Bacterial viruses are among the most numerous biological entities within the human body. These viruses are found within regions of the body that have conventionally been considered sterile, including the blood, lymph, and organs. However, the primary mechanism that bacterial viruses use to bypass epithelial cell layers and access the body remains unknown. Here, we used in vitro studies to demonstrate the rapid and directional transcytosis of diverse bacteriophages across confluent cell layers originating from the gut, lung, liver, kidney, and brain. Bacteriophage transcytosis across cell layers had a significant preferential directionality for apical-to-basolateral transport, with approximately 0.1% of total bacteriophages applied being transcytosed over a 2-h period. Bacteriophages were capable of crossing the epithelial cell layer within 10 min with transport not significantly affected by the presence of bacterial endotoxins. Microscopy and cellular assays revealed that bacteriophages accessed both the vesicular and cytosolic compartments of the eukaryotic cell, with phage transcytosis suggested to traffic through the Golgi apparatus via the endomembrane system. Extrapolating from these results, we estimated that 31 billion bacteriophage particles are transcytosed across the epithelial cell layers of the gut into the average human body each day. The transcytosis of bacteriophages is a natural and ubiquitous process that provides a mechanistic explanation for the occurrence of phages within the body.

OBJECTIVELittle is known about the optimal duration of antibiotic therapy for diabetic foot osteomyelitis (DFO). This study sought to compare the effectiveness of 6 versus 12 weeks of antibiotic therapy in patients with DFO treated nonsurgically (i.e., antibiotics alone). RESEARCH DESIGN AND METHODSThis was a prospective randomized trial comparing 6-versus 12-week duration of antibiotic treatment. Remission of osteomyelitis during the monitoring period was defined as complete and persistent (>4 weeks) healing of the wound (if present initially), absence of recurrent infection at the initial site or that of adjacent rays, and no need for surgical bone resection or amputation at the end of a follow-up period of at least 12 months after completion of antibiotic treatment. RESULTSForty patients followed at five French general hospitals were randomized be-

TFC5, the unique and essential gene encoding the B" component of the Saccharomyces cerevisiae RNA polymerase III transcription factor (TF)IIIB has been cloned. It (8): the TATA box-binding protein, TBP; the TBP-interacting 67-kDa TFIIBrelated protein, Brf (gene BRFI/PCF4/TDS4) (9-11); and a chromatographically separable component named B" (12). Active B" was previously isolated as a 90-kDa "band" out of denaturing (SDS) gels, renatured, and shown to reconstitute active TFIIIB. In the experiments that are described below, we complete the proof of constitution of TFIIIB by cloning the gene encoding the B" protein, expressing it in Escherichia coli, and using the resulting protein to reconstitute transcriptionally active TFIIIB entirely from its three recombinant constituents.

cMet is a well‐characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody–drug conjugates (ADCs). However, the clinical benefit from cMet‐targeted therapy has been limited. We developed a novel cMet‐targeted ‘third‐generation’ ADC, TR1801‐ADC, that was optimized at different levels including specificity, stability, toxin–linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site‐specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin–linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet‐expressing cell lines but also in medium‐to‐low cMet cell lines (40 000–90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low–medium cMet expression were also very responsive to TR1801‐ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801‐ADC had excellent efficacy with significant antitumor activity in 90% of tested patient‐derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single‐dose administration. Altogether, TR1801‐ADC is a new generation cMet ADC with best‐in‐class preclinical efficacy and good tolerability in rats.

BackgroundOutcome of patients with streptococcal prosthetic joint infections (PJIs) is not well known.MethodsWe performed a retrospective multicenter cohort study that involved patients with total hip/knee prosthetic joint (THP/TKP) infections due to Streptococcus spp. from 2001 through 2009.ResultsNinety-five streptococcal PJI episodes (50 THP and 45 TKP) in 87 patients of mean age 69.1 ± 13.7 years met the inclusion criteria. In all, 55 out of 95 cases (57.9 %) were treated with debridement and retention of the infected implants with antibiotic therapy (DAIR). Rifampicin-combinations, including with levofloxacin, were used in 52 (54.7 %) and 28 (29.5 %) cases, respectively. After a mean follow-up period of 895 days (IQR: 395–1649), the remission rate was 70.5 % (67/95). Patients with PJIs due to S. agalactiae failed in the same proportion as in the other patients (10/37 (27.1 %) versus 19/58 (32.7 %); p = .55). In the univariate analysis, antibiotic monotherapy, DAIR, antibiotic treatments other than rifampicin-combinations, and TKP were all associated with a worse outcome. The only independent variable significantly associated with the patients’ outcomes was the location of the prosthesis (i.e., hip versus knee) (OR = 0.19; 95 % CI 0.04–0.93; p value 0.04).ConclusionsThe prognosis of streptococcal PJIs may not be as good as previously reported, especially for patients with an infected total knee arthroplasty. Rifampicin combinations, especially with levofloxacin, appear to be suitable antibiotic regimens for these patients.