Advances in Hemophilia A Management.

Hemophilia A is an inherited insufficiency of Factor VIII (FVIII), one of the critical clotting factors. The gold standard for the management of moderate-to-severe hemophilia A is prophylaxis using regular replacement therapy with clotting factor concentrates. Compared with conventional treatment, extended half-life products reduce the burden of frequent factor replacement injections. Of note, up to 30% of patients with hemophilia A receiving prophylactic factor infusions develop "inhibitors," neutralizing anti-FVIII autoantibodies. Therapeutic options for patients with hemophilia A and inhibitors include the immune tolerance induction (ie, eradication of inhibitors) and the management of acute bleeds with bypassing agents and/or emicizumab. Emicizumab is a biphasic monoclonal antibody mimicking activated FVIII, approved for patients with hemophilia A with/without inhibitors. Gene therapy is an emerging therapy for hemophilia A, essentially curing patients with hemophilia A or transforming them to a milder phenotype by establishing continuous endogenous expression of FVIII after one-time treatment.

Facilitating Akt clearance via manipulation of Hsp70 activity and levels.

Members of the 70-kDa heat shock family can control and manipulate a host of oncogenic client proteins. This role of Hsp70 in both the folding and degradation of these client proteins makes it a potential drug target for certain forms of cancer. The phenothiazine family of compounds, as well as the flavonoid myricetin, was recently shown to inhibit Hsp70-ATPase activity, whereas members of the dihydropyrimidine family stimulated ATPase function. Akt, a major survival kinase, was found to be under the regulation of Hsp70, and when the ATPase activity of Hsp70 was increased or decreased by these compounds, Akt levels were also increased or decreased. Also, increasing Hsp70 levels concurrent with inhibition of its ATPase function synergistically reduced Akt levels to a greater extent than either manipulation alone, providing new insights about client fate decisions. Akt reductions mediated by Hsp70 inhibitors were prevented when Hsp70 expression was silenced with small interfering RNA. Inhibiting Hsp70 ATPase function produced cytotoxic events only in breast cancer cell lines where Akt dysfunction was previously shown, suggesting therapeutic specificity depending on the Hsp70 client profile. Thus, increasing Hsp70 levels combined with inhibiting its ATPase function may serve to dramatically reduce Akt levels and facilitate cell death in certain types of cancer.

Mechanisms generating cancer genome complexity from a single cell division error.

The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes alongside chromothripsis, another catastrophic mutational phenomenon. We explain this association by elucidating a mutational cascade that is triggered by a single cell division error-chromosome bridge formation-that rapidly increases genomic complexity. We show that actomyosin forces are required for initial bridge breakage. Chromothripsis accumulates, beginning with aberrant interphase replication of bridge DNA. A subsequent burst of DNA replication in the next mitosis generates extensive DNA damage. During this second cell division, broken bridge chromosomes frequently missegregate and form micronuclei, promoting additional chromothripsis. We propose that iterations of this mutational cascade generate the continuing evolution and subclonal heterogeneity characteristic of many human cancers.

Comparison of pulmonary function tests and perioperative outcomes after robotic-assisted pulmonary lobectomy vs segmentectomy.

BACKGROUND: Lobectomy is standard treatment for early-stage lung cancer, but sublobar resection remains debated. We compared outcomes after robotic-assisted video-assisted thoracoscopic (R-VATS) segmentectomy vs lobectomy. METHODS: We retrospectively analyzed data from 251 consecutive patients who underwent R-VATS lobectomy (n = 208) or segmentectomy (n = 43) by a single surgeon over 36 months. Pulmonary function tests and perioperative outcomes were compared using Chi-squared test, unpaired Student t test, or Kruskal-Wallis test, with significance at P ≤ .05. RESULTS: Intraoperative complications were not significantly different, but median operative times were longer for R-VATS segmentectomies (P < .01). Postoperative complications were not significantly different, except for increased rates of pneumothorax after chest tube removal (P = .032) and of effusions or empyema (P = .011) after R-VATS segmentectomies. Predicted changes for forced expiratory volume in 1 second and diffusion constant of the lung for carbon monoxide are significantly less after R-VATS segmentectomy (P < .001). CONCLUSIONS: R-VATS segmentectomy should be considered as an alternative to lobectomy for conserving lung function in respiratory-compromised lung cancer patients, although oncologic efficacy remains undetermined.