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We assumed that the effect of adjuvant trastuzumab on survival is mediated by the treatment time and we conducted this trial-level meta-regression to determine the appropriate length of treatment. Twelve adjuvant trastuzumab trials (from January 2000 to June 2019, consisting of 20,271 patients) were included. We considered 12-month trastuzumab treatment as the standard. The primary study endpoint was disease-free survival (DFS). By quantifying the relationship between shortened treatment time (month) and altered recurrence risk (expressed as hazard ratio), we found the regression coefficient β was 0.05 (95% confidence interval 0.02-0.08, P = 0.002), indicating the recurrence risk would increase 5.1% for each month that treatment was shortened. Accordingly, 3, 6, and 9-month reductions in treatment time resulted in 16%, 35%, and 57% increases in recurrence risk, respectively. We revealed a significant linear association between shortened treatment time of trastuzumab and recurrence risk. The clinical duration of adjuvant trastuzumab should be tailored.Emerging evidence suggests that the vaginal microbiota play a role in HPV persistence and cervical neoplasia development and progression. Here we examine a broad range of immune checkpoint proteins in the cervicovaginal microenvironment across cervical carcinogenesis and explore relationships among these key immunoregulatory proteins, the microbiota composition, and genital inflammation. First, we demonstrate that immune checkpoint molecules can be measured in cervicovaginal lavages. Secondly, we identify CD40, CD27, and TIM-3 to specifically discriminate cervical cancer from other groups and CD40, CD28, and TLR2 to positively correlate to genital inflammation. Finally, PD-L1 and LAG-3 levels negatively, whereas TLR2 positively correlate to health-associated Lactobacillus dominance. Overall, our study identifies immune checkpoint signatures associated with cervical neoplasm and illuminates the multifaceted microbiota-host immunity network in the local microenvironment. This study provides a foundation for future mechanistic studies and highlights the utility of cervicovaginal lavage profiling for predicting and monitoring response to cancer therapy.Histologic transformation from non-small cell to small cell lung cancer has been reported as a resistance mechanism to targeted therapy in EGFR-mutant and ALK fusion-positive lung cancers. Whether small cell transformation occurs in other oncogene-driven lung cancers remains unknown. Here we analyzed the genomic landscape of two pre-mortem and 11 post-mortem metastatic tumors collected from an advanced, ROS1 fusion-positive lung cancer patient, who had received sequential ROS1 inhibitors. Evidence of small cell transformation was observed in all metastatic sites at autopsy, with inactivation of RB1 and TP53, and loss of ROS1 fusion expression. Whole-exome sequencing revealed minimal mutational and copy number heterogeneity, suggestive of “hard” clonal sweep. selleck chemical Patient-derived models generated from autopsy retained features consistent with small cell lung cancer and demonstrated resistance to ROS1 inhibitors. This case supports small cell transformation as a recurring resistance mechanism, and underscores the importance of elucidating its biology to expand therapeutic opportunities.

Clinical, neuroimaging, and genetic characterization of 3 patients with

-associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits.

Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clinic. General and neurologic examination, expert dysmorphology examination, and 3T brain MRI were performed. Whole-exome sequencing was performed for the 3 affected brothers, followed by Sanger sequencing in all available family members.

The index patient and his 2 affected brothers presented a complex neurologic syndrome with similar features but marked intrafamilial phenotypical variability, including varying degrees of cognitive impairment, speech impairment, dystonia, abnormal eye movements, and dysmorphic features. All 3 affected brothers are homozygous for a novel, pathogenic frameshift mutation in

, c.1672_1679del, and p.Gly558Pro

*22, whereas both parents and healthy sibling this rare disorder. The 3T-MRI data from our 3 patients and review of the neuroimaging data in the literature showed unspecific brain MRI changes. LINS1 protein is a known modulating factor of the Wnt signaling pathway, with important roles in organogenesis including of the cerebral cortex. More research is warranted to disentangle the underlying pathophysiologic mechanisms, leading to cognitive impairment and the complex phenotype of LINS1-associated disorder.

To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms.

We performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing.

Using ES, we discovered individuals with known pathogenic SNVs in

(p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and

(p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in

and

. Based on aCGH, we additionally discovered cases with an

duplication and heterozygous intragenic

deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the

locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors.

Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for

and

CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PRKN CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.