal deviation or neck masses, facial hair, and assessment of tonsillar size. Shared airway anesthesia cases, occurring both in- and outside the hospital, often employ open airway techniques. These techniques include (1) monitored anesthesia care, (2) mask ventilation, (3) insufflation with spontaneous respiration, (4) jet ventilation, and (5) laryngeal mask airway. When endotracheal intubation is required, standard oral tubes can be used; however, nasal RAE tubes are often preferred due to better visualization of the oral cavity. For shared airway cases with difficult airways, videolaryngoscope-guided intubation, fiber-optic-guided intubation, or a surgical airway may have to be considered as alternatives to standard intubation techniques. Respiratory compromise is the most feared complication in shared airway anesthesia. Complications that can lead to respiratory compromise in the perioperative period include failed intubation, loss of airway due to laryngospasm or foreign body aspiration, surgical fire, and vocal cord paralysis.

Perioperative dental injury is the result of mechanical trauma typically sustained during upper airway management for general anesthesia. Despite well-documented risk factors and a simplistic mechanism, iatrogenic damage to the dentition remains very prevalent. In fact, both the Accreditation Council for Graduate Medical Education and the American Association of Oral and Maxillofacial Surgeons have had to publish guidelines specifically addressing this complication (Miller and Pardo (2011). Airway management. Basics of anesthesia, 6th edn. Elsevier, Philadelphia, p 219–251; AAOMS parameters of care: clinical practice guidelines for oral and maxillofacial surgery. (AAOMS ParCare 2012)). A decrease in the rate of patient edentulism coupled with an increased predominance and cost of dental restorations has made this complication even more significant (Thomson and Ma. Singap Dent J 35:3–8, 2014). This chapter briefly discusses the most common causes of perioperative dental injury with specific focus on direct laryngoscopy and tracheal intubation. Risk factors are also discussed with the most pertinent including preexisting dental disease as well as a predicted difficult intubation (de Sousa and Mourao. Braz J Anesthesiol 65(6):511–518, 2013). A review of the necessary dental anatomy, dental pathology, and dental restorations is provided for the perioperative personnel without dental training. Next reviewed are preventative measures including correct laryngoscopy technique, preoperative patient-provider communication, and various other clinical aids to minimize risk. The treatment of perioperative dental injury always begins with a rapid diagnosis in order to identify any possible acute stage treatment necessary to prevent further damage. Once stable, the provider must then consult the treating service with an urgency determined by the morbidity of the injury. Finally, a discussion of the most relevant medical legal implications is provided.

BACKGROUND/AIM: Hydrogen sulfide (H(2)S) 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, H(2)S concentrations have not been directly measured in a human malignancy. Here we directly measured in vivo H(2)S 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: H(2)S 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: H(2)S concentrations and the enzymes that synthesize it are significantly increased in OSCC. Here, for the first time H(2)S concentrations within a living human malignancy were measured and compared to adjacent counterpart benign tissue.

The ataxia telangiectasia-mutated and Rad3-related (ATR) serine/threonine kinase plays a central role in the repair of replication-associated DNA damage, the maintenance of S and G2/M-phase genomic stability, and the promotion of faithful mitotic chromosomal segregation. A number of stimuli activate ATR, including persistent single-stranded DNA at stalled replication folks, R loop formation, hypoxia, ultraviolet light, and oxidative stress, leading to ATR-mediated protein phosphorylation. Recently, hydrogen sulfide (H(2)S), an endogenous gasotransmitter, has been found to regulate multiple cellular processes through complex redox reactions under similar cell stress environments. Three enzymes synthesize H(2)S: cystathionine-β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Since H(2)S can under some conditions cause DNA damage, we hypothesized that ATR activity may regulate cellular H(2)S concentrations and H(2)S-syntheszing enzymes. Here we show that human colorectal cancer cells carrying biallelic knock-in hypomorphic ATR mutations have lower cellular H(2)S concentrations than do syngeneic ATR wild-type cells, and all three H(2)S-synthesizing enzymes show lower protein expression in the ATR hypomorphic mutant cells. Additionally, ATR serine 428 phosphorylation is altered by H(2)S donor and H(2)S synthesis enzyme inhibition, while the oxidative-stress induced phosphorylation of the ATR-regulated protein CHK1 on serine 345 is increased by H(2)S synthesis enzyme inhibition. Lastly, inhibition of H(2)S production potentiated oxidative stress-induced double-stranded DNA breaks in the ATR hypomorphic mutant compared to ATR wild-type cells. Our findings demonstrate that the ATR kinase regulates and is regulated by H(2)S.

Purpose We present a series of cases of mandibular symphysis fractures treated at our institution with a 3-dimensional strut plate. The aim of the present study was to confirm the stability of this fixation technique and discuss its advantages, disadvantages, and potential complications. Patients and Methods We designed and implemented a retrospective cohort study of patients who underwent surgery by the same surgeon at our institution from July 2012 to April 2014 for a mandible fracture with a symphysis component. The patients were evaluated to identify aspects of occlusion, fracture mobility, postoperative infection, and the need for hardware removal. Results The sample included 12 subjects who had met the inclusion criteria. The inclusion criteria were a linear noncomminuted fracture, sufficient distance from the mental foramina, a maximum of 5 days between the trauma and surgery, and a minimum postoperative period of 3 months. The mean age of the sample was 33.4 years, and 1 of the 12 patients (8.3%) was female. Of the 12 patients, 10 did well, and 2 developed a surgical site infection, 1 of whom also experienced nonunion and required additional fixation. Conclusions The results of the present study suggest a 3-dimensional strut plate applied to symphysis fractures provides adequate fracture stabilization with a risk of complications comparable to that of more traditional fixation methods. In addition, the technique has the added advantage of minimal manipulation and adaptation, which could shorten the overall operating time.

This report establishes a novel application of a commercially available porcine urinary bladder extracellular matrix, MatriStem (ACell, Inc., Columbia, MD), in the salvage of partial loss of the skin paddle of a fibula osteoseptocutaneous free flap that was utilized for mandibular reconstruction.