MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs.

The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.

Role of nitric oxide in the small intestinal microcirculation during bacteremia.

Nitric oxide (NO) is an important mediator of the hemodynamic effects of sepsis; however, its microcirculatory effects are unknown. To determine the role of NO in the small intestinal (SI) microcirculation, an intact SI loop was exteriorized from decerebrate rats into a controlled Krebs' bath. Bacteremic rats received 10(9) Escherichia coli intravenously. Videomicroscopy was used to measure arteriolar diameters (A1, A3) and optical Doppler velocimetry to quantitate flow. In controls, topical NO synthase (NO-S) substrate L-arginine (L-ARG; 10(-4) M) did not affect diameters or flow. Inhibition of NO-S by N omega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) caused constriction (A1 = -18%; A3 = -24% from baseline diameter) and reduced A1 flow by 62%. These alterations were similar to bacteremic controls (A1 = -20%; A3 = -18%; A1 flow = -42%), despite the increased cardiac output (+21%). L-NAME treatment of bacteremic rats resulted in further constriction (A1 = -31%; A3 = -32%) and decreased A1 flow (-75%). Topical L-ARG (10(-4) M) ameliorated constriction (A1 = -6%; A3 = +7%) and improved blood flow (-5%) during bacteremia. We conclude that: 1) NO is important for basal SI microvascular tone; 2) bacteremia causes SI arteriolar constriction and hypoperfusion; 3) NO-S inhibition during sepsis may exacerbate SI vasoconstriction and hypoperfusion.

Tube thoracostomy. Factors related to complications.

OBJECTIVE: To determine the complication rate and risk factors associated with tube thoracostomy (TT) in the trauma patient. DESIGN: Retrospective hospital chart review. SETTING: Level I trauma center. PATIENTS: Four hundred twenty-six consecutive patients who underwent TT were initially reviewed; 47 deaths occurred unrelated to TT placement. The remaining 379 patients required 599 tubes and composed the study population. MAIN OUTCOME MEASURES: The determination of adverse outcomes related to TT, including thoracic empyema, undrained hemothorax or pneumothorax, improper tube positioning, post-tube removal complications, and direct injuries to the lung. RESULTS: The overall complication rate was 21% per patient. Although complications were not related to the Injury Severity Score, the presence of shock, admission to the intensive care unit, and the need for mechanical ventilation were associated with the increased incidence of complications. There were fewer complications (6%) when the TT was performed by a surgeon compared with TT performed by an emergency physician (13%, P < .0001) or TT performed prior to transfer to our hospital (38%, P < .0001). CONCLUSIONS: Tube thoracostomy is associated with significant morbidity. The striking difference in the complication rate between surgeons and other physicians who perform this procedure suggests that additional training may be indicated.

Haemophilus pneumonia is a common cause of early pulmonary dysfunction following trauma.

BACKGROUND: Haemophilus species are a common cause of community-acquired pneumonia; however, their significance in posttraumatic pneumonia is unclear. DESIGN: Case series. SETTING: University hospital, level I trauma center. PATIENTS: Two hundred fifty-seven consecutive patients with blunt and penetrating trauma treated for pneumonia. MAIN OUTCOME MEASURES: Length of stay in the intensive care unit, duration of ventilatory support, rate of recurrent or persistent pneumonia, and mortality. RESULTS: Ninety-six (37%) of 257 patients treated for pneumonia had a Haemophilus species isolated on sputum culture. Of these 96 patients, 49 (51%) had only Haemophilus species, while 33 (34%) had associated gram-positive organisms and 14 (15%) had gram-negative organisms. Seventeen pure cultures (29%) and seven mixed cultures (15%) (P < .05) were beta-lactamase-positive trains. Compared with patients who had pneumonia caused by other bacteria, patients with Haemophilus species were younger (mean +/- SE, 35 +/- 1.7 vs 42 +/- 1.6 years; P < .05) and more severely injured (Injury Severity Score, 20.7 +/- 1.1 vs 17.5 +/- 0.9; P < .05). There were no differences in any outcome variables between the two groups. Only one (1%) of 96 patients had persistent Haemophilus species on sputum cultures after 7 days of treatment. CONCLUSIONS: Haemophilus species are a frequent cause of pneumonia following traumatic injury. This occurs primarily in the early postinjury phase and therefore should be included in the differential diagnosis of early posttraumatic pulmonary insufficiency.

Delayed gastric emptying after gastric surgery.

BACKGROUND: The reported incidence of delayed gastric emptying (DGE) after gastric surgery is 5% to 25% and usually is based on operations for peptic ulcer disease. Ongoing improvements in perioperative care, nutritional support, and new prokinetic drugs may have had a beneficial effect on the frequency and course of postoperative DGE. METHODS: We therefore studied our recent experience with DGE in 416 patients who had gastric surgery for ulcer disease (283), cancer (92), or trauma and other indications (41) between January 1985 and December 1993. DGE was defined as inability to eat a regular diet by postoperative day 10. RESULTS: DGE occurred in 99 of 416 patients (24%). In 75 of these 99 patients, a postoperative contributing factor for DGE was identified. These factors were sepsis (32), anastomotic edema and leaks (23), obstruction (4), pancreatitis (3), multiple system organ failure (5), and miscellaneous conditions (8). In 24 patients there was no obvious cause for DGE; these patients recovered with nutritional support and time. Re-operation specifically for gastric stasis was not performed. Among the 99 patients with DGE, 67% were eating by day 21, 92% by 6 weeks, and 100% by 10 weeks. Significant risk factors for DGE were diabetes (55%), malnutrition (44%), and operations for malignancy (38%). The Whipple procedure had the highest incidence of DGE (70%), highly selective vagotomy the lowest (0%), while truncal vagotomy had no significant effect. The response to metoclopramide was 20% and unpredictable. CONCLUSION: DGE continues to affect a considerable number of our patients (24%) after gastric surgery and is particularly common in patients with diabetes, malnutrition, and gastric or pancreatic cancer. However, gastric motility does return in 3 to 6 weeks in most patients and the need for re-operation for gastric stasis is rare.

Platelet-activating factor and sepsis-induced small intestinal microvascular hypoperfusion.

Platelet-activating factor (PAF) and bacteremia both cause small intestinal (SI) hypoperfusion which may contribute to mucosal injury, and PAF has been postulated to mediate impaired SI microvascular blood flow during sepsis. Our previous studies demonstrate that sepsis-induced SI hypoperfusion is associated with both arteriolar and venular constriction, but the microvascular mechanisms by which PAF impairs SI blood flow are not well defined. Microcirculation studies in other tissues indicate that PAF is an arteriolar dilator, but this effect in the SI would not explain PAF-mediated hypoperfusion. We studied the effects of PAF on SI microvessels to characterize the microvascular mechanisms which mediate PAF-induced hypoperfusion. We also determined the role of PAF as a mediator of microvascular effects in the intestine during bacteremia by PAF receptor antagonism. Animals received either 10(9) live Escherichia coli IV or PAF applied topically to the SI (30, 80, and 300 nM). Arteriolar and venular diameters and red blood cell velocity (A1, V1) were measured with intravital microscopy and velocimetry. Both PAF and sepsis resulted in impaired SI blood flow (maximum decrease in blood flow -37 and 65%, respectively), but sepsis was associated with both arteriolar and venular constriction (20 and 30% diameter reduction each), whereas PAF produced only venular constriction (50% diameter reduction). Inhibition of PAF action prevented the microvascular alterations of bacteremia (blood flow unchanged, P < 0.05; venular diameter unchanged, P < 0.05), suggesting that PAF is an important mediator of these responses.

Nitric oxide synthase inhibition aggravates intestinal microvascular vasoconstriction and hypoperfusion of bacteremia.

Nitric oxide (NO) is an important hemodynamic mediator of sepsis; however, its visceral microcirculatory effects are largely unknown. To determine the role of systemic nitric oxide synthase (NO-S) inhibition on the microcirculation of the small intestine (SI), an intact loop of SI was exteriorized from decerebrate rats into a controlled tissue bath. Videomicroscopy was used to measure arteriolar diameters (A1, A3) and optical Doppler velocimetry was used to quantitate flow. In nonbacteremic controls inhibition of NO-S by N omega-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg IV) caused vasoconstriction (A1 = -7%; A3 = -24% baseline values) and reduced A1 flow by 26%. Bacteremic controls received 10(9) Escherichia coli IV, which resulted in arteriolar constriction and hypoperfusion (A1 = -16%; A3 = -21%; A1 flow = -44%), despite increased cardiac output (+33%). Treatment of bacteremic rats with L-NAME corrected the increased cardiac output (-3%), but exacerbated vasoconstriction (A1 = -24%; A3 = -27%) and did not improve A1 flow (-49%). These data indicate that (1) NO mediates basal microvascular tone of the SI; (2) hyperdynamic bacteremia causes arteriolar constriction and hypoperfusion of the SI; and (3) although systemic NO-S inhibition normalizes cardiac output and increases blood pressure, it aggravates vasoconstriction in the SI and does not improve hypoperfusion.

Postoperative nasogastric decompression: a prospective randomized trial.

To determine which type of patient should receive routine postoperative nasogastric decompression (NGD), we observed 76 patients who were randomized into two groups: those who received routine NGD (n = 39) and those who received selective NGD (n = 37). Eighteen patients in the selective NGD group never required intubation, while 19 did require intubation within a mean of 3 days after surgery. In both groups, tubes remained in place for a mean of 4.7 days. The routine NGD group had a 2.5% incidence of emesis, while the selective NGD group had a 51% incidence of emesis. The return of bowel function, return to a regular diet, and postoperative length of hospital stay were similar in both groups. The patients in the selective NGD group who did not require intubation had a shorter postoperative stay. Fifty-eight percent of patients in the selective NGD group who required intubation had had major vascular or retroperitoneal dissections. These data support selective use of NGD in general surgical patients and routine use of NGD for patients having major retroperitoneal or vascular procedures.